mutations of mortality

With thanks

2012-01-24T21:28:00.002Z

We, the family of Terry Hamblin, would like to thank everyone for their kindness in recent days. We have been much touched by the many cards and messages we have received, the various internet tributes, including responses to this blog, and the great attendance, in person and virtually, at today's thanksgiving service. This has been, as you can imagine, a profoundly difficult time for all of us, but the clear articulation of the regard and love in which Terry was held by so many people has been a source of great comfort.

With our thanks

Diane, Karen, Richard, Angela and David Hamblin

Thanksgiving Service Details

2012-01-16T13:56:00.001Z

A Service of Thanksgiving for the life of Professor Terry John Hamblin, will take place at Lansdowne Baptist Church, Bournemouth, UK, at 1.30pm GMT on Tuesday 24th January 2012. All are most welcome to attend. The service will also be streamed live across the internet at the following URL. http://www.lansdownebaptistchurch.org.uk/live/

Donations if so desired can be made in favour of the Bournemouth Leukaemia Fund, via Harry Tomes Ltd, Funeral Directors, (01202) 394340, http://tributes.harrytomes.com/terence-john-hamblin/

Terence John Hamblin 1943 – 2012

2012-01-08T15:45:00.000Z

It is with great sadness that we announce that Terry peacefully passed away shortly before 1.00 AM on Sunday 8th January 2012.

The family wish to thank everybody for their prayers and kind messages sent over the period of Terry’s illness.

Further details of the thanksgiving service will be posted on this blog in the near future.

John 8:29-30:The Trinity

2011-12-06T19:54:00.002Z

The one who sent me is with me; he has not left me alone, for I always do what pleases him.” Even as he spoke, many believed in him.

So much of John's gospel emphasises the intimate relationship between the different persons of the Trinity. Even though the word "Trinity" is not mentioned in the Bible, you would have to be wilfully blind not to see it in John's Gospel.

No wonder many believed in him.

Lying

2011-12-06T12:09:00.002Z

Two recent news items have drawn me to the idea of truth. We know that Pilate asked "What is Truth?" but he was talking about how truth is relative and we might all see it from our own viewpoint. No, what I am taking about is blatant lying.

The first incident concerned a convicted murderer; a farmer who had killed his wife and buried her and then sworn at his trial that he was innocent. Now some years later he had confessed and shown the police where the body was buried. At his trial he had just told lies under oath. Nevertheless he had a wedge of supporters who were crying about a miscarriage of justice.

The second case concerned a railway station manager in the New Forrest who had broken the safety regulations at a level crossing and been dismissed from his job. He was now seeking unfair dismissal in view of the fact that someone had left a shopping trolley on the line, and he had had to remove it. I remember the case on the Local TV news and it garnered a lot of public sympathy. We now hear (though not on TV) that this was a tissue of lies. There was no shopping trolley. Case dismissed.

A news item tells us that only 22% of BBC employees claim to be Christians. The largest group are atheists. I imagine that most who claim Christianity are tea-ladies and cleaners. The intellectual elite there are secular humanists. That being so, what is the point of them giving evidence under oath? In days past people feared fro their immortal soul. Nowadays they don't believe they have a soul.

What is the absolute standard of truthfulness? A man's word? Recent happenings have putrefied the word of politicians (expenses scandal), journalists (Levenson enquiry), the police (Stephen Lawrence case) civil servants (economical with the truth), celebrities (X-Factor), businessmen (Financial disasters) and scientists (global warming). The same can be extended to priests, who openly declare that they are taking office (and stipends) when they do not believe in God, and doctors who hide the truth from dying patients.

We know that eye-witnesses can be mistaken, photographs can be Photo shopped, and DNA can be contaminated. Criminals can beat lie-detector tests. Experienced judges have a higher conviction rate than lay-juries. Are they less gullible or more cynical?

Should we believe anyome?

Bereavement

2011-12-06T09:44:00.006Z

I have been watching the Danish thriller, The Killing, continuing my exploration of Continental dramas with subtitles. What has particularly impressed me has been the acting of Bjarne Henriksen, who plays the father of the murdered girl. Whether or not he turns out to be involved, I know not, but the way he has dealt with the emotion of grief has been impressive. On Sunday, I watched the latest episode of Garrow's Law on BBC1 where Garrow says that he understands what a woman feels who has just lost her father. She protests that no-one could. But Garrow has just been bereaved of his friend and fellow-lawyer, Southouse, and is able to eloquently describe the feelings of grief.

The words sounded familiar and, of course they are very reminiscent of Shadowlands, the story of the bereavement of CS Lewis, when his wife Joy died. I recommend both versions, either with Anthony Hopkins or Joss Ackland. Both are based on the little book "A Grief Observed" finally published posthumously under his own name. "A Grief Observed comprises the reflections of the great scholar and Christian apologist on the death of his wife after only a few short years of marriage. Painfully honest in its dissection of his thoughts and feelings, this is a book that details his paralysing grief, bewilderment and sense of loss in simple and moving prose." says the blurb and it is very accurate.

In The Killing, the Lutheran Pastor makes the crass statement to the mother of the murdered girl, "At least she is now with the Angels." To which the mother angrily replies, "She shouldn't be with the Angels; she should be with me!" It ill betides any doctor or Pastor to meddle with a person's grief.

Very few doctors or pastors have no trouble with their own mortality. I know the Scriptures on this, and I had my moment of reconciliation with God more than 35 years ago when my father died, but I felt the pastoral counselling that I received then pretty useless.

I know a few old ladies who grieve terribly for their lost husbands of more than 30 years ago. It would be easy to say that they should put it aside now. That if theirs was a true faith that they would lost that burden at the foot of the cross, but I would never make that judgment. People are always different. There were many who waited for that long and longer for Jesus to take away that burden.

Anna, the daughter of Phanuel, had lived with her husband for seven years and then was a widow until she was 84. She never left the Temple but worshipped night and day, fasting and praying, waiting for the Christ Child.

Grief is unpredictable and although wew can remember to give a sympathetic hug, very few of us can find the correct form of gentle words to assuage it.

health news

2011-12-06T09:31:00.001Z

I have finally heard from the Cancer drug fund. The news came through at about 5-45 this evening (Monday). The monoclonal antibody has been approved and I should be able to get it this week.

First I have arranged for my ascites to be tapped this week which should be able to relieve me from the abdominal pressure that I have been increasingly suffering from.

John 8:28. Crucifixion is coming

2011-12-04T20:11:00.001Z

So Jesus said, “When you have lifted up the Son of Man, then you will know that I am he and that I do nothing on my own but speak just what the Father has taught me.

Jesus knew how he was to die. Here he predicted it. The crucifixion is coming. They will know the answer then if they will only open their eyes.

Remembrance 2011

2011-12-04T20:06:00.001Z

Gary Speed, MBE: the young men stand with red knees glowing
Perplexed as they applaud at Cardiff, Liverpool and Leeds.
He had it all; fame, kids, nice wife and home, success; still showing
Despite their grief, that these will never satisfy their needs.

Eleven eleven eleven; time to remember the dead and missing.
Black garbed crows with ribbons, wreaths and sticks
March fearlessly this time, ignoring boos and bitter hissing
Of the Muslims, students, and mad anarchists thrown in the mix.

We are not saved by this display of silent drinking and eating
Of scraps of desiccated bread and cups of inferior wine.
The precious act that we remember was totally sin-defeating
And it demolished yours just as it forever abolished mine

John 8:26-27: tell them about the father

2011-12-03T15:57:00.004Z

“I have much to say in judgment of you. But he who sent me is trustworthy, and what I have heard from him I tell the world.” They did not understand that he was telling them about his Father.

Isn't it dangerous to be guided by the blind? Much of the Christian church is guided by the blind or at very least the near-sighted. Visionaries like John Stott, Jim Packer, Alec Moyteer, Billy Graham, Michael Green and Dick Lucas are old men now, but read their writings. Look out for Michael Ots our own home-grown evangelist if we are hear the truth about God.

We are all to be witnesses but some are called to be evangelists.

Up-to-date news.

2011-12-03T12:23:00.007Z

I am sitting in my office looking out on a beautiful day. The sun is shining and although it is not hot, we have a temperature of about 53 degrees F and a soft SW breeze. The leaves on the trees are yellow and gold and the sky is light blue with small patches of white.

My wife is polishing the wood block floor and there is a delicious smell of polish mingled with a beef casserole in the oven.

I should hear about the monoclonal antibody on Monday afternoon. The delay has been because the chairman of the Committee (don't you hate that word) has been on annual leave and nobody has been brave enough to take the decision until he returns.

I was told by a patient who was an Insurance man that taking out Private Medical Insurance in the UK was not cost effective. Companies like PPP and BUPA were frauds against the general public. You can get a good deal through a company scheme, but if you have to fund it yourself, you would find it more cost effective to put your money in Unit Trusts via a PEP or ISA scheme that shields the growth from tax and draw on it when you need it. This is what I shall do if the answer on Monday is NO.

Talking of medical insurance, it seems to me that NICE has taken a strange view of what medication it should be supporting. If it were dealing with car insurance rather than medical insurance it would not be funding low cost items. We all have an excess on our car policies. The first £350 of damages incurred in an accident I pay myself so as not to lose my no-claims benefit. I can afford to pay that myself. It's the £10,000 write off bill and the £1 million damages when the other driver loses a limb that I want help with. So it should be with medical expenses. I can buy my own indigestion medicine, I need help with long term treatment for a handicapped child or maintenance therapy for cystic fibrosis or for cancer therapy.

My general health is quite good though I have to be careful only to eat small meals. My main problem is ascites - fluid secreted by the cancer and accumulating in the peritoneum between loops of bowel. At some stage this will need to be drained away with a thin plastic tube under ultrasound guidance.

My daughter the hematology registrar is on-call in Oxford this weekend. Among her patients is one who has a very difficult lymphoma with translocations on both chromosome 14s at the site of the promoter for the Ig heavy chain gene. On one chromosome the translocation is to BCL-2 and on the other to c-myc. This is a very rare combination and in the literature there are no long term survivors. It is ironic that I described the first such case back in the early 1980s.

My son, the F1 engineer, has finished his globe trotting to Grand Prix and in future will be in charge of procuring and providing at AP Racing. He has been thrown in the deep end with a computer glitch which he has sorted much to the approval of the CEO.

My older son, will be emigrating to New Zealand on Jan 7th. He has been head-hunted to do healthcare risk management there. Apparently his Visa came through in two days, so keen were they to have him. He is glad to leave the CQC which has become mired in an internecine dispute engineered by a two supposed whistleblowers. One is a passed over inspector, not clever enough to advance in her division (she can't grasp Bayesian statistics) and now angling for 'constructive dismissal' and the other is a Board Member who was appointed for her special interest in mental disease; her special interest being that she had suffered from it and was getting increasingly disturbed as the year went on.

My older daughter took voluntary redundancy earlier in the year and has set up her own company doing business analysis. In the meantime she is in partnership with her step-son in an arts and crafts business which is making and selling objets-arts around Christmas time.

I ought to explain what the monoclonal antibody does:

Every cell in the body needs to either grow or die. This is as true for normal cells as cancer cells. Each cell receives a growth signal from a growth factor which reacts with a growth factor receptor on the cell surface. This message is then transmitted to the nucleus where a transcription factor sets the cell dividing at its set rate. This will be different for a skin cell compared to a blood cell compared to a brain cell. Cancer cells will tend to divide faster.

The message must be taken from the cell surface to the nucleus by a series of second messengers. Mistakes (mutations) can take place in the growth factor, the growth factor receptor, any of the second messengers or the transcription factors. A common mistake is in the second messenger k-ras and it is known that these monoclonal antibodies, which block the epidermal growth factor receptor do not work very well if k-ras is mutated. Happily mine is not.

In view of the fact that my disease is very indolent (in its metastatic form it has been present for over 3 years) the cancer does not seem to be carrying too many mutations and I have every hope that EGFR blockade with this monoclonal will be successful.

In the football it is an important weekend for the Premier League. Chelsea have just beaten Newcastle and later today Man U play Aston Villa, Spurs play Bolton, and Man C play Norwich. These are all games that could go either way and the Champions will come from this group of clubs. England were fortunate with the draw for the European Championships and will not have to meet a really top team until Wayne Rooney returns from suspension.

In the News today is a report which suggests that 3000 women in Britain are suffering from so-called "honor beatings" from family members because of the alien "shame culture" brought into Britain by (mostly) Muslims. And Jacques DeLors, the instigator of the Euro, has admitted that it was badly introduced since most countries, including Germany, broke the entry rules.

For all Biblical Creation Society members who may be reading this blog, thank you for your prayers. Another explanation for why my cancer has taken so long to kill me is that I am being sustained by the prayers of Christians all over the world, and because in response to those prayers the Holy Spirit still finds me useful where I am am rather than in taking me home. If that is the case would you pray that he keeps me free from pain and keeps making innovative suggestions on how I may more easily bear this period of difficulty. In particular I should like wisdom on when it would be right to tap the ascites.

It has been a very eventful week with fillings falling out, dishwasher delays, eyesight tests, earwax bothers, monoclonal hold-ups, bad days, good days, CT scan, visits from children and grandchildren, reading too late some nights, sleeping too long some mornings, a fall down stairs, and difficult decisions; but the Lord has brought me through all this and does sustain me in the worst of times.

I have discovered that the nicer you are to other people the nicer they are to you.

Abortion and cytotoxic drugs

2011-12-02T15:15:00.004Z

One of the things on my conscience concerns abortion. I have always held strict opinions about it and would opt out of being concerned in any matter to do with it. The only grounds that I could see for abortion would be if the baby had little chance of surviving the pregnancy. To ask a prenant woman with an anencephalic child to wait 9 months to deliver a baby that would die immediately seems to me too cruel to contemplate.

There was one occasion when I was faced with this. A young married woman with polycythemia was being treated by me with hydoxyurea (hydroxycarbamide). She was taking this during the first trimester of her pregnancy. She came to me worried that the baby would be affected by the carcinogenic/teratogenic drug.

Now I have always taken the view that hydroxyurea is a safe drug from this respect, and have believed that it is safe to use this drug in young people. But it is a fact that patients with polycythemia do tend to develop acute leukemia after about 13 years follow up. My opinion is that this is part of the nature of the disease rather than because of hydroxyurea since sickle cell patients who receive hydroxyurea to increase their HbF production do not develop acute leukemia. (There are only 2 cases in the literature - probably a chance encounter.)

However I could not be absolutely sure. (On one occasion a patient of mine in this situation switched from hydroxyurea to venesection when she moved to a different part of the country and promptly had a severe stroke.) In the UK it is necessary for 2 doctors to sign a form to permit the abortion to go ahead. I could have passed the buck, but it was really my decision to make, and I signed the form - the only occasion that I have.

Now there is a report in JCO (2011; 29:2410-5) which suggests that I was right all along and could have refused with a clear conscience. (Well not exactly clear, because I would also have to deal with a weeping woman who was very frightened.) The Swedish Chronic Myeloproliferative Neoplasm Study Group has reported on 11039 patients and concluded that despite a 35 fold higher risk of patients with Myeloproliferative conditions developing MDS/AML, there is no higher risk for those who have only received hydroxyurea as chemotherapy. Of course, I am talking about carcinogenicity here not teratogenicity, but they tend to go together.

This was a judgment call that I may have got wrong.

Another attempt to get FCA up front

2011-12-02T15:05:00.003Z

This is not quite the right trial, but it is an attempt by the Dutch group to introduce alemtuzumab up front in high risk patients. The other arm should have been FCR not FC and they were wrong to include trisomy 12 in the high risk group.

290 Immunochemotherapy with Low-Dose Subcutaneous Alemtuzumab (A) Plus Oral Fludarabine and Cyclophosphamide (FC) Is Safe and Induces More and Deeper Complete Remissions in Untreated Patients with High-Risk Chronic Lymphocytic Leukemia (CLL) Than Chemotherapy with FC Alone. An Early Analysis of the Randomized Phase-III HOVON68 CLL Trial

In CLL unmutated immunoglobulin heavy chain (IGH) genes, deletions of chromosome 17p or 11q and trisomy 12 are associated with an unfavorable outcome. At the outset of the present trial, phase II studies had shown promising results of immunochemotherapy with FC + rituximab, but the optimal immunochemotherapy regimen was not known, especially not for high-risk CLL patients. The aim of this trial was to improve the outcome of high-risk CLL by the addition of the monoclonal antibody alemtuzumab to the currently best known chemotherapy FC. Because of the recognized immunosuppressant activity of both treatment modalities, a low-dose alemtuzumab approach was chosen and vigilance and prophylaxis towards infection upheld throughout the study.

Previously untreated, fit patients up to 75 years of age with high-risk CLL in need of treatment according to the NCI/IWCLL guidelines were randomized to either oral FC (F 40 mg/m2 D1-3 and C 250 mg/m2 D1-3) or AFC: oral FC + subcutaneous (sc.) alemtuzumab 30 mg, in cycle 1 day -1 to +1, in cycles 2-6 30 mg day 1 only. Responses and endpoints were defined according to NCI/IWCLL guidelines. The primary endpoint was progression-free survival (PFS) on intent-to-treat with progression defined as no response after three cycles of induction treatment, progression of disease, relapse or death whichever occurred first. Secondary endpoints included the rate of complete remission (CR) and the rate of MRD – negative CR (by PCR or flow cytometry), overall survival (OS) and toxicity. We assumed that the addition of alemtuzumab to FC could increase the CR rate from the estimated 20% to 40% and the median PFS from 30 to 42 months.

The study population of 281 patients was included 2006-2010. As of July 2011 262 patients (93%) were evaluable, 129 in the AFC arm and 133 in the FC arm with a median follow-up of 30 months (range 2-63 months). The median age was 60 years (range 27-75) and 75% were males. Twelve % had Binet stage A, 54% stage B and 34% stage C. Beta-2-microglobulin was increased in the majority of the patients (median 3.7 g/ml). Eighty-nine % had unmutated IGH genes and FISH revealed 27% with del 11q, 18% with trisomy 12 and 11% with del 17p according to the hierarchical model. All risk parameters were well balanced between the two arms. Sixty-three% completed all six cycles in each arm, 73% completed at least 5 cýcles AFC while 66% completed 5 cycles FC.

The overall response to AFC and FC was 88% and 80% respectively (NS), the CR rates were 57% and 45% respectively (P=0.049), and the rates of MRD-negative CR were 29% and 17% respectively (P=0.02). The median PFS following AFC and FC was 37 and 31 months respectively (P=0.08). The median OS has not been reached. In the subgroups with 17p deletions, 11q deletions, trisomy 12 or unmutated IGH genes a trend of improved PFS following AFC was seen, but this did not reach significance due to small numbers. There were no differences in response or PFS between treatment arms according to Binet stage or beta-2-microglobulin level.

Severe adverse events, mostly grade 3, were significantly more frequent following AFC than FC: 145 vs 90 (P=0.0001), including flu-like syndrome due to the antibody (27 vs. 2), opportunistic infections (25 vs 11), and organ affection (34 vs 14). The numbers of neutropenic and other infections did not differ. Six treatment related deaths were reported in each arm to a total treatment related mortality of 4%.

In this selected high-risk CLL population, the addition of low-dose sc. alemtuzumab to FC induced a higher rate and higher quality of complete remission than FC alone, which, however, in this early analysis, did not yet translate into significantly prolonged PFS or OS. As expected, the combination is more immuno-suppressant than chemotherapy alone, leading to a higher number of opportunistic infections. With proper vigilance and prophylactic measures, these infections were manageable and did not lead to any excess mortality.

Second-line treatment after CLL8

2011-12-02T14:42:00.002Z

What do the early relapsers from CLL8 actually get as second line treatment and does it work? The information in this German ASH abstract tells us and the results are rather surprising.

2863 Second-Line Therapies After Treatment with Fludarabine, Cyclophosphamide, and Rituximab (FCR) or Fludarabine and Cyclophosphamid Alone (FC) for Chronic Lymphocytic Leukemia (CLL) within the CLL8-Protocol of the German CLL Study Group (GCLLSG)

The CLL8-trial is the first study that has shown not only an increase in complete remission rates and progression-free survival, but also an improved overall survival (OS) in physically fit, treatment-naúve CLL-patients (pts) with FCR-chemoimmunotherapy in comparison to FC alone. Despite this remarkable progress, CLL remains an incurable disease and virtually all pts will eventually relapse. So far, little is known about the efficacy of 2nd-line therapies of these pts.

The combination CHOP-R was the most common treatment (35 pts, 15% of all 2nd-line therapies), applied mainly in cases with a relapse ≤24 months after FC/FCR, whereas FCR or BR were administered predominantly in case of relapse less than 24months (32 and 27 pts, 14% and 12%). Other prevalent 2nd-line therapies were single agent Alemtuzumab(A) (20 pts) or Bendamustine (17 pts), CHOP and FC (11 pts respectively), chlorambucil (9 pts) as well as R monotherapy (7 pts). 9 pts underwent stem cell transplantations. Second-line therapies with FC+/-R and B+/-R were found to be more effective with regard to treatment-free survival (TFS, time to 2nd relapse) and OS when compared to A or CHOP-R and CHOP-like chemotherapies. However, the outcome of 2nd-line therapies seemed to be influenced by the 1st-line treatment. In pts initially treated with FC, FCR was found to be the most effective 2nd-line therapy (TFS: 23 months, OS: not reached), whereas in pts initially treated with FCR, a substitution of the chemotherapeutic agents FC by B seemed justified, as TFS was superior after 2nd-line treatment with B+/-R (16 and 18 months respectively) when compared to FC+/-R (11 and 8 months). Furthermore, in pts who had received FCR for 1st-line treatment, chemotherapy with FC or B was found to be at least equally or even more effective in prolonging OS than FCR or BR (OS calculated from beginning of 2nd-line therapy: FC: not reached, B: 45, FCR: 19, and BR 18 months).

Second-line treatments of pts with a relapse after FC or FCR were found to be surprisingly heterogeneous even though the patient collective examined is comparatively homogenous due to the inclusion/exclusion criteria of a clinical trial. As the majority of CLL8-patients is still in remission and has not yet received a 2nd-line treatment, the therapies captured in this analysis are predominantly 2nd-line therapies for earlier relapses. Therefore and because of the short follow-up time, the results ought to be considered as preliminary and descriptive trends. The worse outcome of CHOP-like regimen and A-based therapies in comparison to more established CLL-therapies such as FC+/-R and B+/-R might be related to the fact, that these therapies were administered more often in case of an early relapse after FC/FCR, which is known to be related to other poor prognostic factors. Nevertheless, the observation of favorable TFS and OS times after 2nd-line treatment with FC+/-R and B+/-R supports the recommendation to repeat chemoimmunotherapy in case of a relapse >24 months after 1st-line treatment. Further analyses are needed to confirm the observation that chemotherapy (FC or B) without rituximab might be sufficient for for 2nd-line treatment after FCR.

Should we CT scan all new Rai stage 0 patients?

2011-12-02T14:26:00.003Z

2837 Inclusion of Total BODY Computed Tomography (TB-CT) SCANS In the INITIAL WORK-up of Binet STAGE A CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) PATIENTS On CLINICAL Grounds: PRELIMINARY RESULTS of the Prospective, MULTICENTER O-CLL1- GISL STUDY
Rai and Binet staging systems are not devoid of some limitations, including the lack of evaluation of thoracic and abdominal lymphadenopathies. The widely-used IWCLL guidelines do not incorporate use of TB-CT scan in the diagnostic algorithm. In the present study, we investigated whether TB-CT scans could up-stage Binet stage A CLL patients included in the prospective multicenter O-CLL01 GISL study and whether this subgroup presented differences in prognostic markers and in progression-free survival (PFS).

To date, 454 patients have been enrolled and TB-CT scans were available in 238 patients. The median age was 60 years (range, 33-71) and 136 (57%) were male. According to Rai, 180 patients were at low risk (stage 0) and 58 at intermediate risk (stages I-II). b2-microglobulin was elevated in 35.5% of cases. Seventy-eight patients (32%) were IgVH unmutated, 108 patients (45%) had a high ZAP-70 expression, 45 patients (19%) were CD38 positive (>30%). FISH data were available in 226/238 cases; the most frequent abnormality was del(13)(q14) (105 pts, 46.5%), followed by trisomy 12 (24 pts, 10.6%), del(11q22.3) (13 pts 5.5%), del(17p13) (4 pts 1.8%) while 80 cases (35.4%) cytogenetics were normal. Cytogenetic abnormalities were clustered in 3 risk groups [i.e. low (del(13q14) and normal), intermediate (trisomy 12) and high risk (del(11q22) and del(17p13)]. Two hundred six out of 238 patients had a minimum follow-up of 6 months and were evaluable for PFS.

Considering TB-CT scan, 54 out of 238 analyzed (22.7%) patients converted into Binet stage B. Notably, 63% were male, b2-microglobulin was elevated in 50% of cases, 42.6% were IgVH unmutated, 48.1% had a high ZAP-70 expression, 27.8% were CD38 positive, and 17.6% showed a high-risk FISH. Binet B patients showed a statistically higher rate of cases with high risk cytogenetic abnormalities than Binet A patients (17.6% vs 4.6%; p=0.032). While, no statistically different distribution of gender, age, B2-microglobulin, IgVH mutational status, CD38 or ZAP-70 expression were observed between the two subgroups. After a median follow-up of 24 months 46/206 (22%) evaluable cases showed disease progression. Binet B patients showed a PFS significantly shorter than those with a normal TB-CT (2-years PFS probability, 85.6% vs 68.5%; p=0.0001). According to the Rai classification 102/180 (56.7%) low risk patients were re-defined as intermediate risk with the integration of TB-CT scan. This subset of patients showed a statistically higher rate of cases with elevated ZAP-70 (51.5% vs 35.9%; p=0.049) and CD38 (22.5% vs 10.3%; p=0.045) than patients at low risk. After a median follow-up of 25 months, 23/154 (15%) of evaluable cases showed disease progression. Patients with an intermediate risk Rai stage showed a PFS significantly shorter than those with a low risk (2-years PFS probability, 82% vs 96%; p=0.002). In this setting 70 cases met the diagnostic criteria of monoclonal B-lymphocytosis (less than 5 × 10e9/L B-lymphocytes in the blood). With the integration of TB-CT scan 30/70 (42.9%) monoclonal B-lymphocytosis patients were re-defined as intermediate risk according the Rai classification. No statistically different distribution of clinical and biological parameters were observed between cases who remained in the low risk stage and those who became at intermediate risk. After a median follow-up of 28 months 4/57 cases evaluable for PFS showed a disease progression (2 cases for each subgroup). Considering low risk Rai stage, no statistical difference in PFS was observed among non CT-upstaged MBL, CT-upstaged MBL, non CT-upstaged Rai 0, while CT-upstaged Rai 0 cases showed a statistically shorter PFS (p<.0001) than the other groups (Figure 1). Finally, TB-CT scan allowed the early identification of a second neoplasia in 2 cases (lung cancer 1 pt, renal cell carcinoma 1 pt).

Our preliminary data indicate that the integration of TB-CT scans in the clinical staging allows for an effective clinical discrimination of Binet A CLL cases in approximately 23% of cases at more advanced stages, predicting a worse clinical outcome. However, the use of TB-CT scanning for upstaging is not beneficial for predicting PFS in MBL cases. A longer follow-up will demonstrate whether the inclusion of TB-CT scan in the initial work-up of patients with early-stage CLL will provide clinically relevant prognostic information.

Clearly there is prognostic information to be had in scanning all new cases of stage o CLL; but all previous prognostic information in the literature would have to be ditched.

A role for ras genes in chlorambucil resistance?

2011-12-02T14:02:00.003Z

From this Italian ASH abstract it seems that Chlorambucil-rituximab is a promising regimen in CLL patients over-65. Those who respond have molecular differences to those who don't. ras genes seem to be important.

294 Rituximab Plus Chlorambucil As Initial Treatment for Elderly Patients with Chronic Lymphocytic Leukemia (CLL): Effect of Pre-Treatment Biological Characteristics and Gene Expression Patterns on Response to Treatment Robin Foa, Stefania Ciolli, Francesco Di Raimondo, Giovanni Del Poeta, Francesco Lauria, Francesco Forconi, Antonio Cuneo, Agostino Cortelezzi, Francesco Nobile, Vincenzo Callea, Maura Brugiatelli, Massimo Massaia, Stefano Molica, Livio Trentin, Rita Rizzi, Giorgina Specchia, Lorella Orsucci, Achille Ambrosetti, Marco Montillo, Pier Luigi Zinzani, Felicetto Ferrara, Fortunato Morabito, Maria Angela Mura, Silvia Soriani, Marilisa Marinelli, Maria Stefania De Propris, Alessandra Alietti, Eva J. Runggaldier, Enrica Gamba, Ilaria Del Giudice, Silvia Bonina1, Francesca Romana Mauro, Sabina Chiaretti and Anna Guarini.

Rituximab plus fludarabine/cyclophosphamide (R-FC) is currently the standard of care for fit patients with untreated or relapsed CLL. However, patients with CLL are predominantly an elderly population and many of these patients may have comorbidities that make them less suitable to receive fludarabine-containing therapy. Chlorambucil-based treatments are frequently used for these patients despite the fact that clinical benefits are limited. There is a need for well-tolerated and more efficacious treatment regimens for these patients.

The ML21445 study evaluated the combination of rituximab and chlorambucil (R-chlorambucil) as first-line treatment for patients with CLL considered ineligible for treatment with the current standard of care, R-FC. Patients aged >65 years (or 60–65 years and ineligible for fludarabine) were treated with eight 28-day cycles of chlorambucil (8 mg/m2/day Days 1–7) with rituximab administered on Day 1 of cycle 3 (375 mg/m2) and cycles 4–8 (500 mg/m2). Patients with a response at the end of induction were randomized to rituximab maintenance therapy (375 mg/m2 every 8 weeks for 2 years) or observation. The induction phase of the study is complete while the maintenance phase is still ongoing.

This is a rather low dose for chlorambucil. 10mg/m2/day for 10 days would be equivalent to what patients got in LRF CLL4

The overall response rate (ORR) in 85 patients who received at least one dose of rituximab during induction was 81.2% (n = 69) with 16.5% (n = 14) achieving a complete response (CR) and 2.4% (n = 2) a CR with incomplete bone marrow recovery (CRi). ORR and CR rates were similar across the different Binet stages (ORR: Binet A 86.4%, Binet B 79.6%, Binet C 78.6%) and age categories (ORR: 60–64 years 84.6%, 65–69 years 85.2%, 70–74 years 75.0%, ≥75 years 81.0%). Two of four patients aged ≥80 years responded to induction treatment.

ORR of 81% is excellent for a chlorambucil containing regimen.

Logistic regression analysis revealed no correlation between known biological prognostic factors – CD38, cytogenetics, IGHV mutational status, ZAP-70, thymidine kinase, soluble CD23, and beta-2 microglobulin – and response to treatment. To further investigate possible factors influencing response, pre-treatment patterns of gene expression were analyzed in different patient subgroups. Material was available for 62 patients, including 16 with CR/CRi, 41 partial responders and 5 non-responders. In an exploratory analysis, mRNA expression was examined using Affymetrix® Human Genome U133 microarrays. This revealed marked differences in pre-treatment gene expression profiles between response groups. Non-responders showed a homogeneous gene expression signature involving up-modulation of transcripts involved in anti-apoptotic and pro-proliferative pathways, including K-ras and N-ras. CR/CRi patients also showed a homogeneous pattern of gene expression that was clearly distinct from non-responding patients, while patients with a partial response showed a more heterogeneous pattern of gene expression before treatment.

Apart from TP-53 effects response rates usually do not vary with rituximab containing regimens, but PFS does.

These initial findings reflect the heterogeneity of CLL and suggest that microarray analysis of gene expression may be useful in predicting response to R-chlorambucil in elderly patients with CLL.

More outrage in Nigeria

2011-12-02T13:52:00.001Z

From Open Doors

Over 150 people have been killed and 10 churches demolished in a carefully planned attack on the Christian community in Damaturu.

More than 200 heavily armed Boko Haram members invaded the community of New Jerusalem after Friday prayers on 4 November, detonating bombs in churches and shooting any believer in sight. Carrying sophisticated guns, explosives and knives, and chanting "Allahu Akbar", the Islamists began to shoot passers by who could not recite any Islamic verses - the only condition for survival. All the Christians who were trapped were either shot or slaughtered with knives. Boko Haram spent about four hours killing and demolishing churches without hindrance from police or security personnel. At least 17 military and police were killed during the attack and both the new and old Police Headquarters were demolished.

Concentrated in northern Nigeria, the extreme Islamist sect is openly agitating for the full implementation of Sharia throughout the country. "War on the church of Jesus Christ" A new settlement of believers in the New Jerusalem area of Damaturu has been described as a haven of churches and Christians - one with which extremist Muslims are not happy. "We are dumbfounded by this attack. It is a war on the church of Jesus Christ," said Rev. Garba Idi, pastor of the ECWA Gospel Church that suffered a bloody blast during the attack. "Boko Haram is out to destroy the church," he concluded while inspecting his damaged church. "Their plan was to kill all of us, but the Lord has spared us. We have a great challenge as a church in this part of the world. We are living on the mercy of God, because they promised to come back and destroy our homes."

Mrs. Grace Samaila, 30, newly married in June, saw her husband shot in the head in front of their church. "We were on my husband's motorbike just outside the gate of the church. The Muslim militants stopped us and asked my husband if he was a Muslim. He said, ‘No, I am a Christian.' In my heart I knew that calamity will soon befall, so I was praying. They asked me to get down from the bike and go my way [although] I asked them to allow my husband [to go] so that he could take me home. They shouted at me and pushed me with a stick as my husband was pleading with them to allow me [to go]. "They asked him to accept Islam and he said no. So they shouted at him to keep going. As soon as he moved some meters away from them, they shot him in the head. He fell from the bike [and died next to the road]. "I could not sleep, and every day the scene of the incident appears to me," she said. "I want God to take away my life, to join my husband."

The present situation

Believers in Damaturu remain fearful. Many have fled the city, convinced that the few security men deployed in the area are insufficient to contain the situation. Local church leaders tried to meet with His Royal Highness the emir of Damaturu, but they were denied an audience by the palace attendants.

In claiming responsibility for the attacks in Damaturu, the spokesperson for Boko Haram, Abu Qaqa, threatened to launch more attacks all across northern Nigeria. With the intention of imposing full Sharia, this Islamic sect has apparently designed a plan to eliminate all churches throughout the northern cities and villages. About 10 people have been arrested in connection with the attacks; further investigation is underway, according to the state police commissioner.

Please pray:
For comfort and healing for Christians caught up in these attacks

For protection, strength and wisdom for Open Doors co-workers seeking to encourage our persecuted brothers and sisters in situations such as this

That God would reveal Himself to the leaders of Boko Haram and change their hatred to love.

What's going on with Occupy London?

2011-12-02T13:39:00.002Z

This from Today's Times:

It was supposed to be a protest against the evils of capitalism, among other things, but the St Paul’s Cathedral campers have been spending as much of their time on their own economic affairs as on the global financial system. It was on Tuesday evening, after the campers had gathered for a meeting about money in their unofficial conference space, a Starbucks, that the equal people first came to blows with those who, to some minds, are more equal than others. While some Occupy London demonstrators cradled cappuccinos and others drank nothing because they considered the coffee house to be a “symbol of capitalism”, heated exchanges took place over the state of the financial system — the one within the campsite.

The self-appointed finance committee, angry voices among the protesters have since claimed, had turned into an all-powerful and unaccountable force comparable to the ruling elite in George Orwell’s political satire Animal Farm. Yesterday, amid a growing row over transparency and allocation of funds, the committee, which consists of between four and six people, stood down en masse. One of its key members, Tess Jones, 25, from New York, said, however, that she would stay on and help to form an interim committee after receiving a vote of confidence.

During Tuesday’s meeting, the camp’s first aid team and “tranquillity” team, which is responsible for welfare and night patrols, had asked the committee for £1,200 to buy equipment including walkie-talkies and trauma kits for treating stab and gunshot wounds. (Delusions of grandeur, methinks - are they that afrais of jeremy Clarkson?) The request came after what protesters described as threats and safety concerns at the site. The committee was accused of dithering and withholding money, putting campers at risk. It was claimed that it reduced funds for food, while other working groups such as the technology tent were able to buy expensive equipment.

Last week, the committee said that a drop in donations meant that it would have to be “stricter” about funding. The camp’s bank balance was £12,000, Ms Jones said yesterday, including £8,000 in an account held by the London Camp for Climate Change and £4,000 cash in a secure location off site. She added that about £25,000 has been donated to the camp by well-wishers since it formed seven weeks ago. As tensions rose at the meeting, Ms Jones was implicitly accused of using the donations to fund flights to New York, prompting her to storm out in exasperation at the “wild rumours”. The first aiders and the tranquillity group stood down in protest at their treatment by the “elitist” committee, though both have since reformed.

Yesterday, Ms Jones, who did a master’s degree in sociology at the London School of Economics, said that the allegation was completely untrue and that she and her mother had paid for the flights in question. After The Times was contacted by a whistleblower and made inquiries, the committee announced its disbandment. Ms Jones said: “We had a public meeting, and there was support and faith in the finance group. We decided that the working group will no longer be doing the finances . . . We are now trying to move forward, and deal with rumours and negativity.” She said that the maximum balance ever held by the camp was £17,000, but an anonymous whistleblower said: “About two weeks ago we had £21,000 in donations and there must have been more now but they said there would be no more money for the food tent or the tranquillity tent and that the legal team couldn’t use taxis or buy stationery.
“We want to know where all the money has gone. The people who made the donations thought it was going to feed us but one younger mother has had to leave because they said there was not enough food. “It is becoming a nightmare and people are starting to leave. It is becoming intimidating. If you don’t agree with what the leaders say they shout at you and can be quite aggressive. We are now being ruled by an elite inner circle. They are telling us what to think.” She said the two main leaders were two veteran anarchists in their 40s or 50s, and three people in their 20s. “Paul [in his 40s or 50s] has written a charter which gives all the power to a tiny group of people,” she added. “We are all calling it the Animal Farm manifesto. They are always smartly dressed. I don’t know how they manage it when we are all camping, and they go off and have these secret meetings at Starbucks. A small number have decided they are more equal and are controlling the rest of us.”

Which occupiers have gone the distance?

Occupy Wall Street Evicted from Zuccotti Park after nearly two months on November 15. Activists are planning their next move.

Occupy Oakland Evicted from Frank H. Ogawa Plaza on November 14 and from smaller camps by November 21. Demonstrations continue.

Occupy LA Earlier this week, the two-month old encampment outside City Hall was cleared by 1,400 police with 300 arrests.

Occupy Philadelphia At 1am on Wednesday, 100 protesters were cleared from their camp by police. Occupy Bristol Protesters are still camped at College Green and aim to stay into the new year.

Occupy Exeter A camp of about 18 tents remains outside Exeter Cathedral. A second camp was set up on Wednesday in Totnes.

Occupy Edinburgh The continuing occupation of St Andrew Square was recognised by the City Council on November 24.

Occupy Toronto Came to a peaceful end after a month on November 23.

Occupy Berlin The Bundespressestrand, near the government district, has been occupied by 50 protesters since November 9.

Occupy Bournemouth was disbanded a couple of weeks ago. It comprised a couple of dozen beggars, drug addicts and publicity seekers. they has reassembled in a back alley, out of public view.

John 8:25-26. No excuses

2011-12-02T12:21:00.002Z

“Who are you?” they asked. “Just what I have been telling you from the beginning,” Jesus replied. “I have much to say in judgment of you. But he who sent me is trustworthy, and what I have heard from him I tell the world.”

The sin is unbelief. If we refuse to believe God, what hope is there for us?

How do we know what God is saying? Paul tells us in Romans Ch 1 "What may be known about God is plain. For since the creation of the world God's invisible qualities - his eternal power and divine nature - have been clearly seen, being understood from what he has made, so that men are without excuse.

We can look at nature. But since the 19th Century men have thought up theories about how these could be self-generating - not that these theories are convincing - the arguments were all demolished in the nineteenth century - but so that they might find an excuse for not believing in God.

Others will point to the tradition of the Church that there is a God, but I admit that this is hearsay evidence and often wild and poorly attested. But we have better evidence than that. God sent his son. And we have the evidence of those who met him and heard his testimony. That which was heard and seen has been written down by those witnesses within 20 years of the actual event and that actual event included the death and resurrection of Jesus.

I don't know about you, but I can recall actual conversations that I had 30 years ago which were much less stupendous than this: conversations with colleagues, administrators and patients. And we have the benefit of many witnesses and detailed researchers who went about asking questions: "How do you remember that?" asked Luke of Peter, John Mark, Mary and the other women and many others.

WE have Scripture, and according to Scripture we have the Holy Spirit.

So we really are without excuse when we do not believe.

Aid to India. Even they are embarrassed and have asked us to stop it next year.

2011-12-02T08:04:00.003Z

I don't believe everything I read in the Daily Mail. It is a right-wing tabloid with an agenda. But here is what Sue Reid writes after a visit to India. A genuine grass-roots investigation or a gathering of evidence to illustrate her point?

At the Rolls-Royce showroom, behind imposing iron gates off dusty Ashoka Road, the chief salesman is pleased with his latest sale of a £600,000 Phantom to a billionaire Delhi businessman. Thirty-five Phantoms, the biggest and most expensive Rolls-Royce, have been bought in India already in 2011. By the end of the year, another 35 will be sold to Indian tycoons and Bollywood film stars. ‘There’s always someone here with enough cash to buy a Rolls-Royce, even though the import tax doubles the price,’ the sharp-suited salesman says with pride.

Ferrari, Aston Martin and Land Rover have each opened up showrooms here. On sale too is the king of supercars, the Bugatti Veyron, with an eye-watering price tag of almost £1.5 million. The country is racing up the league of rich nations. Indeed, its soaring economy will outstrip the UK’s by 2022. According to financial advisers Merrill Lynch, India has 153,000 dollar-millionaires — a 20 per cent rise in a year, compared with Britain’s own paltry increase of less than 1 per cent. Indians have squirrelled away more money in Swiss bank accounts (a total of £900 billion since independence from Britain in 1947) than the rest of the world combined. And when they were invited recently by the Indian Government to exchange for paper money the gold bars and jewellery stashed in their homes (so pumping cash into the national economy), a horde of £160 billion was offered up. Such is the economic power of India that it now gives out more foreign aid than it receives, and has handed over £3.5 billion to cement relations with impoverished Africa.

Meanwhile, it invests huge sums in ambitious projects: £2 billion will put the first Indian astronauts into space by 2016, and the annual defence budget tops £22 billion, with a third aircraft carrier now under construction in an Indian shipyard. Perhaps the perfect example of the garish spending of India’s newly-rich is the £2 billion, 27-storey skyscraper in Mumbai built by a local industrialist as a home for his wife and three children. It is the most expensive house anywhere in the world.

But if this is a nation with enormous reserves of wealth, it is also blighted by widespread and endemic corruption at every level of society. An official report has revealed that 90 per cent of government officials have accepted a bribe for favours, from ripping up a speeding fine to rubber-stamping a building deal. Corruption, as the Indian prime minister confessed the other day, is as much a national sport as cricket. No wonder that in broke Britain questions are at last being asked about why we are handing billions to India in aid. A new report from an independent watchdog says that the rapid expansion of the UK’s aid programme has left taxpayers’ money at risk from corruption and fraud overseas.

The Independent Commission for Aid Impact (ICAI) last week criticised the work of the British government department that doles out the money as ‘fragmented’ and in need of ‘significant improvement’ to stop millions being squandered. It also demanded anti-corruption measures to protect funds sent to countries — such as India — where there is a high risk of fraud. They are concerning findings, given that David Cameron has decided to give India £1.4 billion between now and 2015. The sum is almost 1 per cent of Britain’s own £159 billion debts. So do we need to re-think our aid profligacy, especially in light of the shockingly grim economic forecast announced by Chancellor George Osborne this week? Despite the fact that Osborne has extended his austerity programme in Britain — which includes cuts to welfare payments and housing benefits — beyond the next election, David Cameron doesn’t seem to think so.

The Government is trimming just £1.164 billion off the aid budget over the next three years, meaning we are still committed to spending more than £29 billion on overseas aid between next April and April 2015. Earlier this week the Government announced that £330 million of taxpayers cash will be poured into Africa to help them with climate change, funding solar panels and investment in low-carbon transport. A few months ago, he made a speech during a trade visit to Africa admitting that foreign aid has been ‘wasted’, but that it was still imperative for us to shell out more.
But does India really need our funds, and, perhaps more pertinently, what’s happening to it when it gets there? During my inquiries in India, I discovered that much of our money is frittered away or stolen. India’s assassinated former prime minister Rajiv Gandhi once estimated that only 15 per cent of funds given to the country’s welfare schemes, whether financed by foreign or Indian aid, reach the poor people they are meant to help. His views were endorsed by Barun Mitra, director of a Delhi-based think-tank, the Liberty Institute, who told me: ‘I am surprised that Department For International Development [DFID] officials work so hard to continue their presence in India. Is it really to help some of the poorest Indians, or is it to justify their own existence? Apart from wastage, which is hardly a surprise in India, there seems to be little effort to assess how the money is spent.’

A growing group of ‘aid-sceptics’ go much further. One leading economist and expert on the Third World, Zambian-born Dambisa Moyo, says that aid has made the poor poorer. ‘Aid has been, and continues to be, an unmitigated political, economic and humanitarian disaster for most parts of the developing world,’ she warns. So are we helping at all? I spoke to politicians, officials, teachers, doctors and parents in four regions of India where the British government’s DFID runs education and health programmes.

The very first primary school I went to — opened this summer in Bhopal, the capital of Madhya Pradesh state in central India — was half empty of pupils. It had not one desk or chair because they had never been delivered and are presumed stolen from the factory where they were made or from the lorries taking them to school. The children sat on the concrete floor, which was riddled with holes because the builders had put too much sand into the concrete mix so they could, I was told, sell off the spare concrete. Officials admit that £70 million of the £388 million given by Britain towards a national flagship education programme called Sarva Shiksha Abbiyan (‘education for all’), which promises free classes for every child from the age of six to 14, has been squandered though widespread corruption and theft.

Standards of writing, reading and arithmetic are down since the education programme began. Half of ten-year-olds cannot read a sentence, and only a third can perform a simple sum. Meanwhile, teachers in a quarter of primary schools are routinely absent because they take part-time jobs outside school to compensate for low pay. In another scandal, India’s auditor-general discovered £14 million of DFID aid had simply been snaffled by Indian officials and never reached schools. Education chiefs used the money to buy themselves cars. An estimated 8,000 colour TVs bought for schools never arrived. In any case, many would never have worked because few of the classrooms have electricity. What’s more, tens of thousands of pounds were ‘allocated’ to schools that don’t even exist. As a result, even poor parents scrimp to send their children to private schools to escape the government-run ones which receive British aid. A recent report by Indian vice-president Shri Hamid Ansari revealed that British taxpayers’ money spent on education has been wasted. ‘Close scrutiny reveals a sobering truth, that this large investment has been spent poorly,’ he said bluntly. Certainly, many Indians I met scoffed at DFID’s boast that: ‘Because a third of the world’s poor people live in India, this has been our largest programme for more than a decade. It is our bold ambition to give every mother the healthcare she needs to give birth in safety and raise a healthy child who has a chance to learn.’ In a country with such deep-rooted poverty (despite the inexorable rise of the rich) that is a mountain to climb. Indian cities are riddled with slums and there are 500 in Bhopal alone. Thousands of families — even those from the middle classes — live in squalor. Sewage runs down the muddy streets lined with shacks made of corrugated iron with no front doors. It was in one such slum — Rahul Nagar — that I found the new primary school with no furniture. On the walls were posters of the English alphabet and nursery rhymes. On a Tuesday morning, only 170 of the children on the roll of 350 turned up. In the class for eight and nine-year-olds there were 21 children instead of the expected 70. The headmistress Ratnaprabha Verma says she is not surprised because the pupils have nowhere to sit, apart from the floor, and their parents object to this. ‘At five or six, the children enrol in a big rush. The parents know we give out free uniforms, books and pencils. But within days they begin to drop out, one by one. Some simply come for the free midday meal and leave before classes start again. There are no toilets here. Even with the aid money, no one thought to build them.’

All this begs the question: why does DFID insist that our money gives millions of Indian children free schooling and their families a better life? As youth worker Sen Vijay, 27, said with a concerned look as we travelled to the Bhopal school: ‘We think your government is playing a game with statistics. It means they can boast they are helping India. But it is a lie.’ His words are echoed by one of India’s most respected academics, Delhi University’s former dean of education. Professor Anil Sadgopal told me: ‘I don’t know what the British mean when they say their free school project is ‘proving very effective and making remarkable progress. ‘I think the British people should be asking their Government why it is funding such bad-value projects out of your public exchequer.’

His question is equally pertinent when it comes to Indian maternity services, which have received £60 million in British aid. At the first maternity clinic I visited, an operating theatre with thousands of pounds of equipment was gathering dust because a surgeon, anaesthetist and theatre nurse cannot be hired as there is no money to pay them. A rare oversight? Not at all, Sudhir Pattnaik, an editor and political commentator in the impoverished north-eastern state of Orissa, has revealed: ‘In the health sector, the British Government provides infrastructure which is unused. So what is the point of putting the money in? When somebody comes with a big money bag and says: “I will support this,” the state government here will say yes. But there is no practical plan.’ He added: ‘At one city hospital, the medical officer took me to an intensive care unit. Inside, there were six beds and life support units but no patients. The equipment was bought with your aid money, but there was no manpower to operate the machines. This is happening in all other areas, too.’

Back in the Madhya Pradesh region, thousands have been spent on giving pregnant women cash incentives to persuade them to travel, often miles, to a clinic to give birth. But what do they find when they get there? The region’s health officer, Raj Gopal Nair, told me that women often give birth by candlelight because there is no electricity. Many of the clinics’ doctors have quit because of poor pay. I visited a small maternity clinic in busy Bhopal. It has five beds, although it caters for 250,000 people. The operating theatre on the first floor has a new anaesthesia machine which is still in its plastic cover, the instructions in an unopened manual. The theatre bed is unused. Not one child has been delivered here since it was opened a few years ago. ‘We do not have the money to pay for medical staff to perform an operation, such as an emergency Caesarean, in the operating theatre. We can only deal with the uncomplicated births at our clinic,’ says Dr Rajasree Bajaj, the medical director, bluntly. ‘The expensive equipment bought with your aid money has been wasted.’ Then she adds, with sadness: ‘None of your Government people has been to see what is happening here. You are the only British person to come and ask where your country’s money has gone.’

CLL8 the same bad news is bad news.

2011-12-01T18:53:00.003Z

977 Prediction of Poor Outcome in CLL Patients Treated with FCR (Fludarabine, Cyclophosphamide, Rituximab) in the CLL8 Trial of the German CLL Study Group (GCLLSG) Anna Fink, Raymonde Busch, Natali Pflug, Sebastian Boettcher, Dirk Winkler, Andreas Buehler, Matthias Ritgen, Kirsten Fischer, Barbara Eichhorst, Clemens-Martin Wendtner, Myriam Mendila, Michael K. Wenger, Hartmut Doehner, Michael Kneba, Stephan Stilgenbauer and Michael Hallek.

Introduction:

For physically fit patients (pts) with chronic lymphocytic leukemia (CLL) the first-line treatment with fludarabine, cyclophosphamide and rituximab (FCR) is the new standard therapy. However, subgroup analyses in the CLL8 trial revealed that patients with a median progression free survival (PFS) of < 24 months after randomization showed a significantly shorter overall survival (OS) compared with pts achieving a PFS of ³ 24 months. 15 % of these patients were characterized by both, the presence of 17p deletions and TP53 gene mutations, another 7.5% by TP53 mutation alone. Interestingly, the majority of patients with a poor prognosis could not be defined by a mutation of p53 or del(17p). Therefore, an effort was made to further characterize the subgroup of patients with poor prognosis.

Methods:

In 143 patients out of 408 patients who received FCR in the CLL8 trial of the GCLLSG, an assessment of minimal residual disease (MRD) was available at final restaging. These patients were used for this analysis. Results for the primary endpoint PFS, the secondary endpoint OS, and central diagnostics performed for genomic aberrations by FISH and the IGHV gene status as well as for serum parameters before the start of therapy were available for all pts. MRD was determined at final restaging by multi-color flow cytometry from peripheral blood with a sensitivity of at least 10-4. The Kaplan-Meier method and the log-rank test were used to compare PFS and OS in pts with various combinations of risk factors.

Results:

This patient cohort used for the analysis was representative of the entire FCR population (n=408). There were no significant differences compared with the entire FCR population for age, ECOG status, B-symptoms, Binet or Rai stages, deletion of chromosome 17p, 11q, or 13q, trisomy 12, serum levels for s-TK or s-ß2m. A combination of MRD levels of less than 10e2 or of MRD levels of less than 10e4 to less than 10e2 plus at least one of the following three parameters (del(17p) or TP53 mutation or an unmutated IGHV-status) defined a group of patients at high risk of early progression (HR). The median PFS of HR pts was 22 months, the median PFS for patients defined as low risk (LR; n=103) was 69 months. HR patients had a 6.4 fold increased risk for progression (HR 6.4 95% CI: 3.970-10.347; p=0.0001) and a 5.7 fold increased risk for death, with a median OS of only 57 months (assessed from the beginning of FCR therapy). In contrast, median OS was not reached in the LR group at the time point of the analyses (HR 5.758, 95%CI:2.799-11.844, p=0.0001)

Conclusion:

The combined use of genetic markers and an MRD assessment at final restaging allows to identify CLL patients with a very poor outcome after FCR therapy. The high risk group identified by this approach should be treated within clinical trials using novel strategies including maintenance protocols or allogeneic stem cell transplantation.

A predictable picture is emerging. The same old prognostic factors - IGVH mutations and TP53 abnormalities determine the pace of the disease. It confirms my opinion that all CLL patients ought to get them done.

ASCT buys a later second treatment for 4 months of impaired quality of life.

2011-12-01T18:34:00.005Z

There is still some lingering thought that autologous stem cell transplant is an advantageous way of treating some cases of CLL, despite papers suggesting that the risk of secondary MDS/AML is higher than with conventional therapy. This abstract from ASH this year seems to gainsay that.

1989 High-Dose Therapy and Autologous Hematopoietic Stem Cell Transplantation (ASCT) Has a Significant but Transient Impact on Quality of Life: Lessons From the Chronic Lymphocytic Leukemia (CLL) ASCT Study by the CLL Subcommittee of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation Liesbeth C. de Wreede, Maggie Watson, Donald Milligan, Mauricette Michallet, Peter Dreger, Marleen van Os, Claire E. Dearden, Catherine Cordonnier, Michel Leporrier, Vladimir Koza, Janis Homewood, Bernadette Corront, Gabriela M. Baerlocher, Wolfgang Herr, Dietger Niederwieser, Laurent Sutton, Theo M. de Witte, and Johannes Schetelig,

Objective:

High-dose therapy (HDT) and ASCT is the standard of care in a variety of hematologic malignancies. Whereas for some indications a survival advantage for HDT and ASCT has been demonstrated, a benefit only in terms of better progression-free survival has been shown for CLL. Because of this the quality of life (QoL) deserves particular attention. QoL assessment was a major focus of a randomized controlled EBMT-Intergroup trial on the value of HDT compared to observation in first or second remission of CLL.

Methods:

222 patients were enrolled into the study and allocated to either ASCT or observation. In the transplant arm, 72% received HDT and ASCT (for those median time from randomization to transplant was 3.01 months); in the observation arm 9% received ASCT. QoL was assessed with the EORTC QLQ C30 version 3.0, a questionnaire that has to be filled in by the patients. The answers to the questions yielded 15 scores, each on a scale from 0 to 100. The scores represent 15 domains: global health status/QoL, 5 functional scales (100 representing perfect health) and 9 symptom scales (0 representing no complaints). QoL forms had to be completed at randomization and at months 4, 8, 12, and 24. Data on 56%, 53%, 54%, 61%, and 50% of the baseline patients are available for the respective periods. Missing forms were not systematically related to baseline variables or relapse. The numbers of drop outs due to death at 2 years were 5 patients in the HDT arm and 4 patients in the control arm.

All QoL outcomes were analyzed with mixed models according to the intent to treat principle. Time (as factor), age, gender, treatment arm and the interaction of time and treatment arm were modelled as fixed effects, whereas individual random effects were added for the intercept.

Results:

Global health status/QoL at 4 months (estimated effect from the multivariate model -7.15, p=0.034) was significantly inferior in the transplant cohort compared to the control group. At 8 months the estimated effect of HDT on global health status/QoL was -3.06 (p=0.36). This difference further diminished over the first year (estimate at 1 year -0.53, p=0.87). QoL did not decrease independently from the treatment during the first 2 years. The same global pattern of change over time was observed for physical functioning, role functioning and social functioning; however, the treatment impact was still significant at 8 months for physical functioning (-6.58; p=0.025) and social functioning (-11.18; p=0.014). No significant covariate effects could be delineated for either of these scales apart from age having a beneficial effect on social functioning.

Conclusions:

Quality of life is affected multi-dimensionally in the first year after high-dose therapy and autologous stem cell support. The negative impact of HDT on QoL has disappeared after two years. Patients should be informed that HDT followed by ASCT impairs quality of life in the first year after transplantation.

The plain facts are that you cannot get improved survival from ASCT, but you do delay your next treatment at the cost of a worse quality of life for 4 months.

Persecution in Kashmir

2011-12-01T17:44:00.003Z

An Indian pastor who baptised converts from Islam was arrested and his church raided following a sharia court hearing.

Rev. Chander Mani Khanna was called by the Grand Mufti of Kashmir to a sharia court on 8 November to explain alleged forced conversions of young Muslims, after a video appeared on YouTube that shows the pastor baptising seven adult converts from Islam. He was accused of converting Muslims in exchange for money. Muslims responded angrily to the footage, threatening to burn Mr Khanna to death, kill all Christian missionaries and burn their buildings, schools and churches.

Amid concerns for the pastor’s safety following the sharia court hearing, the police initially asked him not to move from his home in Srinagar, saying that they were protecting him. But they then raided his church and arrested him on charges of fomenting communal strife. He was released on bail after spending ten days in police custody. The seven men and women who were baptised by Mr Khanna were also arrested and allegedly beaten by police in a bid to get them to testify against him.

Kashmir’s Grand Mufti, Mohammed Bashiruddin, warned that Mr Khanna’s activities “warrant action as per Islamic law” and will not be tolerated. He told the media. The seven men and women who were baptised by Mr Khanna were also arrested and allegedly beaten by police in a bid to get them to testify against him. Kashmir’s Grand Mufti, Mohammed Bashiruddin, warned that Mr Khanna’s activities “warrant action as per Islamic law” and will not be tolerated. He told the media: There will be serious consequences of this. We will implement our part and the government should implement its.

Following Mr Khanna’s arrest, Indian Christian leaders have questioned why the authorities are siding with the sharia court in a country with a secular constitution, which guarantees all citizens the “right freely to profess, practice and propagate [their] religion”. Sajan K George, president of the Global Council of Indian Christians (GCIC), said: Allowing a Sharia Court to enforce its laws on Christians represents an end to the rule of law and equality of Indian citizens.

While a number of Indian states have introduced “anti-conversion laws”, Jammu and Kashmir is not one of them. Mr Khanna was instead arrested under Articles 153A (Promoting enmity between different groups on ground of religion, race, place of birth, residence, language, etc., and doing acts prejudicial to maintenance of harmony) and 295A (Deliberate and malicious acts intended to outrage religious feelings of any class by insulting its religion or religious beliefs) of the Indian Penal Code.

Religious freedom in Kazakhstan

2011-12-01T17:35:00.002Z

Religious freedom is not something that most countries in the world subscribe to. In the UK religious freedom is subsidiary to supporting gay rights.

But things are far worse in the former Russian Republics.

A teenager was knocked unconscious by a policeman in a raid on a church meeting in Kazakhstan as the authorities continue their crackdown on religious freedom under strict new laws.

The 17-year-old girl was hit by the officer in a raid on a worship service by an officially registered Protestant church in Atyrau. The congregation was targeted because it was meeting away from its legal address, which is not allowed under the new Religion Law. They had been forced to gather at a hotel because the authorities had blocked them from using their regular venue. Since the new legislation came into force on 11 October, Baptist churches, which refuse to register with the authorities on principle, have reported increased harassment and pressure from officials, who interrupt their services and issue threats. Children who attend Baptist churches are being taunted by their classmates, who say that their churches will be closed down and their parents sent to prison, having apparently heard this on television and from some teachers.

In other developments, churches and mosques in the Almaty’s Turksib District have been instructed to report “on a daily basis” what measures they are taking to counter extremism, while regulations are being drawn up regarding the state censorship of almost all imported religious literature and objects. Only registered religious organisations may import “informational materials of religious content”, apart from small quantities for personal use, with prior approval from the Agency of Religious Affairs (ARA), which will conduct an “expert analysis” of each title. It will be an offence to import, produce or distribute any literature rejected by the ARA, punishable by fines and, if done by a registered organisation, a suspension of the organisation’s activity for three months.

Observers have highlighted the fact that such censorship directly violates Kazakhstan’s international human rights commitments. The new Religion Law also requires compulsory state registration of both foreigners and Kazakh citizens engaged in “missionary activity” and “spreading a faith”. ARA chairman Kairat Lama Sharif said that this was to prevent and counter “the destructive influence of several non-traditional religious organisations on the process of the spiritual/moral development of Kazakh society”.

The new legislation favours the country’s “traditional religions”, notably the Hanafi school of Islam and Russian Orthodox Christianity, leaving smaller Christian denominations and other religious minority groups concerned that their activities will be targeted and curtailed. The New Life Protestant Church in Almaty has already fallen victim to this. Five foreign guest speakers could not attend a conference the church organised following a ruling from the ARA just four days before the event. Officials have insisted that they did not ban the speakers, but the ARA wrote to the church recommending “refraining from inviting” them, leaving the church with no real alternative in the current climate.

The Kazakh authorities are speedily implementing the new laws; regulations are now being prepared that will govern other elements including the re-registration process, how and where places of worship can be built, and where religious books and materials are allowed to be sold.

Hindu threats to Christians in Nepal

2011-12-01T17:28:00.003Z

My home town of Aldershot has had a massive influx of Nepalese Ghurkas, which has embarrassed the town council in their ability to provide housing, education and medical services. In grateful recognition of this hospitality the Nepalese government has turned against Christians in Nepal.

An extremist Hindu group behind a bomb blast outside a Christian mission building in Nepal has demanded that the country become a Hindu state and all churches in the capital be closed within 50 days. An explosive device was detonated beside the offices of the United Mission to Nepal, an association of Christian and government organisations devoted to social justice and poverty alleviation, in Kathmandu on Tuesday 22 November. The building is situated in a residential area, but there were no casualties and minimal property damage. Another bomb found nearby was defused by a bomb disposal squad. Five days later, a bomb was discovered outside a Protestant church in central Kathmandu by the janitor; it was defused by security forces.

The Nepal Defence Army (NDA), an extremist Hindu group that wants to reinstate the country’s Hindu monarchy, claimed responsibility for the blast outside the United Mission. Pamphlets signed by the group reportedly demanding that Nepal should be a Hindu state, that all churches in Kathmandu should be closed within 50 days and that all missionary organisations should leave Nepal, were found by the police.

The NDA bombed a church in Lalitpur, south of Kathmandu, in May 2009. Three people were killed and more than a dozen injured in that attack, which happened on the eve of national elections for a new prime minister. The group has also been behind the murder of a church pastor and other attacks against Christians, who are feeling increasingly under threat in Nepal. They are concerned about proposed new legislation that would outlaw converting from one religion to another or inciting someone else to do so. Offenders could face up to five years in prison.

Christian leaders fear that the witness of the Church in Nepal will be seriously threatened if the government proceeds with the legislation. It would be a retrograde step for religious freedom in Nepal, overturning the provisions of the 2007 interim constitution, which guarantees freedom of religion and expression to all groups. In a worrying indication of the growing climate of hostility over religious conversions, especially to Christianity, two people were beaten and forcibly evicted from their village in Sindupalcowk on 22 November because they had become Christians.

How exactly do American doctors treat CLL?

2011-12-01T16:18:00.002Z

Back to the ASH abstracts. This is one that tries to work out what is actually hapenning in America with the treament of CLL.

2864 Patterns of Care for Patients with Chronic Lymphocytic Leukemia (CLL): The Connect® CLL Disease Registry Jeff Sharman, Christopher R Flowers, Mark Weiss, David Grinblatt, Charles Farber, Neil Kay, Thomas Kipps, Nicole Lamanna, Chris Pashos, Ian W Flinn, Mark Kozloff, Susan Lerner, Arlene Swern, Kristen A Sullivan, Thomas K. Street, and Michael Keating.

Introduction:

Clinical trials have illuminated a number of unique treatment strategies for patients with CLL. The impact of these strategies on routine practice remains unknown as trial participants may not reflect the same population encountered outside of a clinical trial setting. Many questions remain regarding the sequencing of therapies based on age and performance status. By characterizing current patterns of care; patients, treating physicians, and regulatory agencies will be able to understand the current landscape of CLL treatment. The Connect® CLL registry was designed to report the natural history and real world management of patients receiving therapy for CLL. In this first report, we characterize the therapeutic approaches used for the treatment of patients with CLL of different age groups (i.e. < 65 years, 65–75 years, and ≥ 75 years) and with an ECOG PS status score of 0 compared to 1 or greater.

Methods:

Connect® CLL is a prospective, longitudinal, observational, multi-center registry conducted in community and academic research centers in the United States. At present, 237 sites are actively participating with a projected study enrollment of 1500 patients. Eligible patients are to be enrolled within 2 months of being initiated on any line of therapy; whether initial therapy or salvage therapy. Each patient will be followed for up to 60 months. Clinical data, physician choices, patient-reported health-related quality of life, response and survival are to be collected approximately every 3 months during participation.

Results:

A total of 607 patients have been enrolled (4% from academic sites) with a median age of 70 years. 198 were < 65 years old (age group 1), 187 were between 65–75 years old (age group 2), and 222 were ≥ 75 years old (age group 3). ECOG status varied across the three age groups, with an ECOG status score of ≥ 1 for 39%, 52%, and 70% of patients respectively. Treatment patterns varied across the age groups and by ECOG status in the 496 patients reporting therapies. The most commonly recorded first-line regimens independent of age included fludarabine (F) cyclophosphamide (C) and rituximab (R) (33%), bendamustine (B) +/- R (19%), F +/- R (15%), or investigational therapy (15%). For second-line regimens and beyond, the most frequently recorded regimen was B +/- R (30%), FCR (23%), other F-based regimens (13%), or investigational therapy (8%).

Note that nearly three quarters of patients over-75 had a poor ECOG score. This is why you can't translate clinical trials results to how to treat most cases of CLL. The average age of diagnosis in CLL is at least 70 and the age thay theu need treatment for the first time is even older.

The use of FCR for first-line treatment decreased significantly with increasing age group, (45%, 32%, 20%, for age group 1, 2, 3 respectively, p=0.04, spearman correlation) while use of F +/- R remained level across the age groups (14%, 15%, 15%, respectively). Compared to age group 1, first-line therapy with B +/- R in age groups 2 and 3 (15%, 22%, 21%, respectively) was higher but did not achieve statistical significance. B +/- R represented the most common treatment for all age groups (37%, 26%, 29%, respectively) as second line therapy but did not vary by age (P=0.35). The use of chlorambucil was infrequent in all age groups, but was more common in age group 3 patients compared to the others (P=0.01), in both first-line (2%, 4%, 12%, respectively) and subsequent lines of therapy (0%, 1%, 8%, respectively).

Note: only 35% of the over-75s even had fludarabine, let alone FCR. Mind you this would have included many mutated patients who would never need any treatment.

Treatment assignments did not vary by ECOG PS score for patients in age group 1. First-line therapy for patients with an ECOG PS score of 0 in age groups 2 and 3 consisted of FCR (32% and 15%, respectively), F +/- R (19% and 15%, respectively), B +/- R (16% and 15%, respectively), and alkylating agents (3% and 23%, respectively). Patients in age groups 2 and 3 with ECOG PS score ≥ 1 received B +/- R regimen (33% and 22%, respectively), FCR (23% and 21%, respectively), F +/- R (14% and 10%, respectively) and alkylating agents (7% and 9%, respectively) as first-line therapy. Further description and clarification on the various treatment regimens based on the three age groups and by ECOG PS score will be presented at the meeting.

Note: B +/- R does not have any validation by clinical trials in this situation. It is toxic, but I am willing to believe that there is another mechanism by which it has an advantage second line.

Conclusion:

The Connect® CLL Registry is the largest prospective, multicenter registry in the United States evaluating management for patients with CLL. With the currently available data, we characterize the extent to which age and performance status are associated with treatment selection in both first-line and subsequent lines of therapy in routine practice. As enrollment increases and additional follow-up is completed, the data will provide more extensive and real world overview of the current treatment strategies used in CLL patients.

This study is obviously funded by Celgene. I wonder what their ulterior motive is in doing so.

Yesterday's strikes

2011-12-01T13:20:00.002Z

Withe the Help of David Aaronovitch of the Times:

Yesterday’s strikes were, in historical terms, a pinprick. The co-ordinated day of action was a huge organisational feat by Britain’s relatively weak trades unions and is not easily repeated. Yet, although a pain to many parents and a worry to patients and relatives, it will be largely forgotten by next week. Then will come the issue of what to do next. Does any public sector union imagine that it can successfully get its membership out on proper strike action — you know, where you go on strike indefinitely until your demands are met or moved towards? David Cameron called them a "damp squib" as part of the propaganda war. True 58% of schools were closed and a further 13% had teachers off, and 7-8000 elective procedures in hospitals were postponed, but the expected chaos at ferry and airports did not materialise and many said that ingress and egress was easier than normal.

A group of pickets stood outside the North London comprehensive that educated both the Miliband brothers. Arranging their placards in the bright, cold breakfast-time air, the strikers were young, clean and happy. The impression they gave was of having fun and of being sure that what they were doing was right. The strikers were the optimists yesterday. People don’t usually take this kind of action out of despair, but out of a belief that somehow things can be made better (at least for them) and that their activities will help things along. Perhaps many of those on the picket lines had lodged somewhere in their psyches a personal version of a Plan B, in which a government started making a different series of decisions and, bingo, good replaced bad.

The image was comforting. You knew where you were with it. In the same way that yesterday’s Prime Minister’s Questions suddenly reverted to the archetypical PMQs of the 1980s and MPs settled down into ancient trenches, dug and furnished by previous more certain generations. Ed Miliband had become a creature of the unions, “irresponsible, left-wing and weak”, according to the PM to hear-hears so loud and contented it seemed they had been pent up for years.

Ed then released the atavistic instincts of his own side with accusations that the Etonians were “demonising the dinner lady, the cleaner and the nurse”. Some of whom, he said, earned in a week what the Chancellor spent on a ski-ing holiday. I doubt they do earn that much, but here was a Labour leader, a Labour leader, who would never do anything so bourgeois as ski.

Why were things so grim? Labour’s fault for spending too much? The coalition’s for not spending enough? The unions? The bankers? Nothing so easily dealt with. The deficit reduction plan, which had banked on private sector growth, was stalled because of oil prices, food prices and the crisis in the eurozone and America. This left us facing the fact that, as I heard the Chancellor say yesterday, “Britain is poorer than it used to be”. And worse than this, even these gloomy assumptions were based on Angela Merkel — who does not rely on many votes in Britain — taking action that she seems disinclined to take.

This means that, whatever is said in Parliament and by union leaders, in general we must expect to be less well off for a while. This notwithstanding the galling spectacle of a very small number of business people who have insulated themselves very effectively against any pain-sharing. An irony here is that this reduction in expectation is just what the Greens have been advocating for years, yet you could find their one MP yesterday supporting action to protect the value of public sector workers’ pensions and pay. Well, a predictable irony.

Aaronovitch reports: "Then, by a series of accidents in early adulthood I found myself more struck against than striking. When staff at the National Union of Students went on strike, all of us Commie and left Labourite reps were to be discovered crossing a picket line and being called scabs by people earning several times as much as we did. There — and later at the BBC — I quickly became aware of some of the cynical theatricality of these occasions. Unions can be ruthless with the truth if it suits them. And employers can be bastards.

Some strikers may fantasise about it after the cheerfulness and colour of yesterday’s actions, but I cannot see it. You don’t put your livelihood and that of your family on the line unless you have a plan you can believe in — and it becomes ever more apparent that there just isn’t one. Which is one reason why the Occupy movement is a relative success in publicity and longevity — exactly because its remedies are so nebulous that you don’t have to imagine them being implemented. Whereas the TUC is extremely unlikely to adopt the slogan “A union is its own demand”. You don’t pay your weekly dues for optimism as airy as that. So if you ask me how bad things are, my reply is that they are so bad that there won’t be many more strikes, but there may be lots of tents."

More troubles

2011-12-01T10:21:00.003Z

I had another fall this morning. I slipped while coming downstairs and twisted the knee I injured 50 years ago. I have a longstanding anterior cruciate tear that was never repaired (there was no operation then) that has left my left knee unstable. For a while I was in great pain, but my wife came and laid hands on my knee and after a bit of massage all the pain was gone. I didn't realise she had that skill. Or perhaps it was a miracle.

We were let down by Currys who delivered the new dishwasher but the fitter was unable to fit it. "More than my jobsworth" he said. I suppose he could have plugged an electric plug into a socket, but the dishwasher was hard-wired into the wall. They were evening threatening to take the old one away. Happily, our friend Bob was visiting us and he was able to disconnect the old machine and allow them to remove it. A private fitter will call in to connect it this evening.

Still waiting for the monoclonal antibody; I am now expecting a positive result by lunchtime.

John 8:23-24. Only believe

2011-12-01T10:13:00.001Z

But he continued, “You are from below; I am from above. You are of this world; I am not of this world. I told you that you would die in your sins; if you do not believe that I am he, you will indeed die in your sins.”

Three more "I AMs" The demand that God makes on us is not a Herculean cleansing of the stables, but to believe. Unbelief is the unforgivable sin.

Another benefits cheat

2011-12-01T10:05:00.003Z

A drummer in a marching band who claimed he could walk no more than 15 yards and couldn’t even tie his own shoelaces has been exposed as a benefits cheat, after investigators secretly filmed him marching through the streets. Alexander Clarkson was caught marching through Great Harwood in Lancashire in full Scottish pipe band regalia and kilt. At the same time, the 63-year-old was receiving thousands of pounds every year by claiming he could walk only short distances and was always falling over because of his disabilities.

Clarkson, from Blackpool Lancs, admitted cheating the Department of Work and Pensions (DWP) out of £17,329 over a six-year period by failing to tell them his disabilities had improved. District judge Jeff Brailsford at Blackpool Magistrates’ Court handed Clarkson a 56-day jail term, suspended for a year. He was told the former soldier turned bricklayer had not worked for 33 years.

Prosecutor Michael Woosnam told how Clarkson lived a double life. On one hand he said he needed crutches to get about and could not travel anywhere alone. As well as a disabled living allowance Clarkson also claimed carer's allowance because he needed help cooking meals. But at the same time he was a dedicated member of the City of Preston Scottish Pipe and Drum band and a member of the Blackpool Male Voice Choir. The court heard that the DWP were tipped off about Clarksons's cheating and sent a surveillance team to follow him. They filmed him at a Remembrance Day ceremony in the Lancashire town of Great Harwood where he was lead drummer marching the streets for 30 minutes. When he was confronted about his actions Clarkson said that he had been mistaken for someone else who had borrowed his car for the day.

The following day he was followed walking to a funeral and then attending the wake that followed. Mr Woosnam said: ‘In interview Clarkson said he had continued to claim benefits because he quite simply did not want to lose the money. He also said he had applied to have the carer's element of his claim upgraded.’

Peter Manning, defending, said that Clarkson did have arthritic knees, asthma and diabetes and had recently had an operation on his groin. ‘My client accepts he should have informed the department about his improved mobility.’ Sentencing Clarkson, the judge said: ‘It is clear from the film I have seen, you got pleasure from being in the band. You clearly marched and bent down to pick up your drum. There seemed to be no hindrance to your mobility. ‘And when you were questioned about it you denied it was you. ‘You have been living a comfortable lifestyle as a result of your benefits allowing you to pay £100 a month TV subscriptions and £80 a month on drink and £120 a month on travel.’

Benefits culture

2011-12-01T09:50:00.002Z

What benefits frauds do with their ill-gotten gains:

For the past decade, the Whitney family have been spoken of in hushed tones on the backstreets of Anfield, just a stone’s throw from Liverpool Football Club. Drug addicts turned to them when they needed their next hit of heroin or crack cocaine. Those unfortunate enough to live in the same street as the family’s semi may have whispered about the carrier bags of cash exchanging hands on the Whitneys’ doorstep, but they turned a blind eye for fear of reprisals.Seven members of the clan were jailed last week at Liverpool Crown Court, making them one of Britain’s most shameless — and dangerous — families.

The Whitneys made hundreds of thousands of pounds from what police have described as a ‘24-hour drugs cash and carry service’. They were caught after one of Merseyside police’s largest surveillance operations. During the 18 months officers followed the family, they saw an accomplice throw 2kg of heroin, with a street value of £120,000, from the window of a speeding Mercedes in a bid to avoid being caught with it.

The Whitneys’ arrogant police mugshots make a gruesome mockery of the traditional family photograph. At the head of the clan is Leslie Whitney, a 57-year-old former factory worker known as the Godfather. His estranged wife Carol, 54, was nicknamed the Banker by police officers, who discovered thousands of pounds in cash hidden at her home, as well as cocaine and 12 kg of uncut heroin. The couple’s three children, Paul, 33, Lisa, 31, and Anthony, 30, were found guilty of conspiracy to supply Class A drugs, along with Lisa’s boyfriend Wayne Hincks and Leslie’s girlfriend, Emma Mackenzie, 29. Emma’s mother Mary McCabe was also part of the gang. When police searched her car, they found a stolen SA80 assault rifle, stolen from an Army base, and 1,200 rounds of ammunition.

But for the Whitneys’ innocent relatives, many of whom live in Liverpool, the past week has been filled with shame and humiliation. They are struggling to come to terms with how this once typically hard-working family deteriorated into a feared drugs gang. ‘They’ve brought shame on the family,’ says one relative, who asked not to be named.

Iran: is this a prelude to war?

2011-11-30T17:15:00.004Z

A few straws in the wind in Iran.

I have been keeping a weather eye on what has been happening in Iran over November. Of course the longstanding issue is over what has been going on with the development of nuclear power in that country. While Iran claims that they are developing a nuclear option to provide power and medical supplies, the US is pretty sure that they are developing a bomb. Why should we believe otherwise? It's a strange fact that people tell lies and there are always some gullible people who believe them.

Here is the gist of a speech that even Obama gave a couple of weeks ago:

Barack Obama to consider all options to stop Iran getting nuclear weapons

US president Barack Obama has said economic sanctions against Iran to contain Tehran's nuclear ambitions have "enormous bite," and he will consult with other nations on additional steps to ensure that Iran does not acquire an atomic weapon.

14th November 2011:

Mr Obama expressed confidence that Russia and China in particular understand the threat of a nuclear armed Iran would pose and said their leaders agree that Iran cannot develop nuclear weapons and trigger a nuclear arms race in the region.

The president, answering questions at a press conference during an Asia-Pacific economic summit, did not specifically say he would consider military action if Tehran were to persist in arming itself with a nuclear weapon. But he added: "We are not taking any options off the table. Iran with nuclear weapons would pose a threat not only to the region but also to the United States."

A report on Friday from the International Atomic Energy Agency provided new evidence that Iran's nuclear program includes clandestine efforts to build a bomb. The report, circulated among the UN watchdog agency's member countries, includes satellite images, letters, diagrams and other documents. It alleges Iran has been working to acquire equipment and weapons design information, testing high explosives and detonators and developing compute models of a warhead's core. Taken together, it's the most unequivocal evidence yet that the Iranian program ranges far beyond enriching uranium for use in energy and medical research, which is what Tehran says it's for.

In meetings on Saturday with Russian President Dmitry Medvedev nor Chinese President Hu Jintao, Mr Obama sought to rally support for putting new pressure on Iran's regime. But there was little public sign either country was ready to drop its opposition to additional sanctions. Four rounds of UN sanctions have caused economic hardship in Iran, but have yet to force any change in the nuclear program.

Remember back to Suez in 1956? At this time Britain, France and Israel entered into a conspiracy to stop Col Nasser from nationalizing the Suez Canal. They were stymied by the US using its financial muscle to threaten to paralyze the markets in London and threaten the British economy. Now with international markets especially in the Eurozone so vulnerable it is possible that the freedom to act politically by the West would be compromised. So I was heartened to read this in the afternoon editions today:

The Bank of England, together with the Federal Reserve, the European Central Bank, the Bank of Japan, the Swiss National Bank and the Bank of Canada, today announced co-ordinated action to enhance their capacity to provide liquidity support to the global financial system. In a dramatic move welcomed warmly by the markets the banks said that their actions aimed to ease strains in financial markets and alleviate the effects of such strains on the supply of credit to households and businesses and thus boost economic activity.

A couple of days ago this was in the news:

Mystery explosion rocks Iran city

A large explosion has been reported in the Iranian city of Isfahan as the regime issued conflicting reports apparently designed to deny any suggestions of a sabotage attack on its nuclear facilities. Officials gave varying accounts of a "huge explosion" in the ancient city, which hosts one of Iran's main facilities for refining uranium in its nuclear programme. While some sources told news agencies there had been a blast on military facilities, others said there had been a fireball at a petrol station. Residents of the city were independently telling relatives and friends overseas that the city had been shaken by a massive blast in the early afternoon.

The reports immediately prompted speculation that Iran had suffered another sabotage attack, just two weeks after a blast at a missile base gave rise to similar suspicions. Isfahan is home to Iran's largest facility for research and development of ballistic missiles. Multiple reports said the blast did not emanate from the nuclear facility.

Then yesterday we had this:

Iranian hardliners storm British Embassy in Tehran.

Two British Embassy compounds were stormed mid-afternoon on Tuesday during a demonstration in the street outside the main building in downtown Tehran, smashing windows, torching a car and burning the British flag in protest against new sanctions imposed by London.

Protesters also broke into the residential compound at Qolhak in north Tehran, a sprawling, wooded property which used to be the embassy's summer quarters. The scenes at the British embassy in Tehran inevitably conjured up memories of the hostage crisis at the nearby US mission that erupted in 1979, during Iran’s Islamist revolution. Then, as now, the mob that stormed the building was led by militant youngsters - but there the similarity ends. The students behind the assault on the US embassy held 52 American nationals hostage for 444 days, with the connivance of the regime.

Privately, Iranian diplomats were disturbed and confused by the scenes in the British embassy. At a time when London has dealt a severe blow to Iran's economy by severing the country's ties with the UK financial system, they hoped to stress the suffering this decision would inflict on ordinary Iranians. Instead, their embassy in London has been shut down and the latest deterioration in diplomatic relations will dominate the agenda.

All this undoubtedly reflects deep divisions within Iran's regime. The two men at the pinnacle of the country's opaque power structure, President Mahmoud Ahmadinejad and Ayatollah Ali Khamenei, the supreme leader, have become bitter rivals. Beneath them, factional struggles have taken over the government, complicated by the approach of presidential elections in 2013. In simple terms, the supreme leader's allies have supported the mob who stormed the embassy; the president's friends have voiced their disquiet. In the shifting sands of Iranian politics, Mr Ahmadinejad appears to be the unlikely voice of moderation in this particular dispute.

From the British Foreign Secretary, William Hague:

The Iranian Chargé in London is being informed now that we require the immediate closure of the Iranian Embassy in London and that all Iranian diplomatic staff must leave the United Kingdom within the next 48 hours.

If any country makes it impossible for us to operate on their soil they cannot expect to have a functioning Embassy here.

This does not amount to the severing of diplomatic relations in their entirety. It is action that reduces our relations with Iran to the lowest level consistent with the maintenance of diplomatic relations.

The House will understand that it remains desirable for British representatives to be in contact with Iranian representatives, for instance as part of any negotiations about their nuclear programme or to discuss human rights. But it does mean that both Embassies will be closed.

We wish to make absolutely clear to Iran and to any other nation that such action against our Embassies and such a flagrant breach of international responsibilities is totally unacceptable to the United Kingdom.

There was a certain inevitability about the British government's decision shut down the Iranian Embassy in London. Now that the British mission in Tehran finds it impossible to function and all of its staff have been withdrawn, it would have been impossible to allow Iranian diplomats to carry on as normal over here.

But the nuances of all this are important. William Hague was at pains to point out that Britain is not breaking off all diplomatic relations with Iran. Instead, bilateral ties are being reduced to the bare minimum, but not severed altogether. This is designed to give the Iranians a bridge back to respectability.

Britain will support an embargo on Iranian oil imports following the deterioration of relations between the two countries, a diplomatic source told Reuters on Wednesday, in an apparent reversal of its former position.

"Now that the UK has downgraded diplomatic relations with Iran, it will support increased sanctions...and would likely go ahead with those sanctions unilaterally or with France and Germany," said a diplomatic source, referring to the ban on Iranian crude oil imports.

Italy will also discuss with its European allies and the US the option of an oil embargo against Iran. Italy is also considering closing its embassy in Tehran, Reuters reports. In light of yesterday's events in Tehran, Foreign Minister Guido Westerwelle decided that the German ambassador in Iran should be recalled to Berlin for consultations.

All UK based staff have now left Tehran, Hague announces.

French president, Nicolas Sarkozy, is the latest world leader to condemn the attacks. During a cabinet session, "the president firmly condemned the scandalous attack on the embassy of Great Britain" in the Iranian capital, the French government spokeswoman said. Mr Sarkozy said the attacks "confirmed" the decision to impose new sanctions on Iran, the spokeswoman, Budget Minister Valerie Pecresse, told journalists. UN Security Council President Jose Filipe Moraes Cabral condemns the attacks. Norway said it had temporarily closed its embassy but its diplomats continued to work from elsewhere in Tehran

Will this spread beyond Iran? In this little noticed report I notice that Khamenei has been speaking in Saudi Arabia, supposedly bitterly opposed to Iran:

Iran – Supreme leader calls for "Islamic power-bloc"

In a message to more than 2.5 million Hajj pilgrims in Saudi Arabia on 5 November, Iran’s supreme leader called on the world’s Muslim-majority nations to form an “international Islamic power-bloc”, laying down an ominous challenge to Western powers. Ayatollah Seyyed Ali Khamenei said that Islamic countries should “make the most of [the] opportunity” created by the Arab Spring, as well as the anti-capitalist movement across the world.

According to the Ayatollah, Islam has become the guiding principle of the Arab uprisings despite the efforts of secular rulers to curtail the influence of religion in their countries. Pointing to the victory of the Islamist Ennahda Party in Tunisia’s recent elections, he predicted similar outcomes elsewhere, saying, “Without doubt, free elections in any Islamic country will hardly result in anything except what happened in Tunisia.”

Heralding a global power shift and issuing an ominous challenge to Western powers, the Ayatollah said that “the West, the United States and Zionism are weaker than ever before”. He urged the entire umma (Islamic nation) and especially the revolutionary nations to continue to be vigilant “against the plots of arrogant international powers”.

The Hajj is a strange thing. Muslims should be committed to visit Mecca once in their lifetimes. I know many Muslims for whom this is a holy and life-changing experience, but many Muslims leave it very late in their lives and actually die on the visit. Charter airlines arrange cheap flights with poor conditions and there is an 8 mile walk at the other end in searing heat. Although there are rickshaws to carry them for this journey many demur and insist on walking. Those who die are often propped upright in their airplane seat and leak body fluids on the way home to European destinations. For the other passengers it is not a pleasant experience.

The kinetics of MRD

2011-11-30T14:10:00.003Z

The German CLL8 trial has been the most important study in CLL thus far reported. But there are a lot of scientific data that derive from this trial that are yetto be reported. The value of minimal residual disease measurements is an important investigation that will be reported at ASH. Here is the German abstract:

1777 Minimal Residual Disease (MRD) Re-Growth Kinetics Are An Independent Predictor for Progression Free Survival (PFS) in Chronic Lymphocytic Leukemia (CLL) and Are Related to Biologically Defined CLL-Subgroups – Results From the CLL8 Trial of the German CLL Study Group (GCLLSG) Sebastian Boettcher, Matthias Ritgen, Kirsten Fischer,, Stephan Stilgenbauer, Raymonde Busch, Gunter R. Fingerle-Rowson, Anna-Maria Fink, Andreas Buehler, Dirk Winkler, Michael K. Wenger, Myriam Mendila, Clemens Wendtner, Barbara Eichhorst, Hartmut Döhner, Michael Hallek, and Michael Kneba.

MRD single time point assessments during therapy and at the end of treatment have been identified as independent predictors of PFS and overall survival in CLL patients (pts) by our group and others. However, it is currently unknown whether MRD kinetics during follow-up (FU) also have prognostic significance and whether kinetics show associations with CLL risk features. We therefore investigated MRD during treatment-free FU within the CLL8 trial of the GCLLSG.

MRD kinetics were analyzed in 256 pts who had not progressed 1 year after completion of therapy and for whom at least 2 peripheral blood MRD assessments during the subsequent year were available. The slope of the common logarithm of MRD / time was calculated for 193 patients with at least 2 positive MRD measurements. Median MRD increase was 6.3fold during the observation period for the whole group (i.e. 0.80 log MRD unit increase / year). We compared groups of pts who (1) were always MRD negative (25% of all 256 pts), (2) had measurable disease with a slope below median (slow re-growth, 37% of pts), and (3) had measurable disease with a slope above median (fast re-growth, 39 %).

The medians of the first measurable MRD levels during observation did not differ significantly between groups 2 (4.3 x 10-3) and 3 (1.7 x 10-3, p=.16). Pts with faster MRD re-growth kinetics (group 3) experienced a shorter median PFS (40 months) than pts with slower re-growth (group 2, 66 months), whereas median PFS has not been reached in pts who were always MRD negative (group 1, log-rank p= 3 x 10-14). Compared to group 1, group 2 and 3 pts carried increasingly higher risks of progression (HR 3.1 and 7.7, resp.). Pts showing a slow re-growth pattern (group 2) had a 2.5fold lower risk of clinical progression than pts with a greater MRD slope (group 3, p=5 x 10-6).

The prognostic significance of MRD kinetics for PFS was also tested in Cox regression analysis together with clinical response, deletion 17p, IGHV mutational status, number of treatment cycles, treatment arm, thymidine kinase, beta2-microglobulin, pre-therapeutic WBC and MRD levels 1 year after completion of therapy. MRD kinetics (p=4x10-9), MRD levels (7x10-14), cycle number (8x10-5) and IGHV mutational status (1x10-3) remained independently significant for PFS in this multivariate analysis.

We next correlated MRD slopes during the second year of FU and prognostic features in 204 pts (groups 2 and 3 plus 11 pts with early clinical relapse but measurable MRD slope during second FU year). Pts who required treatment within 2 years from diagnosis experienced a faster re-growth after therapy (.92/a) than pts with a longer treatment-free interval (.68, p=.04). The slope was significantly lower in pts with Binet A disease prior to therapy (.43/a) than in Binet B (.77/a, p =.03) and Binet C (.88/a, p=.02) pts. Pts carrying a chromosomal deletion (del) 13q as single abnormality had a significantly slower MRD re-growth pattern (.58/a) than those with del(11q) (1.0/a, p=.0004) or without cytogenetic abnormalities (1.1/a, p=.001), while the difference to pts with 12q+ (.71/a) was not significant. Pts with a mutated IGHV gene progressed slower (.54/a) than those with unmutated IGHV (.96/a, p=.0002). A thymidine kinase of at least 10 U/L was associated with a steeper MRD slope (.82/a) than lower levels (.61/a, p=.03). MRD slopes were not significantly associated with gender, WBC prior to therapy, beta2-microglobuline levels, presence of B-symptoms, or treatment arm.

We demonstrate for the first time the independent prognostic significance of MRD kinetics during FU in CLL. MRD kinetics improve the prediction of PFS even when single time point MRD assessments during FU and other major risk features in CLL are additionally considered. MRD kinetics classify known CLL risk factors into two groups. IGHV, cytogenetics, thymidine kinase, stage, and time to treatment distinguish CLL subgroups with different re-growth kinetics, likely characterizing the relationship of proliferation to spontaneous apoptosis of the CLL clone itself. Other risk features did not show an association with kinetics in spite of proven significance in the CLL8 trial. Those features likely identify differences in responsiveness to therapy. We hypothesize that maintenance strategies will chance the course of the disease most effectively in patients who are responsive to therapy but relapse early due to fast CLL re-growth.

What this paper is saying is that the prognostic factors already identified determine how rapidly MRD relapses. MRD negativity is not a cure; it just lowers the bulk of disease to a greater amount and from here the disease starts reaccumulating at the same rate as it had been before. There is no 'immune reaction' that wipes out tiny bits of CLL.

Maintenance R after FMCR

2011-11-30T13:41:00.003Z

Another topic that has been insufficiently addressed is the whole question of maintenance rituximab. This Spanish abstract deals with the question after the use of FMCR which is a particularly intensive, but effective induction regime.

293 Rituximab Maintenance In Patients with Chronic Lymphocytic Leukemia (CLL) After Upfront Treatment with Rituximab Plus Fludarabine, Cyclophosphamide, and Mitoxantrone (R-FCM): Final Results of a Multicenter Phase II Trial On Behalf of the Spanish CLL Study Group (GELLC)Francesc Bosch, Pau Abrisqueta, Neus Villamor, María José Terol, Eva González-Barca, Marcos González, Christelle Ferrà, Eugenia Abella, Julio Delgado, Jose A. Garcia-Marco, Yolanda Gonzalez11, Felix Carbonell, Secundino Ferrer1, Encarna Monzo, Isidro Jarque, Ana Muntanola, Mireia Constants, Lourdes Escoda and Emili Montserrat.

The effectiveness of rituximab, fludarabine, cyclophosphamide, and mitoxantrone (R-FCM) followed by rituximab maintenance in the treatment of CLL has been investigated in a phase II clinical trial that includes two treatment parts. First, patients were given induction therapy with R-FCM up to 6 cycles, achieving an overall response (OR) rate of 93% and a CR rate of 82% (46% MRD-negative CR).

Note: this is the maintenance part of their study. The induction part of the study was published in 2009 in JCO (JCO gets the clinical parts; Blood the scientific parts of studies, but JCO tends to have a bigger Impact Factor)

Patients achieving CR or PR with the initial part of the treatment received rituximab maintenance. Here we present the final results of the treatment maintenance part, initiated three months after concluding R-FCM, and consisting of rituximab 375 mg/m2 every three months for two years (up to 8 cycles). Sixty-four patients (median age 60 years, 70% male) receiving > 4 cycles of maintenance therapy were evaluated for response, including bone marrow (BM) examination and MRD assessment by four-color flow cytometry of peripheral blood and BM. Patients in whom rituximab maintenance was prematurely interrupted (≤ 4 cycles) due to toxicity were considered as failures.

Note: the lymphoma dose of rituximab rather than the CLL dose was used.

Median number of cycles of maintenance administered was 8 (range, 1 to 8) and 76% of patients completed the entire planned treatment. Treatment was delayed due to insufficient hematological recovery in 9 cycles (2%) and to non-hematological toxicity in 4 cycles (0.8%). Neutropenia was observed in 31.3% of cycles (grade 3&4 in 8.5%), thrombocytopenia in 4.6%, and anemia in 1.2%.

Note: presumably because of toxicity, it was not possible to administer the planned dose of maintenance treatment.

At the end of the maintenance therapy, 45% of patients had low IgA serum levels, 37% low IgG, and 66% low IgM. Sixteen patients experienced grade 3&4 infectious episodes, including 9 pneumonia, 2 febrile neutropenia, 1 appendicitis, 1 myositis, 1 herpes zoster, and 1 cerebral abscess. Two patients died, one due to multifocal leukoencephalopathy and the other due to hemophagocytic syndrome. Infectious episodes grade 3&4 were observed in 19.5% of cycles with neutropenia 3&4, but in only 3% of cycles with neutropenia inferior to grade 3 (p=0.001). In contrast, no relationship was observed between infectious events and the presence of low levels of immunoglobulins or diminished CD4+ T lymphocyte counts.

Note: an extra toxicity from maintenance rituximab will be hypogammaglobulinaemia but in this case they weren't able statistically to link infectious complications to the rituximab. However, I sould be very worried about about the cerebral abscess and the two patients who died, one due to multifocal leukoencephalopathy and the other due to hemophagocytic syndrome. These are not usual post-chemotherapy complications.

After rituximab maintenance, 40.6% of patients were in MRD-negative CR, 40.6% in CR, 7.9% in PR, and 10.9% failed to treatment. Failures were due to disease progression (two patients), severe neutropenia (three patients), infectious toxicity (one patient) and death (one patient). Among 35 patients in MRD-negative CR after R-FCM induction, 22 maintained the MRD-negative status at the end of maintenance treatment, 9 (25.7%) switched from MRD-negative to MRD-positive, and 4 failed to treatment. Median time to conversion from negative to positive MRD was 45.4 months, significantly longer than that observed in patients treated with FCM only (45.4 vs. 16.4 months; p=0.011) (Bosch et al. Clin Can Res 14:155-161,2008). Moreover, among 21 patients that achieved MRD-positive CR with the initial R-FCM treatment, 2 (9.5%) became MRD-negative upon rituximab maintenance, 17(81%) continued in MRD-positive CR, 2 achieved PR, and 2 failed to maintenance therapy. Among the 8 patients in PR, 4 patients achieved CR (2 MRD-negative and 2 MRD-positive), 3 patients continued in PR, and one patient progressed. Three-year progression-free survival was 94% (95% CI 88-100%). Compared to the FCM series, maintenance with rituximab significantly prolonged the time to next treatment in patients that after the initial treatment with R-FCM were in MRD-positive CR (44.1 vs. 54.5 months, p=0.049) or PR (6.5 vs. 54.4 months, p=0.001).

Note: so it is not the whole answer. We await overall survival rates in a randomized phase 3.

In conclusion, treatment maintenance with rituximab after R-FCM in patients with CLL is feasible and might improve patients' outcome, particularly those who do not attain a MRD-negative CR after the initial, upfront therapy. However, its toxicity is not negligible. Further, ongoing studies should help to clarify the role of maintenance therapy with rituximab in the management of patients with CLL.

Moorlands College

2011-11-30T12:43:00.003Z

Moorlands College is one of the Charities that I support. My former Pastor, Steve Brady, whose book I recently reviewed, is the Principle there. It is an Evangelical Bible College administered under the University of Cheltenham and Gloucester.

My son-in-law, Tim Johnson, is an air-traffic controller. He may one day become a lecturer at the College of Air Traffic Control. I have just had this press release from Moorlands:

Moorlands is very grateful to the Bournemouth College of Air Traffic Control for the donation of furniture made this month. God’s timing is always perfect and as we continue to grow and develop as a College there are various needs that arise. The need for furniture is always high as we have new staff, more students and more advanced technology. So when the nearby College of Air Traffic Control closed down to move to a different site, the offer came to Moorlands to inherit some of their furniture.

We are so grateful to them for thinking of us and we look forward to putting some of their teaching equipment, desks and filing cabinets to good use. So a massive thank you goes to Bournemouth College of Air Traffic Control, to Paul Craddock for making this possible and of course to God for His continued provision for us!

CHOP-R in refractory patients

2011-11-30T11:56:00.002Z

Chris was kind enough to publish a link to the ASH abstracts for this year and I have just started looking at them. The first one from the German group tickles all the boxes that I have been concerned about:

2860 Cyclophosphamide, Adriamycin, Vincristine and Prednisone Plus Rituximab (CHOP-R) in Fludarabine (F) Refractory Chronic Lymphocytic Leukemia (CLL) or CLL with Autoimmune Cytopenia (AIC) or Richter’s Transformation (RT): Final Analysis of a Phase II Study of the German CLL Study Group Petra Jenke1, Barbara Eichhorst, Raymonde Busch, Nadine Anheier, Ulrich Duehrsen, Jan Duerig, Martin H. Dreyling, Manuela Bergmann, Maria Elisabeth Goebeler, Hans Juergen Hurtz, Martina Beate Stauch, Stephan Stilgenbauer, Hartmut Doehner, Prof. Dr. med., Anna-Maria Fink, Kirsten Fischer, Clemens-Martin Wendtner, and Michael Hallek,

Introduction: In the last decade, important progress has been achieved in the treatment of CLL through the use of purine analog-based chemoimmunotherapies. Several conditions remain a challenge, often with a poor outcome. Amongst these therapeutic problems are Richter’s transformation (RT), refractoriness to F-based therapies (Fref), and the occurrence of AIC, which are sometimes induced by F. Fref and RT pts have a very poor prognosis with an estimated overall survival (OS) of only 10 and 8 months (mos), respectively. Therefore, therapeutic alternatives are urgently warranted. CHOP-R has improved the outcome of pts with aggressive non-Hodgkin’s lymphoma. To test the efficacy and tolerability of the CHOP-R regimen in CLL patients with RT, Fref, or AIC, the GCLLSG initiated a prospective phase II trial.

With the usual German efficiency, rather than rely on anecdotes this is a formal phase 2 (reasonably sized) clinical trial. Of course being a phase 2 it is primarily looking at response rate, but since we have ample historical controls over what usually happens in this group of patients, we probably won't need a phase 3 to determine outcome unless this trial should prove to be a stupendous outlier.

Material and Methods: 62 patients were included in the study. Due to protocol violations, 2 patients were excluded. Within the group of Fref pts, the medical review detected 11 patients who had received pre-treatment with F (Fpret), but were not refractory according to the updated 2008 guidelines. Thus, 26 pts were classified as Fref/pret, 19 pts as AIC and 15 pts as RT. All patients received CHOP every 3 weeks (cyclophosphamide 750mg/m², adriamycin 50mg/m² and vincristine 1,4mg/m² d1; prednisone 100mg/m² d1-5). Rituximab was added starting with the 2nd cycle (375mg/m² on each d0, and 21 days after the last CHOP-R). RT pts received up to 8, Fref/pret and AIC up to 6 courses of CHOP-R. In case of PD after 3 cycles, pts went off-study. The primary endpoints were remission rate, quality and duration of response.

Note: this was the lymphoma dose of R, not the CLL dose.

Results: 79%, 73%, and 40% of AIC, Fref/pret, and RT pts were male, respectively. The median age was 65 years (y) for Fref/pret-pts, 66y in the AIC and 69y in the RT group. Binet stages for Fref/pret pts were: A: 8%; B: 27% C: 65 %. All but 3 AIC pts were at Binet stage C. Initial RT stages according to Ann Arbor were: II: 13%, III: 13%, IV 73%. The median number of previous therapies were 3 for Fref/pret, 2 for AIC and 2 for RT.

Note: these were younger patients, but most had advanced disease and were a poor risk lot with many previous types of treatment.

A total of 314 cycles were administered, with a median number of 3 cycles for AIC and Fref pts and a median number of 4 cycles for the RT group. Due to toxicity 73% of cycles in the Fref/pret group, 66% in the AIC and 87% in the RT group were dose-reduced. 69% of Fref/pret-pts and 58% of AIC-pts received full 6 cycles of therapy and only 40% of RT-pts completed 8 cycles of therapy. Treatment was stopped in 6 pts because of PD. Due to treatment related toxicity treatment was stopped in 16 pts (27%). Treatment related mortality was 3% (2 pts). Treatment toxicity was reported according to NCI common toxicity criteria (CTC) version 2.0. Adverse events grade 3 or 4 for anemia, neutropenia and thrombocytopenia were documented in 75%, 55% and 65% of patients, respectively. Infections were the most common non-hematologic toxicity and occurred in 67%; severe infections CTC grade 3 or 4 occurred in 28%.

Treatment was not administered with the dose intensity that was planned for. This was because of toxicity - as would be expected with so many stage C patients in the mix.

All 26 Fref/pret-pts were available for response evaluation. CHOP-R achieved 54% PR, 35% SD and 12% PD. The median progression-free survival (PFS) and median treatment-free survival (TFS) were 11 and 14 mos. OS was 27 mos with a significant difference concerning F-ref (n=15) and F-pret (n=11) pts (17 vs. 35m; p=0.05). We evaluated the response of all 15 RT-pts with 60% PR, 7% CR, 13% SD and 20% PD. The PFS was 15 mos, TFS was 17 mos and OS 27 mos. 17 AIC pts were available for response evaluation with 82% PR, 6% SD and 12% PD. The PFS and TFS were only 14 and 16 mos. The OS was 50 mos.

Note: although the PR rate was respectable, it is artificially high because only some of the pret patients would have been refractory to fludarabine and the difference between overall survival for Fref and pret was more than double and statistically significant. If patients lived long enough they could benefit from other treatment including lenolidemide, alemtuzumab and transplant.

The population had a high incidence of unfavourable genetic markers: deletion of chromosome 17p [del(17p)] was detected in 24%, del(11q) in 34% and unmutated IGHV in 70%. 85% had high levels of serum thymidine kinase (sTK > 10 U/l), and 49% had high levels of ß2-microglobulin (ß2M > 3.5 mg/l). Patients with del(17p) had an unfavourable response rate and achieved significant less a PR or CR (36% vs. 76%; p=0.03). Multivariate analyses showed that del(17p) and ECOG performance status had a negative prognostic impact on OS (p = 0.0001). Moreover the presence of a del(17p) predicted a short PFS (6 vs. 16.9 mos; p=0.001).

Note: This is of course old news, but we are now discerning other factors involved in Richter Syndrome and fludarabine refractoriness.

Conclusion:

CHOP-R achieves promising response rates in CLL patients with Fref and RT and very good response rates in patients with AIC. However, the progression-free survival and overall survival remain unsatisfactory. Therefore, CHOP-R might be used as induction therapy prior to allogeneic stem cell transplantation in physically fit patients.

Or the agents that interfere with BCR stimulation, or alemtuzumab, or lenalidemide especially early in the disease. Even Bendamustine-R (or Ofatumumab) has not been evaluated in this scenario. Still CHOP-R for AIC might be promising.

John 8:20-22. The sovereignty of God

2011-11-30T09:58:00.003Z

He spoke these words while teaching in the temple courts near the place where the offerings were put. Yet no one seized him, because his hour had not yet come. Once more Jesus said to them, “I am going away, and you will look for me, and you will die in your sin. Where I go, you cannot come.” This made the Jews ask, “Will he kill himself? Is that why he says, ‘Where I go, you cannot come’?”

The attitude of the Jews is what today's secular world would display. With no concept of the supernatural world, they would not detect the Sovereignty of God in these happenings. But we can, can't we?

More female doctors; a good thing?

2011-11-30T09:47:00.003Z

An article in the Student Edition of the BMJ has prompted this article in today's Independent

Female doctors who have laid siege to the male bastion of the medical profession are poised to overtake their male counterparts in what a medical journal describes as a "giant leap for womankind". Women have outnumbered men in medical schools for a decade and are set to become a majority of the medical workforce by 2017. They already dominate in people-friendly areas such as general practice, paediatrics and palliative care, while still struggling in the chauvinistic disciplines of cardiology and surgery.

But the progressive feminisation of medicine carries dangers, experts warn. There is a still a gender pay gap and a reluctance by women to put in the time and effort needed to attain the most senior posts and maintain medicine's influence in the corridors of power. Maham Khan, from Imperial College, London, writing in the student edition of British Medical Journal, says more women doctors could lead to safer practice. Women are less likely to be hauled before the General Medical Council on disciplinary charges or investigated for failures in performance. Over eight years 490 male doctors were banned from seeing patients following performance reviews by the National Clinical Assessment Service, compared with 79 women.

Problems remain, however. Women are under-represented at the top of the profession, according to Professor Jane Dacre, medical school director of University College London, because they are "not investing in the time and effort it takes to get the top jobs". Parveen Kumar, president of the Royal Society of Medicine, told the BMJ: "Women don't like to be seen as putting themselves forward." In 2004, Dame Carol Black, then president of the Royal College of Physicians, triggered a debate about the influence of women in an interview with The Independent in which she warned that the growing numbers could reduce the influence of the medical profession at the highest level. This was not about women's capacity to perform, but about their willingness to devote the time and effort, beyond their medical responsibilities, to furthering the interests of the profession. Men were happy to give up their evenings, sit on committees and eat dinners for a chance to walk the corridors of power. It was not clear, Lady Black suggested, whether women would have the same appetite for networking.

A report by the Royal College of Physicians warned in 2009 that the gender balance of the profession was changing so fast it threatened the care of patients. Women were more likely to work part time and to break their careers to have families, and competition for less female-friendly disciplines such as surgery would be reduced.

Despite the challenges, medicine is ahead of other professions in terms of gender equality, Maham Khan writes. Women will take 55 years to reach equality with men amongst senior judges and 73 years amongst directors of FTSE 100 companies. "In terms of numbers, female doctors have made giant leaps," she says.

Men fare better than women in almost all areas of life – except when it comes to their health. They are twice as likely as women to die before 65. Now a doctors' study is calling for policies to tackle problems caused by men's macho attitude to health – rejecting advice and not seeing GPs soon enough. Alan White, professor of men's health at Leeds Metropolitan University – who led the study published in the British Medical Journal – said intervention should start in schools to give boys "skills to make healthier decisions throughout their lives". Bosses should collaborate with unions to promote men's health in the workplace, while pubs, clubs and sports centres should also be targeted, the study urges.

I got into trouble for predicting this in 1984. Here is my comment today:

More female doctors means more part-time posts, more juggling between home and work commitments, more hand-overs that are not completed, more overlapping double shifts that are paid for twice, less continuity, more patients falling through the cracks, less working late to paper over the cracks.

Worst off will be those unmarried female doctors, especially those without children who will be expected to work extra long hours (unpaid) to compensate for their sisters who 'must get off to see to the kids'.

Take a look at what is actually happening on the ground rather than in some idealized image of how the 'equalities industry' would like it to be.

John 8:19. Among atheists

2011-11-29T17:49:00.003Z

Then they asked him, “Where is your father?” “You do not know me or my Father,” Jesus replied. “If you knew me, you would know my Father also.”

They are still unaware. They are a Godless lot!

How do you argue with those who do not believe in God? It is not our responsibility to convert people, merely to witness, and to witness means to tell our own story, not become a theologian

String of disasters

2011-11-29T17:38:00.002Z

I am still waiting for news about the monoclonal antibody. I am told that we should hear today.

Meanwhile it has been an eventful week. First, our dishwasher broke. Normally this would be something we would do together, but I am not well enough to9 go shopping so my wife went to Currys and bought a replacement which will be installed tomorrow. Then via the MacMillan Unit I had some aromatherapy. While I am sure this does not affect the cancer, it is very relaxing having sandalwood oil rubbed into my feet and legs. These are getting very puffy and despite elastic stockings I have to keep them raised. Then a large amalgam filling fell out of my back teeth. No I don't blame the aromatherapy.

Today as I was dozing in the armchair I heard a clattering from the chimney. My wife was sure that a pigeon had fallen down the chimney and trapped itself there. We phoned Prokill, the pest controller, and she was right. In about 20 minutes they had rescued the bird and released it. Best of all they made no charge for it. What nice people!

University applications fall

2011-11-29T08:57:00.002Z

Universities face a record 15.1 per cent slump in UK applicants after the tripling of tuition fees, official statistics show. Rising numbers of British students are being deterred as charges of up to £9,000 a year are introduced next autumn. The UCAS statistics suggest a looming meltdown in higher education after years of unbridled expansion. Vice chancellors are likely to become reliant on lucrative overseas students who pay the full cost of courses – as much as £26,000 a year – to help boost their coffers.

The figures show that 133,357 home students have applied for 2012 degree courses at UK institutions so far, a drop of 23,759 compared with the same point last year. Applications from other EU students have fallen 13.1 per cent to 9,034. However, the number of applicants from outside the EU has risen by 11.8 per cent – from 14,306 to 15,996 – amid extensive overseas recruitment drives. There has been a 31.8 per cent rise in applications from Hong Kong alone – up to 2,248 – as British institutions target this market.

Overall applications – including British, other EU and non-EU students – to UK universities by November 21 have dropped by 12.9 per cent to 158,387. At the same point last year, overall applications for courses starting in autumn 2011 had soared by 11.7 per cent to 181,814. Students cancelled gap years in the rush to get places ahead of next year’s increase in fees.

Last night Professor Alan Smithers, director of the Centre for Education and Employment Research at Buckingham University, said: ‘I think this is the highest drop outside of the two World Wars, when some universities almost became bankrupt due to falling applications. They were rescued by State support. ‘In the 1980s, when the number of 18-year-olds dropped by a third, the shortfall in applications was made good by mature students and part-time students.’ He added: ‘It will be the less popular universities that will struggle. ‘Students will be questioning whether they would be getting sufficient value from £9,000-a-year from those universities.’ The largest fall in applications (17.1 per cent) is among Scottish students, even though they get free tuition in Scotland. This is believed to be due to a fall in the birth rate, together with a 19.1 per cent fall in their applications to English universities. Applications are down among English students by 15.2 per cent, Welsh by 10.3 per cent and Northern Irish by 16.9 per cent. Areas of the UK with the largest falls in applications include the North East (-21.4 per cent) and the East Midlands (-20.1 per cent).

Sally Hunt, general secretary of the University and College Union, said the figures were worrying, adding: ‘Putting financial barriers in front of young people who have been told their entire lives to aim for university is nothing more than a policy of penalising ambition.’ UCAS chief executive Mary Curnock Cook said: ‘We expect some depression of demand due to a decline in the young population, but it is much too early to predict any effects from changes in fees.’

Mr Willetts said: ‘Most new students will not pay up front and there will be more financial support for those from poorer families.’ Students have until January 15 to apply for 2012 courses. Research suggests they will face an average total bill of £48,503 for three years’ study at a Russell Group university, including the higher fees and living costs.

When higher fees were introduced, part of the reason was to embarrass those 'universities' that gave poor value for money. It is almost universally accepted that the expansion of Universities allowed some to provide very poor value with too many courses in 'Media Studies' and the like attracting students who would be better off in apprenticeships learning to be craftsmen or mechanics or secretaries. Tony Blair's "Education, education, education." warcry was misdirected.

The polls

2011-11-29T08:14:00.003Z

Peter Kellner is a left-leaning pollster and journalist. Here is what his blog is saying about the state of the parties just before the Chancello's Autumn statement:

Here's the bad news.

By a two-to-one majority (60-31%), voters think the coalition is managing the economy badly. Five times as many people (57%) think their family's financial situation will get worse rather than better (11%) over the next 12 months. Only 27% think the government is managing the public spending cuts fairly; 57% think they are being done unfairly. More people think the cuts are too deep (43%) than too shallow (10%) or about right (27%).

Faced with these figures, most chancellors and prime ministers would be twitching uncomfortably. However, other YouGov data suggest reasons for surprising equanimity.

One major reason is that the figures quoted above have changed little in recent months. The past month or two has seen some stinking economic news, as spending cuts take effect and the ripples from the eurozone crisis lap at the shores of Britain's economy. Unemployment is up. Growth is anaemic. Expectations for next year are sharply down. One might have expected a marked rise in public disenchantment with the government.

It hasn't happened. The main indicators have been weak for much of this year, but have not weakened further this autumn. Why not? Here are some figures that help to explain what has, or rather has not, happened.

By two-to-one (56-27%) voters think the public spending cuts are necessary. The proportion saying 'necessary' has remained stable since February. The only change since then is that slightly FEWER people say the cuts are 'unnecessary', while slightly more don't know. The opponents of cuts have made no headway for the past nine months. More people still blame Labour (38%) rather than the coalition (22%) for the current spending cuts. If anything, the coalition's position has slightly improved since the summer, when blame for the coalition reached 26% on a number of occasions. In short, the Conservatives continue to win the argument that they are cleaning up a mess they inherited. Last autumn, I believed that Labour was losing this debate because it had spent the summer months engaged in its leadership contest; inevitably, it was talking to itself rather than the wider electorate.

But that contest ended 14 months ago. Labour has a settled duo at its helm: Ed Miliband and Ed Balls. They have not been short of opportunities to attack the government and proclaim their own alternative. Bluntly, they have failed to make an impact. This is why Labour's voting-intention lead averages just 5%. At this stage in a parliament's life, as we approach its mid-term, an economy as weak as Britain's would normally expect to be accompanied by a double-digit lead for the opposition.

Even worse for Labour, they actually lag behind on our 'forced choice' question: If you had to choose, which would you prefer to see after the next election, a Conservative government led by David Cameron or a Labour government led by Ed Miliband? Our latest figures show Conservatives/Cameron on 40% and Labour/Miliband on 35%. This 5% lead is similar to what we found in the spring. Actually, Miliband caught up with Cameron, and briefly overtook him, in the summer, when the news was dominated by phone-hacking and, then, August's urban riots; but normality resumed when the news returned to the state of the economy.

As with financial investments, past performance offers no guarantee of future behaviour. This week's autumn statement and public sector strikes may cause many voters to revise their view of the government's competence. And, as time passes, if the economy stays weak, it is possible that more people will blame the Conservatives and fewer will blame Labour. The next election is more than three years away: only a fool would say its outcome is a foregone conclusion. But for the moment, the Conservatives seem to have the Teflon factor on their side, for they have managed to stop the autumn's bad economic news from sticking to them and messing up their reputation.

I have been watching the Labour lead in the Daily Telegraph each day. It varies from 2% to 9% which seems to bear out Kellner's assertions. There is hope yet.

Rules for citizenship

2011-11-28T18:06:00.003Z

In today's Times Libby Purves has written an article about testing for British Citizenship. Many countries have introduced such a test for immigrants.

The French are planning a new citizenship test that candidates for naturalisation must pass. President Sarkozy places importance on cultural assimilation and understanding of the philosophical basis of French equality, liberty and fraternity. The Interior Ministry adds that there must be basic knowledge of his country’s artistic history, great painters, writers and philosophers, as well as its contemporary culture. The British test has some basic stuff about Parliament and elections, but is mainly a cautious mish-mash of stuff about MoT tests, benefits, and the Council of Europe. It demands that you know the exact number of days per year when schools are legally required to open and is dusted with some dottily detailed questions about population statistics, a ridiculous inquiry as to which “issues” young people in the UK most worried about in a survey made eight long years ago, and a multiple-choice question about whether married women got the right to divorce husbands in 1837, 1857, 1875 or 1882.

Canada’s is detailed and proud, asking for the six main responsibilities of citizenship, the meaning of the Remembrance poppy, major rivers and natural resources, and whether the national symbol is a moose, hawk, beaver or bear. The Dutch are proud, too, at least of their social attitudes. They demand knowledge that nude sunbathing is legal, and preface the test with a film of two men kissing, and a prostitute. (There has been some fuss about whether all this is covertly Islamophobic , and one indignant message-boarder says: “Basically you must be a degenerate to obtain Dutch nationality.”) The German test asks, equally contentiously some say, whether the candidate believes that Israel has the right to exist. Again, one learned paper in a European think-tank attacks that as being anti-Muslim thought-policing.

Libby has made up her own list:

• Who stands on that pillar in Trafalgar Square and why?

• Do we have theatre censorship?

• Why is sea trade important to Britain?

• Who should you complain to about a TV programme that offends you?

• Write 30 words on either the British attitude to pigs or Winnie the Pooh or Alan Bennett or David Beckham or Bob Geldof.

• Who is Dame Vera Lynn? or What is another meaning of the word dame, especially around Christmas?

• Name a Shakespeare play or three songs by Lennon and McCartney.

• What did William Wilberforce achieve?

• What was Dunkirk or D-Day?

• Is Coronation Street (a) a television show or (b) the Queen’s address?

• If you wanted to know about toad-in-the-hole, would you be more likely to ask (a) Sir David Attenborough (b) Delia Smith (c) Alan Titchmarsh?

• Are you allowed to swear at a policeman?

• What is the National Trust? A zebra crossing? The Premier League?

One commentator has answered these :

1. Lord Nelson – naval hero and won a number of battles.
2. Not since the 1960s but the matter is still under discussion
3. We are an island doh! Sea trade is our lifeline.
4. Ofcom
5. Pigs are highly intelligent animals and provide wonderful meat, bacon, ham and sausages. Traditionally, they were fed on household scraps, waste milk products and so were environmentally friendly. So there!
6. Dame Vera Lynn is a singer and performer who performed all over the world in wartime to raise morale. Love her to bits
7. King Lear – appropriate for these difficult times.
8. He abolished slavery
9. D-Day was when our troops landed in Europe, including my father.
10. Corry – TV show
11. Toad in the hole – Delia Smith but I bet DA would have something to say on the matter too.
12. No – not AT a policeman. The recent case was about a man who swore IN FRONT of a policeman as he was so ignorant, the “F” word was part of his normal vocab.
13. The National Trust takes over and runs, for public enjoyment, large houses and estates which are part of our historical heritage.

I don't think that these answers are strictly accurate but they are close enough to pass, but to my mind they are the wrong sort of questions. Another comments thus:

What do any of these questions have to do with true citizenship? Since when did knowing a load of facts and having a good guess at the rest matter? What counts is being able to earn a living, speaking English, good manners etc. and a lot to be said for loving thy neighbour.

I tend to agree.

What we need is not a test but a pledge, and this should apply not only to those applying for citizenship, but to all those entering the country. Those breaking their word on this pledge should be immediately expelled. The pledge would go something like this: Do you agree while living in the UK to respect freedom of speech, freedom of religion, including witnessing for your faith, the right to own property, the right of free assembly, and do you agree to abstain from violence, intolerance of the behaviour of others, insulting behaviour and to obey the criminal law on pain of expulsion from the country without appeal?

Danger at night and weekends

2011-11-28T12:13:00.002Z

The annual hospital guide published by Dr Foster Intelligence using official figures shows that one in eight trusts has higher than expected death rates on Saturdays and Sundays, suggesting they are only working to a five-day week. Many hospitals have far fewer senior consultants on site outside of normal office hours, the data show, and rely on junior doctors and nurses to treat critically ill patients.

In a handful of trusts, the mortality rate rises by 20 per cent or more between weekdays and weekends. Low staffing levels in A&E have been identified as one of the long-standing problems at Stafford Hospital, where hundreds of patients died after receiving “appalling” care, and the unit will close overnight for three months starting this week.

Although I do not take much notice of Dr Foster reports, since they use crude data which is often modified when the CQC produces a more comprehensive view. (Stafford was only one of 6 Trusts identified by Dr Foster - the other 5 were exonerated). Nevertheless, out of hours care has been one of the problems identified by the NHS as one of its deficiencies. As a result there have been major changes to the provision of care. Vascular surgery has been confined to small groups of expert vascular surgeons, who are ready with their teams to appear where the problem is. No junior doctor ever gets to lead on emergency vascular surgery. It is true of almost all elective surgery, which is now conducted between 9 and 5.

When I was young it was quite commonplace for major colorectal surgery to take place in the evening for an elective list arranged by the Senior Registrar from 7pm to 11pm. But we had different types of junior doctors then.

When I was a resident in Bristol there were 6 Senior Registrars in Surgery, aged between 38 and 44. These were very senior and experienced doctors who were just waiting consultant jobs. One of those was John Trapnell, whose obituary I posted recently. Among the others I remember were Colin Davidson, Roger Celestin and Harry Espiner. All have long since retired with great success in their careers. Today, Senior Registrars have all gone and instead we have registrars. These young men have many fewer hours of experience and their training is arranged so that they will get fewer yet. At the age of 35 they expect to get consultant jobs, but although they may get expert in microspecialties (just doing breasts or stomachs or pancreases) they will never become the General Surgeons that their predecessors were.

Physicians were always younger than surgeons when they became consultants, and I was particularly young at the age of 30, but 33-35 would be average. I was always on an on-call rota of at least 1 in 3 throughout my whole career, but we trained a mixed junior doctor/ senior nurse cadre who were competent to deal with the medical emergencies that we would have to deal with urgently (mainly neutropenic sepsis) and more complicated problems (mainly transfusion and coagulation difficulties) could be dealt with from the confines of a warm bed.

General Physicians have largely disappeared from the NHS. Elective work is done in daytime by Gastroenterologists, Chest Physicians, Neurologists, Endocinologists, Cardiologists, Rheumatologists, and Rehabilitation Specialists. We and others have set up Acute Medical Units, attached to Accident and Emergency Units where an on-call Senior Doctor is responsible for the first 24-48 hours of an admission only, although referral to an intensive cardiac unit or stroke unit may be required earlier. Expert endoscopy, CT scanning, MRI and ultrasonography is also available within the first 24 hours.

Changes in junior doctor training have forced more senior involvement at nights and at weekends and have in the best hospitals rethinking on how things should be done. There is one major deficiency that I have identified, though. The European Union forced through its European Working Time Directive, with the consent of the last Labour Government and against protests of the British Medical Establishment. This meant that not only were junior doctors not allowed to work for more than 48 hours a week, but included in that time would be on-call time, when the doctors would be sleeping, not working. This has meant a total revision of doctors' rotas that has neither helped the service they provide nor their training. Now even the Germans think it was a mistake and have conceded that this may be one of the things that the UK can have back to its own control if there have to be renegotiation of the EU charter because of fiscal rearrangements.

SF3B1 in sideroblastic anemia

2011-11-28T11:53:00.004Z

This is the abstract of the paper from the NEJM that I was taling about in the last posting. It comes from the UK (including my old unit in Southampton), Italy, Houston, Boston, the Karolinska and Cologne.

Somatic SF3B1 Mutation in Myelodysplasia with Ring Sideroblasts

Myelodysplastic syndromes are a diverse and common group of chronic hematologic cancers. The identification of new genetic lesions could facilitate new diagnostic and therapeutic strategies. The suthors used massively parallel sequencing technology to identify somatically acquired point mutations across all protein-coding exons in the genome in 9 patients with low-grade myelodysplasia. Targeted resequencing of the gene encoding RNA splicing factor 3B, subunit 1 (SF3B1), was also performed in a cohort of 2087 patients with myeloid or other cancers. They identified 64 point mutations in the 9 patients. Recurrent somatically acquired mutations were identified in SF3B1. Follow-up revealed SF3B1 mutations in 72 of 354 patients (20%) with myelodysplastic syndromes, with particularly high frequency among patients whose disease was characterized by ring sideroblasts (53 of 82 [65%]). The gene was also mutated in 1 to 5% of patients with a variety of other tumor types. The observed mutations were less deleterious than was expected on the basis of chance, suggesting that the mutated protein retains structural integrity with altered function. SF3B1 mutations were associated with down-regulation of key gene networks, including core mitochondrial pathways. Clinically, patients with SF3B1 mutations had fewer cytopenias and longer event-free survival than patients without SF3B1 mutations. Mutations in SF3B1 implicate abnormalities of messenger RNA splicing in the pathogenesis of myelodysplastic syndromes.

The spliceosome: a new factor in bad risk CLL

2011-11-28T11:35:00.001Z

I mentioned some weeks ago that the spliceosome is going to be important in CLL. The spliceosome is an epigenetic mechanism which is involved in splicing together the separated introns of a gene identified on DNA. It had already been identified as a factor in determining the various subtypes of MDS, but it has now been recognized as an important mechanism underlying fludarabine refractoriness in CLL and also in some cases of Richter syndrome.

I have quoted from this paper from Italy in a recent BLOOD

Mutations of the SF3B1 splicing factor in chronic lymphocytic leukemia:association with progression and fludarabine-refractoriness

The clinical course of chronic lymphocytic leukemia (CLL) ranges from a very indolent
disorder with a normal lifespan, to a rapidly progressive disease leading to death. Occasionally, CLL undergoes transformation to Richter syndrome (RS). The variable clinical course of CLL is driven, at least in part, by the disease immunogenetic and molecular heterogeneity.

Despite recent advances, the genetic lesions identified to date do not entirely explain the development of severe complications, such as chemorefractoriness, which still represent unmet clinical needs. Fludarabine-refractoriness is due to TP53 disruption in ~40% of refractory cases, but in a sizeable fraction of patients the
molecular basis of this aggressive phenotype remains unclear. Recently, two independent studies of the CLL coding genome investigated at disease presentation have revealed a restricted number of mutated genes, including NOTCH1. These
studies have provided a proof of concept that, similar to other malignancies, genome-wide mutational analysis might identify novel lesions of biological and clinical relevance in CLL.

On these grounds, the authors have embarked on the investigation of the coding genome of fludarabine refractory CLL in order to identify genetic lesions associated with chemorefractoriness. The initial phases of this analysis have revealed recurrent mutations of SF3B1, a critical component of the cell spliceosome, pointing to the potential involvement of splicing regulation in CLL pathogenesis and chemo-refractoriness.

The study population comprised 3 cohorts representative of different disease phases: i) fludarabine-refractory CLL (n=59), including cases (n=11) subjected to whole exome sequencing; ii) a consecutive series of newly diagnosed and previously untreated CLL (n=301); and iii) clonally related RS (n=33; all diffuse large B cell lymphomas).

Diagnosis of CLL and of fludarabine-refractoriness were based on IWCLL-NCI criteria; RS was based on histological criteria. Peripheral blood tumor samples were obtained as follows: i) for fludarabine-refractory CLL, immediately before starting treatment to which the patient failed to respond because of stable/progressive disease; ii) for newly diagnosed and previously untreated CLL, at disease presentation. All RS studies were performed on RS diagnostic biopsies. Normal DNAs from the same patients were obtained from saliva or from purified granulocytes and confirmed to be tumor-free by PCR of tumor-specific IGHV-D-J rearrangements. Patients provided informed consent in accordance with local IRB requirements and Declaration of Helsinki. The study was approved by the Local Ethical Committee (Protocol Code 59/CE; Study Number
CE 8/11).

Mutation analysis of SF3B1 (exons 1-25, including splice sites; RefSeq NM_012433.2) was performed on PCR amplimers obtained from genomic DNA by a combination of Sanger sequencing and targeted next generation sequencing. FISH karyotype, mutation analysis of IGHV, TP53 and NOTCH1, copy number analysis, and gene expression profile analysis FISH analysis was performed using probes LSI13 and LSID13S319, CEP12, LSIp53, and LSIATM. IGHV sequences were aligned to ImMunoGeneTics directory and considered mutated if identity to corresponding germline genes was less than 98%.3, TP53 and NOTCH1 mutations were analysed by Sanger sequencing.3,7 Genome-wide DNA profiles were obtained using Affymetrix Genome-Wide Human SNP Array 6.0. Gene expression profile analysis was performed using Affymetrix HG-U133_plus2 arrays.

Statistical analysis

Overall survival was measured from date of diagnosis to date of death (event) or last followup (censoring). Treatment free survival was measured from date of diagnosis to date of progression to symptomatic disease requiring treatment according to IWCLL-NCI guidelines (event), death, or last follow up (censoring).

Results and Discussion

Following the initial observation of recurrent SF3B1 mutations in 3/11 fludarabine refractory CLL analyzed by whole exome sequencing, we performed targeted re-sequencing of the SF3B1 coding sequence and splice sites in 48 additional cases of progressive and fludarabinerefractory CLL (total number of cases analyzed: 59). SF3B1 was altered in 10/59 (17%) fludarabine-refractory CLL by missense mutations (n=9) or in-frame deletions (n=1) clustering in the HEAT3, HEAT4 and HEAT5 repeats of the SF3B1 protein. Two sites that are highly conserved inter-species (codon 662 and codon 700) were recurrently mutated in 3 and 5 cases, respectively. SF3B1 mutations were monoallelic, and were predicted to be functionally significant according to the PolyPhen-2 algorithm. These data document that mutations of SF3B1, a splicing factor that is a critical component of the spliceosome, recurrently associate with fludarabine-refractory CLL.

The biological characteristics of fludarabine-refractory CLL harboring SF3B1 mutations are in summary that mutations occurred irrespective of the IGHV mutation status, CD38 expression and ZAP70 expression. At the time of fludarabine-refractoriness, SF3B1 mutations were enriched in cases harboring a normal FISH karyotype (p=.008). Also, SF3B1 mutations distributed in a mutually exclusive fashion compared to TP53 disruption tested by deletion and/or mutation (mutual information I =0.0609; p=.046). By combining SF3B1 mutations with other genetic lesions enriched in chemorefractory cases (TP53 disruption, NOTCH1 mutations, ATM deletion), fludarabine-refractory CLL appeared to be characterized by multiple molecular alterations that, to some extent, are mutually exclusive.

To investigate whether SF3B1 mutations are restricted to chemorefractory cases, we then compared the prevalence of mutations observed at the time of fludarabine-refractoriness to the prevalence of mutations observed in other disease phases. In a consecutive series evaluated at CLL diagnosis, SF3B1 mutations were rare (17/301; 5%)and occurred irrespective of other molecular and immunogenetic features. Remarkably, 5/17 (29%) CLL mutated at diagnosis were primary fludarabine-refractory patients. In these 5 cases, TP53 disruption and NOTCH1 mutations occurred in 1 cases each. None of the 12 remaining cases harbored TP53 disruption or NOTCH1 mutations.

By univariate analysis, SF3B1 mutations showed a crude association with short treatment free survival (p<.001) and overall survival (p=.011). By multivariate analysis, the increased risk of death predicted by SF3B1 mutations was independent (HR: 3.02; 95% CI: 1.24-7.35; p=.015) of confounding clinical and biological variables. Confirmation within the frame of prospective clinical trials will be helpful to fully assess the generalization of SF3B1 mutations as a CLL prognostic marker. In CLL investigated at diagnosis, the hotspot distribution and molecular spectrum of SF3B1 mutations, as well as their mutual relationship with other genetic lesions, were similar to those observed in fludarabine-refractory CLL. SF3B1 mutations were only found in 2/33 (6.0%) clonally-related RS. Across the different disease phases investigated, mutations were confirmed to be somatically acquired in all cases (n=18) for which germline DNA was available. Among the three SF3B1 mutated cases for which serial samples were analyzed, SF3B1 mutations were acquired in 2 cases. One fludarabine-refractory CLL acquired the c.2044A>G p.K666E mutation at the time of refractoriness, and one RS acquired the c.2146A>G p.K700E mutation at the time of transformation. In the remaining case, the SF3B1 mutation was present in all disease phases. Although the relative expression of SF3B1 in CLL was higher compared to normal B-cell subsets, extensive investigation by SNP array analysis ruled out focal copy number abnormalities of SF3B1 in this leukemia (n=0/323). SF3B1 mutations were consistently absent among mature B-cell neoplasms (n=136) other than CLL. These data document that SF3B1 mutations: i) are specific for CLL among mature B-cell neoplasms; ii) occur at a low rate at CLL presentation, whereas they are enriched in fludarabine-refractory cases; iii) play a minor role in RS transformation, corroborating the notion that CLL histologic shift is molecularly distinct from chemorefractory progression without RS transformation.

The identification of SF3B1 mutations in CLL, and the recent discovery of SF3B1 mutations in myelodysplasia, points to the involvement of splicing regulation as a novel pathogenetic mechanism in hematologic malignancies. SF3B1 is a critical component of both major (U2-like) and minor (U12-like) spliceosomes, which enact the precise excision of introns from premRNA. The precise biological role of SF3B1 mutations in CLL is currently elusive, and will require dedicated studies. The pathogenicity of SF3B1 mutations in CLL is strongly supported by the clustering of these mutations in evolutionarily conserved hotspots localized within HEAT domains, which are tandemly arranged curlicue-like structures serving as flexible scaffolding on which other components can assemble. Also, the observation that SF3B1 regulates the alternative splicing program of genes controlling cell cycle progression and apoptosis points to a potential contribution of SF3B1 mutations in modulating tumor cell proliferation and survival. In addition to pathogenetic implications, SF3B1 mutations might also provide a therapeutic target for SF3B1 inhibitors, which are currently under pre-clinical development as anti-cancer
drugs.

John 8:17-18. Is there a God?

2011-11-28T10:07:00.002Z

"In your own Law it is written that the testimony of two witnesses is true. I am one who testifies for myself; my other witness is the Father, who sent me.”

Note: another "I AM". Jesus is playing with them. He cites their own law back at them. The irony is that the Saducees among them do not believe in the supernatural so "God" is just a cipher for them; they do not actually believe in God as we know him. That is why it is futile to argue with the Church hierarchy; they also do not believe in a personal God.

Gary Speed

2011-11-27T14:53:00.003Z

Very sad today to read of the apparent suicide of Gary Speed, the team manager of the Wales soccer team. I remember his playing days at Leeds and Everton. With the selection of younger players he had managed to raise Wales in the FIFA rankings. He seemed to have everything to live for. I don't really want to know what underlies this.

Cord-blood disappointment

2011-11-27T14:38:00.002Z

One of the supposed advantages of cord-blood transplantation is the suggestion that intensive matching is not required. Advocates of this view will be disappointed by this comment in Lancet Oncology

After years of research and debate, findings after umbilical-cord blood transplantation have mirrored those of other sources for haemopoietic stem-cell transplantation—ie, matching of the HLA loci between donor and recipient does matter. Thus cord-blood transplantation now faces the same hurdles as bone-marrow or peripheral-blood stem-cell transplantation. In The Lancet Oncology, in a clear and convincing analysis, Mary Eapen and colleagues1 show that additional matching of donor and recipient for HLA C improved the outcome of patients with a cord-blood transplant. This improvement was identified independently of other known risk factors for outcome after haemopoietic stem-cell transplantation, such as the patient's age or disease stage. Results were based on a homogeneous group of more than 800 patients with leukaemia or myelodysplastic syndrome and with sufficient information for the class I HLA antigens HLA A, B, and C and the class II antigen DRB1 in donors and recipients. Pairs with or without matching for HLA C could be compared with pairs with no, single, or multiple mismatches at HLA loci other than HLA C. Effects of matching for HLA C were greatest when no HLA antigen or only one other HLA antigen differed between the donor and recipient.

The importance of matching for HLA in general was underlined by two additional findings: results were better with full matching than with a single, double, or multiple mismatch at any of the class I or class II antigens; and, in the case of a single mismatch for one class I antigen, results were better when the class II antigens DRB1 were identical.

These findings accord with results from unrelated-donor transplants and are reassuring to immunologists (it was difficult to understand why cord blood should behave differently to other sources). These findings might be disappointing for some who thought minimal matching sufficient, but they have clear consequences. The degree of matching between donor and recipient, including HLA C, needs to be integrated into the algorithm used to select for or against transplantation. The risk of disease should be balanced against the transplant risk, so that overall a better outcome with regard to survival, quality of life, and cost, compared with a non-transplant strategy, is achieved. If cord-blood transplants are to be used in early disease, such as for patients with high-risk acute myeloid leukaemia in first complete remission, the search strategy should aim for the best match and should now include HLA C. The value of high-degree matching in unrelated-donor transplants was recently shown to be specifically important for patients with early disease and low-risk characteristics. Hence, an optimally matched transplant product might tip the balance in favour of immediate transplantation in first remission, whereas a suboptimal product would favour a watch and wait or non-transplant strategy. To allow sufficient time for the selection process, any donor search for an unrelated-living or cord-blood donor needs to be started at diagnosis.

The findings of Eapen and colleagues further support the role of standardised reporting of transplant data, as recently stipulated by the WHO's guiding principles on organ and cell transplantation. Only by such cooperation can results be yielded. Furthermore, other antigens such as HLA DQ, HLA DP, or minor histocompatibility antigens are likely to be important in cord-blood transplants because they are present in unrelated-volunteer donor transplants. Typing for HLA C should now become mandatory, accompanied with storage of samples for later analysis. Cord-blood banks will have to provide this service. The additional costs will be recouped through improved transplant outcomes. Quality management systems such as the Foundation for the Accreditation of Cellular Therapy, the Joint Accreditation Committee: European Group for Blood and Marrow Transplantation and the International Society for Cellular Therapy, or Netcord should implement full typing for class I and II antigens into their standards. These steps will help to further improve the procedure and define those selected patients who will clearly benefit from a cord-blood transplant.

Non-hemic autoimmunity in CLL

2011-11-27T13:59:00.005Z

One of the things I have been complaining about is the idea that there is a high degree of autoimmunity in CLL patients. It is absolutely true that autoimmune hemolytic anemia and ITP are more common in CLL and there may perhaps be a higher incidence of a few non-hemic autoimmunities like paraneoplastic pemphigus and nephrotic syndrome among CLL patients, but most autoimmune diseases are not commoner.

This is an interesting case report in which a patient with CLL developed severe celiac disease. The story of the celiac disease is particularly well told.

A 70-year-old gentleman chronic lymphocytic leukemia presented with a four-day history of weakness and profuse, watery diarrhea. He reported 7-8 bowel movements per day, all of which were large volume, watery and greenish-brown in color. The diarrhea was usually associated with crampy abdominal pain and bloating, which was partially relieved with defecation. He also noted occasional red-tinged toilet paper, although he denied any visible blood in the stool or melenotic stools. He complained of occasional "chills" although he denied any fevers or any nausea and vomiting. He reported a 20-30 lb. weight loss over the past month and complained of overwhelming fatigue, weakness and decreased work tolerance during the week prior to admission.

He was admitted for similar symptoms approximately four weeks prior to this admission. At that time a flexible sigmoidoscopy was essentially negative, and an EGD showed gastric and duodenal inflammation, but the ensuing gastric biopsy was negative. During that admission, the patient received treatment of his CLL with cytoxan and was placed on a lactose free diet. The diarrhea decreased to 1-2 bowel movements per day following these interventions and the patient was discharged home on a lactose free diet.

He was readmitted approximately one week prior to this admission, when he developed a new right foot drop. A diagnosis of idiopathic peripheral neuropathy was made with an MRI showing long-standing spinal stenosis. His diarrhea was present but not severe during this hospitalization. His lower extremity weakness improved during the course of stay, and he was discharged home, still on a lactose free diet, in good condition. However, immediately after discharge the patient's diarrhea returned in a severe form, culminating in the most recent admission.

His past medical history was significant for the aforementioned CLL, diagnosed in 1993. His disease had been well controlled until 1997 when new lymphadenopathy and increasing lymphocyte counts prompted treatment with two courses of fludaribine, after which the patient developed esophageal dysmotility. More recently, the disease was again found to be progressing and treatment with cytoxan and prednisone was instituted. The patient also has a history of hypertension, osteoarthritis, hypercholesterolemia, spinal stenosis and he is known to have had a goiter The patient has had a laminectomy in 1990, a supraclavicular lymph node biopsy in 9/00 (consistent with CLL), port-a-cath placement in fall of 2000 and past bilateral cataract surgeries.

His mother had a history of "thyroid disease" and died at age 90. His father died at age 84 with gastric cancer. He had a sister who died at birth and a has brother with coronary artery disease and coronary artery bypass grafting. His son is alive and healthy.

He is a retired printer with no smoking or alcohol history. He is married. His medications on admission were Cardura and Epogen 20,000 units SQ qd.

On examination, the patient was a pleasant 70-year-old male, NAD, alert and oriented to time, person and place. He was somewhat pale and fatigued appearing. His vitals were within normal limits. HEENT exam was unremarkable, and his oral mucosa was moist. He had shoddy cervical adenopathy bilaterally. His lungs were clear to auscultation bilaterally with no significant chest findings. His cardiac exam was notable for a 1/6 SEM heard best at the base. He had a mildly distended abdomen with a palpable spleen 3-4 fingerbreadths below the left costal margin. The liver edge was palpable at the right costal margin. His extremities were intact without cyanosis, clubbing or edema. There were 2 palpable, non-tender freely movable axillary nodes noted, both 1.5 cm, one in each axilla. The neurological exam was significant only for slightly decreased strength (4/5) with plantar flexion of the right ankle.

Lab tests at the time of admission showed a WBC of 36.9 with 92% lymphocytes, 5% monocytes and 0% segmented neutrophils. The hemoglobin was 9.8 and platelets were 145. His sodium was 138, potassium was 3.7, chloride was 114, bicarbonate was 14 and creatinine was 1.3. The BUN and glucose were normal. CXR on admission showed areas of atelectasis. The patient was admitted with a diagnosis of diarrhea, dehydration and known CLL.

At the time of admission, GI felt the most likely causes for this patient's diarrhea were: 1. Infiltration of CLL into the small bowel wall; 2. opportunistic infections (either micro or cryptosporidium) or; 3. bacterial overgrowth syndrome. Stool gram stains returned showing normal flora and the C. Difficile toxin assay was negative. He was placed on a clear liquid diet, but still had significant diarrhea. Fluid losses were replaced with IV hydration.

A colonoscopy was initially interpreted as normal, but the pathology report the following day was showed lymphocytic colitis, not related to colonic infiltration by CLL. The patient was placed on prednisone for the colitis.

An abdominal CT showed decreased adenopathy as compared to previous films and no obvious infiltration of disease into the bowel. The colon was noted to be moderately distended. The patient underwent an EGD four days post admission where biopsies of stomach and duodenum were obtained. There was no gross pathology noted.

Based on the CT results, it was clear that the patient responded to his last treatment with cytoxan and prednisone. A second dose was given on day 5 post admission and the patient was also started on allopurinol to prevent tumor lysis symptoms. EGD biopsy results were still pending at this time. As the patient was having 7-8 BM's per day of increasing volume and increasing abdominal distention, he was started on metronidazole as the diarrhea had not responded to steroids

On hospital day 6 a regular diet was again resumed and Imodium was started. The patient also began to c/o some vomiting episodes, which were attributed to the metronidazole. Sandostatin 100 mcg was begun in an attempt to reduce the fecal output. The patient was also switched from Imodium to Lomotil at this time, as the diarrhea continued to be severe. A 24-hour stool collection was yielded approximately 10 liters of stool were made during this collection.

On hospital day nine the duodenal biopsy results returned consistent with celiac sprue. The patient was immediately placed on a gluten free diet and antiendomysial and antigliadin antibodies tests were drawn.

Unfortunately, the diarrhea only increased in volume and by day 10, the patient began to have rigors and fever spikes. His blood and urine were cultured but no antibiotics were begun at this time. An abdominal US revealed no significant pathology. TPN was begun as an apparent 50lb weight loss was recognized over the past 6 weeks.

During the admission the patient had been consistently acidotic, with low HCO3 readings but increased Cl causing a non-anion gap acidosis, almost undoubtedly from the chronic diarrhea. This was becoming more severe and correction with bicarbonate in the IV fluids and acetate in the TPN was required. The sandostatin dosage was increased to 100 mcg tid. On day 11, the blood cultures were positive for gram positive cocci and the patient was placed Ceftriaxone and vancomycin. TPN was halted because of concerns over TPN use in a bacteremic patient, but was renewed after a discussion with ID. Antiendomysial and antigliadin antibody test results returned and both IgA and IgG antigliadin were positive. Interestingly, antiendomysial IgA was found to be negative.

In the early evening of day 11, the patient was somewhat more dyspneic and an EKG was ordered. This showed new onset atrial fibrillation with occasional PAC's. As the patient looked acutely ill, was extremely weak and still having massive diarrhea, it was decided to transfer the patient to the MICU for aggressive fluid resuscitation and more continuous monitoring.

The patient continued on TPN in the MICU and was also started on Neupogen for a low WBC count presumably secondary to the cytoxan treatment. He was given nothing by mouth and by Day 13 stool output had begun to decrease. The bacteremia was found to be S. pneumoniae that was sensitive to vancomycin but intermediately resistant to ceftriaxone. The patient's diarrhea continued to improve over the next two days. His TPN was discontinued on day 15 and he was placed back on a gluten free diet. The vancomycin was discontinued and the patient remained on ceftriaxone. He had been afebrile since day 2 of antibiotics. At this time he was place on fluconazole for esophageal candidiasis with odynophagia. He continued to improve and was transferred back to the floor on day 17 and discharged home on day 21 with no diarrhea, a good appetite and increased energy and strength subjectively. He was to continue with a gluten free diet at home.

Discussion

Celiac disease, often called celiac sprue, is an acquired sensitivity to the protein gluten. Exposure to the gliadin moiety of gluten is responsible for the characteristic histopathologic changes and the resulting clinical picture. The classic pathologic changes consist of flattening of the intestinal mucosa, hyperplasia of intestinal crypts and complete absence of normal villi. Remaining absorptive cells are cuboidal rather than columnar and the brush border is greatly reduced. Furthermore, tight junction abnormalities are present, causing an enhanced permeability of the mucosal barrier.

Interestingly, the length of the celiac lesion (ie: the amount of small bowel effected) varies greatly from patient to patient, and has a direct correlation with the severity of clinical disease. Consequently, there is a large spectrum of disease presentations ranging from asymptomatic to life-threatening "celiac crisis." The intestinal lesion may also range from involvement of only the proximal duodenum to complete small bowel involvement. If the lesion does not involve the entire small bowel, the proximal intestine is the most severely effected and the lesion decreases in severity distally.

Appropriate treatment (gluten-free diet) results in a return of normal intestinal architecture. The cytologic appearance of the surface absorptive cells improves first, often within a few days. Cells again become columnar and well developed brush borders began to appear. Later, villi began to lengthen and the crypts revert back to their usual size. The length of time required for complete restoration of gut mucosa is variable, with some patients still having biopsy proven changes years after gluten withdrawal.

Gluten is found in certain cereal grains including wheat, barley, and rye. It is not found in rice or corn, and oat flour is usually safe for celiac patients, although this is somewhat controversial. The gliadin moiety, a complex mixture of glutamine and proline rich polypeptides, seems to be the factor causing the mucosal damage. How gliadin causes the typical celiac mucosal alterations is not precisely known, but it is clear that both genetic and environmental factors are involved. Celiac disease is found in 10% of first order relatives of known celiac patients. Furthermore, a 70% concordance rate is noted in HLA identical twins. Genetic markers for celiac sprue have recently been elucidated. Approximately 95% of affected individuals inherit the DQA1*0501 and DQB1*0201 alleles, mapping on the HLA region of chromosome 6. These code for the HLA-DQ molecule DQ2. No known structural abnormalities in these DQ alleles have been found in celiac patients, and the majority of individuals who have these HLA haplotypes remain healthy. It is likely that these individuals are genetically susceptible to celiac development, but an immunologic or environmental trigger may be necessary for development of disease.

Immune mechanisms clearly play a role in sprue pathogenesis. Antigliadin antibodies are usually found in celiac sprue patients, in both serum and intestinal luminal secretions. These antibodies may participate in cell-mediated cytotoxic destruction of absorptive cells, or cause immune complex formation, which bind complement and cause local destruction. T- cell activation may also play a role, as many cells in the lamina propria of untreated patients are activated. This activation may cause the release of TNF and interferon, resulting in inflammation and epithelial cell damage. Interestingly, mucosal damage in graft-versus-host disease resembles that in celiac sprue, further suggesting that T-cell activation may play a role.

The environmental trigger causing immunologic activation has yet to be determined, but human type 12 adenovirus has an amino acid segment with high sequence homology to alpha-gliadin. Molecular mimicry of the viral segment by gliadin peptides may be the underlying trigger. The gliadin sequences are presented by the specific HLA heterodimers to gliadin specific T-cells. T-cell activation causes cytokine release and B-cell activation. B-cells produce antibodies that may cause antibody dependent cell-mediated cytotoxicity or complement mediated cytotoxicity. The end result is mucosal damage.

Celiac disease is found in about 1 in 1000 people in Europe, South America and North Africa. It effects the sexes equally and the initial presentation may be in any age group, although it is more common in children. The United States was thought to have a much lower incidence, but recent studies show antiendomysial antibodies present in about 8 of 2000 people. If this can be considered a diagnostic test, then the prevalence of celiac in the US is similar to other populations.

The clinical presentation of celiac disease can vary tremendously from patient to patient. The patient in this case presented with the most severe form of this disease, the so-called "celiac crisis," where pan-malabsorption lead to a life threatening nutritional deficit and non-anion gap acidosis. Initial presentation of celiac crisis in adulthood is rare, with most patients being children under two years.

The most common presenting signs and symptoms include diarrhea, weight loss, fatigue, bloating and flatulence. This patient had all of these including diarrhea of approximately 10 liters per 24 hours. Diarrhea is caused by increased stool volume and osmotic load delivered to the colon (secondary to malabsorption). Water and electrolytes are secreted into the small intestine rather than absorbed and if the ileum is involved, absorption of bile salts is impaired. Weight loss in sprue is variable as some patients may compensate by increasing their appetite tremendously, however some, like our patient, actually develop anorexia, predisposing them to marked weight loss.

Celiac disease can manifest in extraintestinal disease as well. Anemia is a very common adult presentation of sprue. It is usually caused by impaired iron of folate absorption in the duodenum, but may be related to vitamin B12 deficiency if the terminal ileum is involved. Mucosal and GI bleeding may also contribute to anemia. This bleeding is the result of impaired coagulability secondary to poor vitamin K absorption. Hyposplenism and thrombocytosis occurs in 50% of adults; the etiology of this is unknown. Osteopenic bone disease is common, resulting from poor calcium and vitamin D absorption. Secondary hyperparathyroidism may result, further increasing the destruction of bone matrix. Interestingly, patients with severe disease may sometimes have neurologic symptomatology. Lesions of either the central or peripheral nervous system have been found, resulting in muscle weakness, paresthesias and ataxia. Our patient was known to have a recent episode of idiopathic peripheral neuropathy causing right foot drop. It is possible this finding was directly related to his as of yet undiagnosed celiac disease.

Diagnosis of celiac disease has clinical, pathologic and serologic components. Clinically, in any patient presenting with intractable diarrhea and weight loss a diagnosis of celiac disease must be considered. The patient should also experience full clinical remission after the removal of gluten from the diet. The typical pathologic findings of flattened villi, hypertrophic crypts and absence of the brush border, should also be biopsy proven. Serologic testing has also become helpful in making the diagnosis. IgA and IgG antiendomysial and antigliadin antibodies are usually present in patients with true celiac sprue. Antiendomysial IgA is the most sensitive and specific test but may be falsely negative (along with antigliadin IgA) when the patient has IgA deficiency, a common associated disorder of celiac disease. This patient was both IgG and IgA antigliadin +, but IgA antiendomysial negative. IgG antiendomysial testing was not ordered. The finding of a negative IgA antiendomysial antibody should not cast doubt on this patient’s diagnosis, as tissue biopsy is still the gold standard.

At first glance, the treatment of celiac disease seems simple, complete removal of gluten from the diet. In reality however, a diet free of gluten is exceedingly difficult to achieve and maintain, especially here in the US where gluten is ubiquitous. Wheat, barley and rye must be completely avoided and oats should be avoided initially as their consumption may or may not exacerbate sprue. Wheat is often hidden in processed foods. It is sometimes found in ice cream, salad dressing, canned vegetables and soups, coffee, ketchup, mustard and candy bars. Therefore a skilled nutritionist is often required to help patients achieve and maintain a completely gluten free diet. Patients generally tolerate rice, soybean, corn, millet, buckwheat, sorghum and tapioca. Furthermore, patients often require replacement therapy in addition to gluten removal. Anemic patients may need iron, folate or vitamin B12 replacement. Electrolyte imbalances must be aggressively treated. In this patient, replacement of bicarbonate was necessary as he developed a significant non-anion gap metabolic acidosis. Serum calcium levels must be strictly monitored and almost all celiac patients should receive both calcium and vitamin D supplementation in an effort to stave off osteopenic changes.

Complications of celiac disease generally fall into three categories, malignancy, stricture and ulceration, and refractory sprue. Malignancy accompanying celiac disease was found in 11-13% of patients. The most common of these was T-cell lymphomas, followed by squamous cell carcinomas of the esophagus and small intestinal adenocarcinomas, the latter showing a full 80 fold increase over the expected population incidence. This patient had a previous diagnosis of CLL, but I was unable to find any studies linking this (or any other leukemia) with celiac sprue. Ulceration and stricture is a rare complication of sprue, but well documented. These patients often present with abdominal pain, intestinal bleeding and obstruction. Peritonitis can develop if not treated early and aggressively with surgical intervention. Finally, some patients may develop celiac disease, which is unresponsive to gluten withdrawal. These patients usually respond to removal of gluten initially, but will later experience relapses even with strict gluten avoidance. Some of these patients will respond to corticosteroid or immunosuppressive medications, but usually not permanently. Refractory sprue can often lead to death even with aggressive fluid and electrolyte management.

Prognosis of celiac patients is generally quite favorable as long as the condition is recognized and appropriate therapy is instituted. Of course, untreated sprue can often lead to life-threatening malnutrition and electrolyte abnormalities. Moreover, patients who develop one of the complications mentioned above will certainly have a much poorer prognosis. In general, patients with gluten responsive sprue and no complications have an only slightly elevated mortality rate as compared with controls, and most die of causes unrelated to their celiac disease.

Before assays for antiendomysial and antigliadin antibodies became available, we had to rely on Type II anti-reticulin antibodies as an indication that celiac disease might be present. In 1986 I published a paper demonstrating that such antibodies were no commoner in CLL patients than in age-matched individuals. Like the authors of this case report I am convinced that the celiac disease and CLL in this patients are unrelated. This goes to point out that treating the CLL in the hope that the autoimmunity might remit is dangerous and futile.

Another trap to avoid falling into is to think that if small lymphocytes are found in strange places, such as the bowel wall, that they must be pathological. In CLL, small lymphocytes are found everywhere.

Scotland wants to go it alone ... again.

2011-11-27T13:31:00.003Z

Alex Salmond, the First Minister of Scotland, has promised a referendum to the people of Scotland to repeal the Act of Union whereby Scotland joined England and Wales to become the United Kingdom in 1707. Since the current financial crisis in the UK was precipitated by the government having to take the Royal Bank of Scotland and the Bank of Scotland into partial private ownership, a lot of English people would be pleased to say "Good riddance". What a lot of people don't know is why the Scots signed up to the Act of Union in the first place.

The Darién scheme was an unsuccessful attempt by the Kingdom of Scotland to become a world trading nation by establishing a colony called "New Caledonia" on the Isthmus of Panama in the late 1690s. In practice the undertaking was marked by poor planning and leadership, lack of demand for trade goods, devastating epidemics of disease, and increasing shortage of food; it was finally abandoned after a siege by Spanish forces in April of 1700. As the Darien company was backed by about a quarter of the money circulating in Scotland, its failure left the nobles and landowners – who had suffered a run of bad harvests – almost completely ruined and was an important factor in weakening their resistance to the Act of Union (finally consummated in 1707).

The late 17th century was a difficult period for Scotland. The country's economy was relatively small, its range of exports very limited and it was in a weak position in relation to England, its powerful neighbour (with which it was in personal union, through James I (VI in Scotland) but not yet in political union). In an era of economic rivalry in Europe, Scotland was incapable of protecting itself from the effects of English competition and legislation. The kingdom had no reciprocal export trade and its once thriving industries such as shipbuilding were in deep decline. Goods which were in demand had to be bought from England for Sterling, the Navigation Acts further increased economic dependence on England by limiting Scots shipping and the navy was tiny. Several ruinous civil wars in the late 17th century had squandered the country's human and other resources, the 1690s also saw several years of widescale crop failure, which brought famine. This period was referred to as the "ill years." The deteriorating economic position of Scotland led to calls for a favorable political union, or at least a customs union, with England. However the stronger feeling among Scots - which played to their pride - was that the country should become a mercantile and colonial great power like England.

In response, a number of remedies were enacted by the Parliament of Scotland: in 1695 the Bank of Scotland was established; the Act for the Settling of Schools established a parish-based system of public education throughout Scotland; and the Company of Scotland was chartered with capital to be raised by public subscription to trade with "Africa and the Indies". The Company of Scotland easily raised subscriptions in Amsterdam, Hamburg and London for the scheme. The English Government of King William III, however, was opposed to the idea. It was at war with France and hence did not want to offend Spain which claimed the territory as part of New Granada. It was also under pressure from the English East India Company, who were keen to maintain their monopoly over English foreign trade. It therefore forced the English and Dutch investors to withdraw. Next, the East India Company threatened legal action on the grounds that the Scots had no authority from the king to raise funds outside the English realm, and obliged the promoters to refund subscriptions to the Hamburg investors. This left no source of finance but Scotland itself.

Returning to Edinburgh, the Company raised 400,000 pounds sterling in a few weeks (equivalent to roughly £40 million in 2007, with investments from every level of society, and totalling roughly a fifth of the wealth of Scotland. The Company of Scotland for Trading to Africa was able to raise what was, for Scotland, a massive amount of capital. Scots born trader and financier William Paterson had long been promoting a plan for a colony on the Isthmus of Panama to be used as a gateway between the Atlantic and Pacific — the same principle which, much later, would lead to the construction of the Panama Canal. Patterson, who had a huge capacity for hard work was instrumental in getting the Company off the ground in London. He had failed to interest several European countries in his scheme but in the aftermath of the English reaction to the Company he was able to get a respectful hearing for his ideas. The Scots' original aim of emulating the East India Company by breaking into the lucrative trading areas of the Indies and Africa was forgotten and the highly ambitious Darien scheme was adopted by the company. Paterson fell from grace when a subordinate embezzled from the Company. The Company took back Patterson's stock and expelled him from the Court of Directors; he was to have little real influence on events after this point.

There were a large number of former officers and soldiers who joined happily as they had little hope of any other employment, many were acquainted from serving in the army and several – the best known being Thomas Drummond – were notorious for involvement in the Massacre of Glencoe, in some eyes they appeared to be a clique and this was to cause much suspicion among other members of the expedition.

The first expedition of five ships (Saint Andrew, Caledonia, Unicorn, Dolphin, and Endeavour) set sail from the east coast port of Leith to avoid observation by English warships in July 1698, with around 1,200 people on board. The journey round Scotland while kept below deck was so traumatic that some colonists thought it comparable to the worst parts of the whole Darien experience. Their orders were to proceed to the Bay of Darien, and make the Isle called the Golden Island … some few leagues to the leeward of the mouth of the great River of Darien … and there make a settlement on the mainland. After calling at Madeira and the West Indies, the fleet made landfall off the coast of Darien on 2 November. The settlers christened their new home "New Caledonia".

With Drummond in charge they cut a ditch through the neck of land that divided one side of the harbour in Caledonia Bay from the ocean, and constructed Fort St Andrew, equipped with 50 cannon, on the peninsula behind the canal; the fort did not have a source of fresh water. On a mountain, at the opposite side of the harbour, they built a watchhouse. Close to the fort they began to erect the huts of the main settlement, New Edinburgh, and to clear land for growing yams and maize. Letters sent home by the expedition created the misleading impression that everything was going according to plan. This seems to have been by agreement as certain optimistic phrases kept recurring, but it meant the Scottish public would be completely unprepared for the coming disaster.

Agriculture proved difficult and the local Indian tribes, although hostile to Spain, were unwilling to buy the combs and other trinkets offered by the colonists. Most serious was the almost total failure to sell any goods to the few passing traders that put in to the bay. With the onset of summer the following year the stifling atmosphere, along with other causes, led to a large number of deaths in the colony. Eventually the mortality rate rose to ten settlers a day. Although local Indians brought gifts of fruit and plantains these were appropriated by the leaders and sailors who largely remained onboard ship. The only luck the settlers had was in giant turtle hunting but fewer and fewer men were fit enough for such strenuous work. The situation was exacerbated by the lack of food mainly due to a high rate of spoilage caused by improper stowing, at the same time King William had instructed the Dutch and English colonies in America not to supply the Scots' settlement so as not to incur the wrath of the Spanish Empire. The only reward the council had to give was alcohol, and drunkenness became common, even though it speeded the deaths of many men weakened by dysentery, fever and the rotting, worm infested food. After eight months the colony was abandoned in July 1699 apart from six men who were too weak to move. Deaths continued on the ships, and those who managed to survive the journey and returned home found themselves regarded as a disgrace to their country and even disowned by their families.

Only 300 of the 1,200 settlers survived and only one ship managed to return to Scotland. A desperate ship from the colony that called at the Jamaican city of Port Royal was refused assistance on the orders of the English government, which feared antagonising the Spanish.

Word of the first expedition did not reach Scotland in time to prevent a second voyage of more than 1,000 people. The second expedition arrived on November 30, 1699 and found two sloops there; one with Thomas Drummond from the original expedition. Some men were sent ashore to rebuild huts, which caused others to complain that they had come to join a settlement, not build one. Morale was low and little progress was made. Drummond insisted that there could be no discussion, the fort must be rebuilt as the Spanish attack would surely come soon, but he clashed with the merchant James Byres who maintained the Counsellors of the first expedition had now lost that status, and consequently had Drummond arrested. Initially bellicose, Byres began to send away all those he suspected of being offensively minded – or of being allegiant to Drummond. He outraged a Kirk Minister by claiming it would be unlawful to resist the Spanish by force of arms, as all war was unchristian. He then showed his real concern was for his own personal safety by deserting the colony in a sloop. The colonists sank into apathy until the arrival of Alexander Campbell of Fonab, sent by the company to organize a defence. He provided the resolute leadership which had been lacking and took the initiative from the Spanish by driving them from their stockade at Toubacanti in January 1700. However, Fonab was wounded in this daring frontal attack and became incapacitated with a fever. The Spanish force – who were also suffering serious losses from fever – closed in on Fort St Andrew and besieged it for a month, although disease was still the main cause of death during this time. The Spanish commander called for the Scots to surrender and avoid a final assault, warning that if they did not no quarter would be given. After negotiations the Scots were allowed to leave with their guns, and the colony was abandoned for the last time. Only a handful of those from the second expedition returned to Scotland. Of the total 2,500 settlers that set off, just a few hundred survived.

The failure of the scheme provoked tremendous discontent throughout Lowland Scotland where almost every family had been affected. Many held the English responsible while believing that they could and should assist in yet another effort at making the scheme work. The company petitioned the King to affirm their right to the colony however he declined replying that, though he was sorry that the company had incurred such huge loses, to claim Darien would mean war with Spain. The continuing futile debate on the issue served to further increase bitter feeling.

Hoping to recoup some capital by a more conventional venture, the company sent two ships from the Clyde, the Speedy Return and the Continent, to the Guinea coast laden with trade goods. Sea captain Robert Drummond was the master of the Speedy Return, his brother Thomas, who had played such a part in the second expedition, was supercargo on the vessel. Neither ship was seen in Scotland again. Instead of seeking to sell for gold as the company's directors intended the Drummonds exchanged the goods for slaves which they sold in Madagascar. Carousing with the buccaneers for whom the island was a refuge, the Drummonds fell in with the pirate John Bowen of Bermuda who offered loot if they lent the Scots ships to him for a raid on homeward bound Indiamen. Robert Drummond was initially persuaded but backed out of the agreement, only for Bowen to appropriate the ships while he was ashore. The Continent was lost to fire on the Malabar coast and Bowen scuttled the Speedy Return after transferring to a merchant ship he had taken. The Drummonds decided against returning to Scotland to explain the loss of the ships they had been entrusted with and no more was ever heard of the tough-minded brothers.

The company sent out another ship but it was lost at sea. Not being able to afford the cost of fitting out yet another ship the Annandale was hired in London with the intention of trading in the Spice Islands, but the East India Company had it seized on the grounds that the venture was a contravention of their charter. This provoked uproar in Scotland, greatly aided by the inflammatory rhetoric of the company's secretary, and relentless enemy of the English, Roderick MacKenzie. Fury at the country's impotence led to what followed: the scapegoating and hanging of three innocent English sailors.

The failure of the Darien scheme has been cited as one of the motivations for the 1707 Acts of Union. According to this argument, the Scottish establishment realised that it could never be a major power on its own and that if it wanted to share the benefits of England's international trade and the growth of the English Empire, then its future would have to lie in unity with England. More so, Scotland's nobles were almost bankrupted by the "Darien Fiasco". Some Scots nobility petitioned Westminster to wipe out the Scottish national debt and stabilise the currency. The first request was not met though the second was and a Scottish Pound was given the fixed value of a shilling. Personal Scottish financial interests were also involved. Scottish Commissioners had invested heavily in the Darien Scheme and they believed that they would receive compensation for their losses. The 1707 Acts of Union, Article 14, granted £398,085 10s sterling to Scotland to offset future liability towards the English national debt.

John 8:16. The judgment next time.

2011-11-27T12:33:00.003Z

But if I do judge, my decisions are right, because I am not alone. I stand with the Father who sent me.

Note the further "I AM". Jesus is not bereft of the ability to judge; he could have judged the world when he came first time, because he stood, co-equal, with the Father. But he was sent by the Father with a particular purpose: not to judge but to warn and to save. The judgment next time.

treasure in pots of clay

2011-11-27T11:40:00.002Z

One of the enduring questions that Christians must ask themselves is why such terrible things are happening to them. From time to time I have posted about suffering Christians garnered from Open Doors or Barnabas Trust. It is not just in Muslim lands, but in parts of India, in former Communists states, In China and North Korea, but also in South America and in so-called Christian lands like Greece that true Christians are suffering. We have also seen Christians persecuted in Britain, Germany and America by secular humanists.

On an individual basis Christians do not have an especial prosperity or freedom from sickness compared to other people. Some Christians have lost their assurance because other Christians have told them that their faith is deficient and they cannot withstand the devil. This is all nonsense of course. A weak faith in a strong God is superior to a strong faith in a weak God.

In Paul's second letter to the Corinthians chapter 4 v 7 Paul tells us that we have the treasure of the Gospel in jars of clay. We don't have the treasure in a fine setting like the Crown Jewels in the Tower of London. It is not their setting that makes them beautiful; in fact the contrast of what we are like against the beauty of the truth is what enhances it.

It is all the more likely that when we are at our lowest will come the opportunity to share the Gospel.

There is no doubt that while the Arab Spring is a good time for freedom and democracy it is also a perilous time for Christians who are being persecuted in Egypt, Libya, Tunisia and next in Syria. Yet in Mali, at the University of Timbuktu, where Christians are very few in number, a remarkable thing is happening. Muslims are seeing visions of a man in bright clothes carrying a book. There have been thousands of such visions and they want to know what it means.

There is a Muslim tradition that Jesus will return, but how to reconcile this vision of the Angel of the LORD with Jesus. They have sought out a solitary secret Christian and set him up in a stall in the Mosque where queues have gathered to quiz him about the story of Jesus. There have been many conversions. You see the vision has coincided with the translation by the Wycliffe Bible Translators of the New Testament into the local Malian language.

We should pray that as the church in North Africa is persecuted, that God would act supernaturally to overcome the Devil and work a great wonder of conversion in its wake. Perhaps our best approach for secular persecution in our own countries is prayer, not the law courts.

F v FA as second line: a phase 3 trial

2011-11-26T12:45:00.004Z

This report on a second line treatment for CLL from Lancet Oncology today

Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial

Despite the increasing number of treatment options, chronic lymphocytic leukaemia (CLL) remains an incurable disease. Estimates of median survival range from more than 10 years for patients with early-stage CLL to less than 1 year for patients with fludarabine-resistant disease. In view of the incurable and chronic nature of CLL, and the worsening prognosis for patients as their disease becomes more advanced or refractory, the development of alternative regimens in earlier treatments is essential to improve their outcome.

Preclinical data suggested that the addition of alemtuzumab to fludarabine-based regimens could have a synergistic effect due to their complementary modes of action. In a report by Kennedy and colleagues, five of six patients with CLL who were refractory to both drugs when administered as single agents achieved remission with the combination of fludarabine and alemtuzumab.

Results from a single-group phase 2 study further suggested that fludarabine and alemtuzumab combination could improve outcomes in patients with relapsed or refractory CLL, with an overall response rate (ORR) of 83% and a median overall survival of 35·6 months. Therefore, we compared the efficacy and safety of this combination treatment with fludarabine monotherapy in patients with relapsed or refractory CLL.

The study was done in five centres in North America and 43 in Europe. Eligible patients had relapsed or refractory CLL according to the National Cancer Institute Working Group's 1996 criteria, with evidence of progressive disease that required therapy after one previous line of treatment for CLL. Patients could have had past treatment with fludarabine or alemtuzumab provided the duration of their response was longer than 12 months. Additional inclusion criteria were Binet stage A, B, or C or Rai stage I–IV disease; WHO performance status (PS) 0 or 1; life expectancy of 12 weeks or longer; age 18 years or older; anticancer treatment, major surgery, or radiation therapy more than 3 weeks before randomisation in the study; complete recovery from acute side-effects of previous therapy; and adequate renal and liver function.

Exclusion criteria were previous treatment for CLL with more than one previous regimen or the combination of fludarabine and alemtuzumab; positive Coombs test and active haemolysis; absolute neutrophil count (ANC) of less than 1·5×10e9 cells per L or platelet count of less than 75×10e9 per L, unless due to bone-marrow involvement with CLL; disorders requiring chronic use of corticosteroids; history of anaphylaxis to monoclonal antibodies; HIV positivity; evidence of active infection or history of grade 4 infection within 3 months before randomisation in the study; active second malignancy; known CNS involvement with CLL; other severe concurrent disease; progression due to a more aggressive B-cell cancer (eg, Richter's syndrome); and a history of viral hepatitis or positive hepatitis B serology in the absence of immunisation.

This study was approved by the institutional review board or ethics committee from each of the participating sites. All patients provided written informed consent before enrolment to the study.

An interactive voice response system (IVRS) was used to randomly assign patients in a 1:1 ratio to fludarabine plus alemtuzumab or fludarabine monotherapy in an open-label trial. At call-in from the site to enrol the patients, IVRS conveyed stratification data to a computer system and initiated the randomisation program. The system retrieved stratification and treatment assignment data for previously enrolled patients, and a computer-generated next random number was provided by the sponsor's statistician. The system used the minimisation method9 with the probability parameter 0·80 to assign patients to treatment. The stratification factors were study centre, Rai stage (I or II vs III or IV), disease status (relapsed vs refractory), age (≥65 vs <65 years), sex (male vs female), past exposure to fludarabine therapy (yes vs no), and maximum lymph node size (≥5 vs <5 cm or none).

During the first treatment cycle, patients in the combination group were given escalating doses of alemtuzumab; 3 mg/day, 10 mg/day, 30 mg/day, intravenously over 2 h. If grade 3 or 4 infusion-related adverse events occurred, the same dose was repeated daily until it was well tolerated (grade 2 or lower toxicity) with appropriate premedication. A maximum of 14 days were allowed for alemtuzumab escalation to 30 mg. After completion of the escalation, patients were given fludarabine; 30 mg/m2 per day, intravenously over 30 min, followed immediately by alemtuzumab (30 mg/day, intravenously over 2 h); both were administered daily for 3 days. Cycles were repeated every 28 days. After cycle 1, alemtuzumab was infused over 4–6 h for the first day of each new cycle and over 2 h during days 2 and 3. Patients randomly assigned to the fludarabine monotherapy were treated with 25 mg/m2 per day for 5 days, intravenously, over 15–30 min, every 28 days. Patients in both groups were scheduled to receive a minimum of four cycles and a maximum of six treatment cycles, depending on response and toxicity. They were assessed for response every two cycles. Patients in the fludarabine plus alemtuzumab group were administered paracetamol 500–1000 mg orally 30 min before alemtuzumab infusion for control of infusion-related events and an antihistamine 30 min before drug administration as prophylaxis for infusion-related events. Patients were premedicated with hydrocortisone (100 mg, intravenously, or equivalent steroid) just before alemtuzumab infusion during the dose escalation phase, on day 1 of each subsequent cycle, and if clinically indicated thereafter. All patients were given prophylaxis with co-trimoxazole (trimethoprim 160 mg plus sulfamethoxazole 800 mg twice a day, three times a week, orally) or equivalent and famciclovir (500 mg twice a day, orally), starting on the first day of the study treatment and continuing until CD4+ cell counts were at least 200 cells per μL.

If patients developed haematological toxicities with a recovery time (ie, retreatment criteria ANC ≥1·0×10e9 cells per L, platelet count ≥100×10e9 per L, and no active infection) from the scheduled start of the new cycle of 14 days or less (days 29–43 of previous cycle), no dose modification was required in those assigned to combination treatment or monotherapy; 15–28 days (days 44–57 of previous cycle), patients assigned to combination treatment were given fludarabine 30 mg/m2 per day plus alemtuzumab 30 mg/day for 2 days every 28 days, and those assigned to monotherapy were administered 16·75 mg/m2 per day for 5 days every 28 days; and more than 28 days (after day 57 of previous cycle), treatment was discontinued in the combination treatment or monotherapy group.

In the event of a non-haematological toxicity of grade 1 or 2, no dose modification was required with combination treatment or monotherapy; grade 3, patients assigned to combination treatment were given fludarabine 30 mg/m2 per day plus alemtuzumab 30 mg/day for 2 days every 28 days, and those assigned to monotherapy were administered 16·75 mg/m2 per day for 5 days every 28 days; if a patient recovered more than 28 days after the date of the originally scheduled start of the next treatment cycle, the patient was withdrawn from the study; grade 4, treatment was discontinued in patients assigned to combination treatment or monotherapy. Patients with a creatinine clearance of 0·50–1·17 mL/s per 1·73 m2 were treated with fludarabine at a 20% dose reduction. Other protocol-mandated reasons for treatment delay or discontinuation were neurotoxicity; serious infection; grade 3 or higher pulmonary, renal, or hepatic toxicity; autoimmune thrombocytopenia; and symptomatic autoimmune anaemia.

Patients were monitored weekly with complete blood count and testing for cytomegalovirus (with quantitative PCR on peripheral blood) during cycles 1 and 2, and every 2 weeks thereafter. Monthly complete blood count, CD4+ cell count, and testing for cytomegalovirus continued after cycle 6 until blood counts recovered or stabilised and CD4+ cell counts rose to more than 200 cells per μL. Patients who were PCR-positive for cytomegalovirus without clinical symptoms of cytomegalovirus infection or had rising viral transcripts on subsequent weekly PCR testing were treated with valganciclovir while on study treatment. Those with clinical manifestations of cytomegalovirus infection (fever or end-organ symptoms) were treated with ganciclovir for at least 10 days. Interruption of study treatment was allowed for up to 28 days before necessitating discontinuation from study participation.

Clinical, radiographic (chest radiography or CT if clinically indicated), and laboratory assessments for response or progression were done every two cycles during treatment and every 3 months after treatment until disease progression. Thereafter, patients were followed up for survival only. Patients with a clinical complete response (CR) or partial response (PR) without recovery of blood counts underwent bone-marrow assessment and testing for minimal residual disease (MRD) 2 months after the end of treatment.

The primary endpoint was progression-free survival (PFS), defined as the time of randomisation to progression or death from any cause, whichever was earlier. The primary endpoint was changed from time to progression (TTP) to a more conservative definition of PFS before any of the planned interim analyses were undertaken to make the data more comparable with data from other randomised studies of patients with CLL.

The main secondary endpoints were ORR, CR rate, overall survival, and safety. Additional, secondary endpoints were TTP, duration of response, time to alternative treatment, incidence of MRD negativity, fludarabine pharmacokinetics, and health-related quality of life. The main analysis of efficacy was based on the assessments of response and disease progression for each patient by the independent response review panel, members of which were masked to treatment assignment. Response criteria and progression were assessed according to the National Cancer Institute Working Group's 1996 guidelines for CLL; criteria for disease progression were specified in the study protocol and were in accordance with these guidelines.8 The health-related quality-of-life instrument was a five-dimensional questionnaire about health status and a visual analogue scale thermometer for self-rating current health-related quality of life. The five dimensions were mobility, self-care, usual activities, pain or discomfort, and anxiety or depression, rated according to three possible levels (no problems, some problems, and extreme problems). Exploratory analyses to investigate the effect of prespecified prognostic factors on efficacy outcomes were also undertaken.

Toxicities were graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0). All patients who were given at least one dose of study drug were included in the safety analysis.

The planned sample size for this study of 300 patients (150 per group) to observe 190 events of progression or death, irrespective of treatment group, was designed to detect a 50% improvement in PFS in either group with 80% power and a two-sided α of 0·05. Two interim analyses were planned to assess safety and efficacy at a third and two-thirds of the total planned events under the jurisdiction of a data safety monitoring board. To protect the overall α of 0·05 for the analysis of the primary endpoint, a Lan and DeMets error spending function with an O'Brien–Fleming boundary was used to allow flexibility with the timing of the interim analyses.

Differences in PFS and overall survival between the treatment groups were tested by use of the Cox proportional hazard model, stratified by Rai stage (I or II vs III or IV). Differences in ORR and CR were tested with the Cochran-Mantel-Haenzsel method stratified by Rai stage (I or II vs III or IV). The main analysis was done on an intention-to-treat (ITT) basis for all patients who were randomly assigned. To control family-wise error rate at the 0·05 level, a multiple-tests' adjustment with the Hochberg procedure12 was prespecified for the three clinically important secondary endpoints: ORR, CR, and overall survival. Statistical analyses were done with the Statistical Application Software (version 9.1.3).

The study is registered with ClinicalTrials.gov, number NCT00086580

From July, 2004, to October, 2008, 335 patients were enrolled (18 in centres in North America and 317 in Europe) and randomly assigned to fludarabine alone or with alemtuzumab. More patients than planned were enrolled to enable an analysis of potential drug–drug interactions. Six patients were not given the study treatment and therefore were not included in the safety analysis. Baseline demographics and disease characteristics used for stratification were well balanced between the treatment groups.

In both groups, patients were given a median of six treatment cycles (range 1–6), and 105 (64%) of 164 patients in the combination treatment group and 107 (65%) of 165 in the monotherapy group were given six cycles. The median cumulative dose of alemtuzumab was 583 mg (range 3–653) and fludarabine 494·5 mg/m2 (0–568·4) in the combination treatment group, and fludarabine 687·5 mg/m2 (20·6–776·5) in the monotherapy group.

Fludarabine plus alemtuzumab significantly prolonged PFS compared with fludarabine. The ORR was non-significantly higher in the combination treatment group than in the monotherapy group. The CR rate was significantly higher in the fludarabine plus alemtuzumab group than in the fludarabine alone group. The independent response review panel identified six patients in the combination treatment group and none in the monotherapy group as MRD negative (p=0·014).

With a median follow-up for all enrolled patients of 29·5 months (IQR 16·5 to 42·1 months), the median overall survival was significantly improved in the fludarabine plus alemtuzumab group, with 117 (70%) of 168 patients in the combination treatment group and 100 (60%) of 167 in the monotherapy group alive at the data cutoff or last follow-up date. After the predefined multiple testing adjustment, the comparisons between groups for CR rate and overall survival remained significant (p=0·018 and p=0·042, respectively). There was no apparent treatment difference in the quality-of-life indicators.

The significantly improved PFS in patients treated with combination treatment compared with monotherapy was consistent for all prespecified subgroups, including those judged to be high risk (advanced disease and older patients). Patients with advanced disease (Rai stage III or IV) who were given combination treatment had a longer median PFS than did those given fludarabine. The ORR and CR rate were also significantly higher. Notably, patients with Rai stage III or IV who were given fludarabine plus alemtuzumab also had significantly improved median overall survival compared with those treated with fludarabine alone, indicating survival benefit in favour of the combination treatment. Improvement in overall survival was not noted in patients with Rai stage I or II CLL (HR 1·07, 95% CI 0·62–1·84; p=0·82). There was evidence of differential treatment benefit in terms of overall survival with the combination treatment in the patients who were Rai stage III or IV compared with Rai stage I or II (p=0·011). In older patients (age ≥65 years), median PFS was significantly longer with the combination treatment than with fludarabine alone. Median overall survival for this older population was not reached in the group assigned to fludarabine plus alemtuzumab, whereas it was 40·9 months in the monotherapy group.

161 (98%) of 164 patients in the fludarabine plus alemtuzumab group and 149 (90%) of 165 in the fludarabine group had all-cause adverse events. In the combination treatment group, non-haematological all-cause adverse events occurring in more than 10% of patients were pyrexia, chills, rash, infusion-related reactions, urticaria, cytomegalovirus PCR positivity, and nausea. In the monotherapy group, none of the non-haematological all-cause adverse events arose in more than 10% of patients. The most common all-cause serious adverse events that arose in more than 2% of patients in the fludarabine plus alemtuzumab group were neutropenia, febrile neutropenia, pneumonia, pyrexia, thrombocytopenia, diarrhoea, and leucopenia. In the fludarabine group, these were febrile neutropenia and anaemia.

Ten patients in the fludarabine plus alemtuzumab group and 12 in the fludarabine group died as a result of adverse events (irrespective of cause). During the treatment period (date of first dose to 30 days after last dose), four patients in the combination treatment group and seven in the monotherapy group died as a result of an adverse event. The causes of these deaths were similar (acute respiratory and circulatory insufficiency [n=2], acute haemolysis [n=1], and cardiopulmonary insufficiency [n=1] in the fludarabine plus alemtuzumab group; disease related [n=2], acute respiratory and circulatory insufficiency [n=2], septic shock syndrome [n=1], acute myocardial infarction [n=1], and pulmonary oedema in the fludarabine group [n=1]). Of these, three fatal drug-related adverse events occurred in the combination treatment group (acute haemolysis [n=1] and acute respiratory and circulatory insufficiency [n=2]) and three in the fludarabine group (acute respiratory and circulatory insufficiency [n=2] and septic shock syndrome [n=1]).

The overall incidence of severe haematological toxicity (defined as laboratory changes from less than grade 3 at baseline to grade 3 or greater post-baseline, or changes from grade 3 at baseline to grade 4 post-baseline) during the treatment period are shown in table 5. The median time to recovery of CD4+ cell counts (>200 cells per μL) was 3·0 months (95% CI 2·7–4·7) in the fludarabine plus alemtuzumab group and 2·0 months (1·8–2·6) in the fludarabine group.

All-cause infections occurred in 67 (41%) of 164 patients in the combination treatment group and in 58 (35%) of 165 in the monotherapy group. The types and severity of all infections were similar in the two groups with the exception of lower-respiratory-tract infections (26 [16%] vs eight [5%]) and viral infections (19 [12%] vs ten [6%]), which occurred more frequently in the fludarabine plus alemtuzumab group. Additionally, the incidences of infections that were greater than grade 3 were similar in both groups—19 patients in the combination treatment group (grade 3 [n=17], grade 4 [n=1, pneumonia], grade 5 [n=1, pneumonia]) versus 17 in the monotherapy group (grade 3 [n=10], grade 4 [n=3], grade 5 [n=4]). Grade 4 infections in the fludarabine group were Escherichia coli gastroenteritis (n=1) and sepsis (n=2), and grade 5 infections were pneumococcal sepsis (n=1), pyelonephritis (n=1), septic shock (n=1), and oral fungal infection (n=1).

Cytomegalovirus-PCR-positive tests were reported in 19 (12%) asymptomatic patients in the fludarabine plus alemtuzumab group and in one (<1%) asymptomatic patient in the fludarabine group. Study drug was not discontinued for any of the patients with asymptomatic cytomegalovirus PCR positivity. The median time to first occurrence of a PCR-positive test was 30 days (range 20–52) for patients in the fludarabine plus alemtuzumab group; only one patient in the fludarabine monotherapy group had cytomegalovirus PCR positivity (on day 69 after the start of treatment). Symptomatic cytomegalovirus infection was reported in four patients (2%) only in the fludarabine plus alemtuzumab group, and their symptoms were fever (n=2), hepatitis (n=1), and fever, fatigue, malaise, and leucopenia (n=1). One patient discontinued study treatment because of symptomatic cytomegalovirus infection. All patients with symptomatic cytomegalovirus infections were treated with ganciclovir and recovered without sequelae.

121 (74%) of 164 patients in the fludarabine plus alemtuzumab group had at least one potentially alemtuzumab infusion-related event (defined as having at least one drug-related adverse event out of the following preferred terms: chills, pyrexia, nausea, vomiting, rash, urticaria, hypotension, bronchospasm, cytokine release syndrome, or infusion-related reaction) during cycles 1–6 compared with 24 (15%) of 165 in the fludarabine group. Potentially alemtuzumab infusion-related adverse events were most common in the initial treatment cycles for the fludarabine plus alemtuzumab group. For chills, pyrexia, nausea, and urticaria, the incidences were highest in cycle 1 and seemed to show a general reduction with progression from cycle 1 to cycle 6 for the fludarabine plus alemtuzumab group. The incidences of bronchospasm, infusion-related reaction, vomiting, and cytokine release were also highest in cycle 1, but the total incidence was low, and therefore a pattern could not be discerned for the fludarabine plus alemtuzumab group. The incidences of hypotension (two [1%]) and rash (21 [13%]) did not seem to be related to the cycle. Furthermore, most of the infusion-related events were mild in the combination and monotherapy groups (grade 1 and 2, 102 [62%] and 22 [13%], respectively), one patient in the fludarabine plus alemtuzumab group had a grade 4 event (pyrexia), and there were no fatal infusion-related events.

No clinically relevant differences in incidence of adverse events were noted between patients with Rai stage I or II versus III or IV, patients aged 65 years and older versus younger than 65 years, or male versus female patients. Furthermore, the safety profile of combination treatment in patients 65 years and older was similar to that of the overall patient population.

The combination of fludarabine and alemtuzumab resulted in a significant improvement in PFS, CR rate, and overall survival compared with fludarabine alone in patients with previously treated relapsed or refractory CLL. Although the difference in ORR between these regimens was not significant, the improvement in PFS and overall survival shows the clinical benefit of the combination treatment. This combination also seemed to provide significant clinical benefit to patients with advanced disease (Rai stage III or IV), a particularly important subset of patients for whom further investigation is warranted.

When compared with single-agent fludarabine, treatment with fludarabine plus alemtuzumab resulted in a similar overall frequency and severity of infectious complications, similar frequency of grade 3 or 4 neutropenia and thrombocytopenia, a lower frequency of anaemia, and, as expected, a higher frequency of lymphopenia. The rate of cytomegalovirus PCR positivity and infections in the combination treatment group was 14% which is lower than the previously reported frequency of 68% with first-line alemtuzumab monotherapy given three times a week. Although there was a discrepancy in grade 3 or 4 adverse events between treatment groups, most of these events were anticipated and they were related to the mechanism of action of alemtuzumab (particularly lymphopenia or leucopenia and infusion-associated reactions). Despite the difference in the occurrence of grade 3 or 4 adverse events, the percentage of patients who discontinued treatment or deaths during treatment was similar in both groups.

Despite the recent advances in treatment options for first-line treatment for patients with CLL, the disease remains incurable, thus treatment decisions require that benefit-to-risk assessments are undertaken for each patient. The National Comprehensive Cancer Network guidelines and European Society of Medical Oncology guidelines suggest consideration of a variety of therapeutic regimens to treat patients with CLL throughout the course of their illness. The substantial heterogeneity of patients with CLL with respect to disease burden, age, and comorbid illnesses means that several options should be available.

Systematic review

A search of the literature identified an earlier phase 2 trial in which excellent results were reported for three times weekly alemtuzumab used in combination with 4-weekly fludarabine, suggesting superadditive effects. At the time of initiation of this trial, results from another phase 2 trial by a German chronic lymphocytic leukaemia (CLL) study group were available, combining alemtuzumab with fludarabine in a 4-week schedule in patients with relapsed and refractory CLL; they also reported high response rates with tolerable toxicity. Since the monthly fludarabine plus alemtuzumab schedule had not been previously investigated in a large, randomised phase 3 study, we designed this study for further assessment of combination treatment.

The findings of our randomised phase 3 study suggest that the monthly administration of alemtuzumab plus fludarabine results in excellent response rates and prolonged progression-free survival and overall survival with a tolerable side-effect profile. Furthermore, the total dose of each drug is substantially reduced and is more convenient for patients. Noteworthy is that patients, especially those with advanced Rai stages, benefited from this treatment approach. Thus, we view this combination as an important treatment option for patients with relapsed or refractory CLL.

Additionally, at the time the protocol was initiated, no combination regimens were approved for use in previously treated patients with CLL and few randomised controlled studies have been undertaken in patients with relapsed or refractory CLL. O'Brien and colleagues reported an ORR of 65% with fludarabine plus cyclophosphamide and 80% with fludarabine plus cyclophosphamide plus oblimersen in patients with relapsed or refractory CLL. It has been reported that in previously treated patients with CLL, compared with fludarabine plus cyclophosphamide, the three-drug combination of fludarabine plus cyclophosphamide plus rituximab extended median PFS (21·9 months vs 27·0 months), and increased ORR (49% vs 61%) and CR rates (3% vs 9%) as assessed by independent review. This comparability is important because fludarabine plus cyclophosphamide and fludarabine plus cyclophosphamide plus rituximab are increasingly used in the front-line setting; additional novel treatment regimens are needed for second-line therapy.

Treatment of CLL has been evolving over the period this study was undertaken. For patients with relapsed or refractory CLL, various guidelines provide options for treatment but no globally recognised standard of care exists. However, fludarabine-based combination regimens have been increasingly used as first-line or subsequent treatments. Although no conclusion can be drawn about the benefit of the combination treatment in the subset of patients with previous exposure to fludarabine because of the small sample size (25 in fludarabine plus alemtuzumab group and 26 in fludarabine monotherapy group], the HR of 0·82 suggests that the combination treatment is beneficial. Additionally, the significant overall treatment benefit noted from all the enrolled patients suggests that the combination treatment provided benefit to all enrolled patients previously given different types of treatment. Also, cytogenetic testing was not required in the initial stages of the study and was added midway through the study. Therefore, cytogenetic data were available for 57% of 335 patients, restricting the statistical precision of analyses in subgroups defined on the basis of these data, and restricting the ability to make conclusions about any effect of cytogenetics on response.

For second-line therapy, the fludarabine plus alemtuzumab regimen has several potential advantages. First, unlike fludarabine plus cyclophosphamide and fludarabine plus cyclophosphamide plus rituximab, the fludarabine plus alemtuzumab regimen spares patients from additional exposure to alkylating drugs, which theoretically might be associated with serious early and late toxicities, such as leukaemia possibly associated with secondary therapy. Second, patients treated with fludarabine plus alemtuzumab had a lower exposure to each drug than with the commonly used dosing regimen when each drug is used alone. The combination regimen uses 50% less alemtuzumab and 30% less fludarabine than the dosing regimen approved by the US Food and Drug Administration for single drug use. Last, the dosing schedule for alemtuzumab of 3 days per month in the fludarabine plus alemtuzumab regimen improves patient convenience compared with the standard dosing regimen of three times per week for up to 12 weeks.

The fludarabine plus alemtuzumab combination provides clinical benefits with an acceptable safety profile in previously treated patients with CLL when compared with single-agent fludarabine. This combination might become an important additional treatment option for patients with relapsed or refractory CLL

John 8:15. Judgment next time, not this

2011-11-25T13:53:00.002Z

You pass judgment by human standards; I pass judgment on no-one.

Shall not the judge of all the earth do right? Abraham so challenged the Angel of the LORD above Sodom and after that in a roundabout way the LORD demonstrated that His judgment was certainly right.

Human judgment is fallible. How often do we see it in our courts! Just as the judgment of the Jews here was flawed, so it is always so. No wonder that Jesus said in the Sermon on the Mount, "Judge not that ye be not judged."

Even here while in person, Jesus refused to judge. He came to warn and to save. Judgment next time.

Health report

2011-11-25T13:10:00.004Z

I am waiting at the moment to hear whether I will be able to have the monoclonal antibody cetuximab. I am cheered by the finding in European Journal of Cancer that response to cetuximab does not depend on previous response to irinotecan, since my response to that drug was not splendid,

I quote, "these findings indicate that the efficacy of irinotecan plus cetuximab in MCRC patients with wild-type KRAS did not differ by previous sensitivity to irinotecan".

I have been waiting for 2 weeks for news and I rang the oncologist this morning to ask him to chase it up.

I am up one day and down the next. Partially, it is the dexamethasone that makes me emotionally labile. I had a weepy day yesterday as I contemplated the things I had left undone. At the end of Schindler's List, Liam Neeson has a scene where he looks at his luxury car and his gold ring and thinks of how many more Jews these could have bought. "I could have done more," he exclaims.

That is how I felt. I told this to Dr John when he visited and he reassured me. None of us can ever do enough. We mustn't reproach ourselves.

Today I am much more cheerful. I went out for the first time in 2 weeks and bought some flowers for my wife. The Scripture tells us not to be weary in well-doing. The Restaurant where we had the reception for my daughter's wedding 2 years ago has just gone bankrupt; I guess they did not market aggressively enough and charged too little. Another shop in our parade has closed. I was glad to patronize the little florist shop. It is a splendid feeling to be able to help out. Some of us with savings should be spreading our wealth around at the present time.

In a rash moment I had bought tickets to see my granddaughter in a school musical tomorrow, but it is a two hour drive and I shall not be well enough to go. Let's hope that the cetuximab will work and I will be able to do these sorts of things again. If I get any sort of response I shall seize the day.

New review of iron metabolism

2011-11-25T12:29:00.003Z

This article from Trends in Molecular Medicine appeals to my long-standin interest in Iron Metabolism. It will only appeal to molecular Biologists and those affected by iron-related diseases. But it adds to the sum of my knowledge as the field moves on.

Iron must enter the body from the diet through absorption in the proximal small intestine. Although some plasma iron is derived from iron absorption, most is derived from the recirculation of hemoglobin-derived iron from senescent red blood cells. This process is carried out by macrophages. Iron that enters the plasma is bound by transferrin and distributed around the body to sites of utilization and storage. Transferrin delivers its iron to cells via an interaction with transferrin receptor 1 (TFR1) found on the plasma membrane of most cells. Iron in excess of immediate cellular needs is stored within ferritin. The coordinated regulation of TFR1 and ferritin is mediated by RNA binding proteins known as iron regulatory proteins. Systemically, iron entry into the plasma is controlled by the liver-derived peptide hepcidin, which is secreted by hepatocytes and acts through its effect on ferroportin, the only known iron export protein. Hepcidin expression is increased by high plasma iron and decreased by low plasma iron. HFE, TFR2 (transferrin receptor 2) and HJV (hemojuvelin) are positive stimuli of hepcidin expression, whereas matriptase-2 is a negative stimulus. In its free form, iron is compatible neither with its transport in the plasma (it would precipitate) nor with the intracellular milieu where it would exert immediate toxicity. Therefore, the human body has developed ways for enabling both iron transport (through transferrin) and intracellular deposition (through ferritin).

Approximately 10% of dietary iron content is absorbed every day in the duodenum, corresponding to 1–2 mg. It is delivered, through the ferroportin channel, to the blood where it is taken up by circulating transferrin which delivers iron, via TFR1, mainly to the bone marrow to contribute to the build-up of red blood cells. Red blood cell degradation within the spleen, and to a lesser degree within the liver, occurs 120 days after production and quantitatively provides the main source of iron to the plasma. Iron of splenic origin is taken up by transferrin and a new iron cycle begins. Almost all cells are able to take up iron from transferrin but in a much smaller amount than erythroid cells. Nevertheless, this small amount of iron is essential to serve in many enzymatic reactions, particularly within the respiratory chain. The total amount of body iron approximates 4 g, with 70% within red blood cells and the remainder within liver, spleen and muscles. Circulating iron represents only 0.05% of total body iron but is functionally of major importance. The amount of iron leaving the body each day (mainly in the feces and urine) is equivalent to the amount entering (i.e. 1–2 mg).

Hepcidin (encoded by the HAMP gene) is the hormone that regulates iron metabolism. It is a 25 amino acid peptide primarily produced by hepatocytes. Released into the blood stream, it mainly interacts with enterocytes of the duodenum and macrophage in the spleen by targeting ferroportin. Ferroportin, once bound to hepcidin, is internalized and then degraded. Iron egress from the cell is subsequently hampered by decreased ferroportin activity. It should be noted that the hepcidin control of iron egress from duodenal cells might also involve modulation of DMT1 degradation. The overall result is an inhibition of intestinal and recycled macrophage iron release to circulating transferrin that occurs particularly in response to increased body iron load to compensate for this increase. The reverse mechanism occurs in cases of body iron deficiency (i.e. increased release of iron from the cell related to increased export activity of ferroportin). Hepcidin regulation is mainly characterized as a multifactorial transcriptional process. A major factor that increases hepcidin levels, in addition to increased iron stores, is inflammation. In addition to reduced iron stores, hypoxia, anemia and increased erythropoiesis are hepcidin-reducing factors. The molecular regulators of hepcidin expression are numerous. The bone morphogenetic proteins (BMPs) signaling pathway is implicated in responding to levels of iron stores. Schematically, BMP6 activates its receptors (BMPRI and II) in the presence of hemojuvelin (BMPRI–II coreceptor), which activates the SMAD (Son of Mothers against Decapentaplegic) proteins 1, 5 and 8. A complex is then formed with SMAD4, leading to translocation to the nucleus and activation of hepcidin transcription. The HFE–TFR1–TFR2 complex is an iron sensor for plasma diferric transferrin, leading to hepcidin transcription by a yet not fully identified pathway. TMPRSS6 (transmembrane protease serine 6) encodes matriptase-2, a negative regulator of hemojuvelin expression that decreases hepcidin expression. The STAT3 signaling pathway is involved in IL-6-dependent hepcidin expression. IL-6, produced during inflammatory processes, interacts with its receptor and leads to phosphorylation of the STAT3 protein, which is then translocated into the nucleus where it interacts with the hepcidin promoter.

HFE-related iron overload disease is, by far, the most frequent form of genetic iron overload disorders. Type 1 hemochromatosis is a recessive disease that is linked to mutations of the HFE gene located on chromosome 6. Homozygosity for the p.Cys282Tyr (C282Y) mutation explains more than 90% of type 1 hemochromatosis. The p.Cys282Tyr mutation inhibits the molecular cascade that results in decreased hepatic production of hepcidin. As a consequence, increased plasma iron leads to increased transferrin saturation, which is associated with the appearance of non-transferrin bound iron (NTBI). NTBI is avidly taken up by parenchymal cells in the liver, the pancreas and the heart, leading to excess iron in these organs. In addition, when transferrin saturation is over 75%, NTBI is considered labile plasma iron (LPI), which might generate radical oxygen species and represents the potentially toxic form of circulating iron. The damaging effect of LPI contributes to the clinical expression of chronic iron overload disorders. The liver increases in volume (hepatomegaly), releases more transaminases into the plasma due to hepatocytic iron-related damage and can develop scarring called fibrosis that can lead to cirrhosis and, later on, to hepatocellular carcinoma. Excessive iron deposition in the pancreas, endocrine glands (pituitary, gonads) and heart can lead to insulin-dependent diabetes, hypogonadism (with impotence in males) and cardiac failure, respectively. Moreover, bone and joints can be affected, leading to osteoporosis and chronic arthritis. The skin becomes hyperpigmented (bronzed) and chronic fatigue is a major symptom.

Of Celtic origin (and not Viking origin), as suggested by the mutation date before 4000 BC, the p.Cys282Tyr mutation is highly prevalent in this population, affecting one allele in more than 10% of Caucasian individuals. At least 1 person in 1000 is homozygous for this mutation, and the usual frequency is approximately 3 people in 1000, with even greater frequency in some areas, such as Brittany (France) and Ireland. Penetrance is partial, but if severe clinical presentation is rare, biochemical penetrance is high. Current research efforts are targeting identification of other genes and polymorphisms that modulate HFE function and the interaction between the C282Y genetic background and environmental factors.

Diagnosis of type 1 hemochromatosis is based on a three-step strategy: the first step is recognizing clinical symptoms, the second is confirming excess iron and the third is molecular diagnosis by genetic testing. Clinical symptoms are numerous, including, more or less combined, chronic fatigue, impotence, joint pains, osteoporosis, mild elevated plasma transaminases, hepatomegaly, cirrhosis, diabetes, cardiac rhythm disturbances, heart failure and skin pigmentation. It should be pointed out, however, that many patients, including those with advanced iron overload, have few or no symptoms and that many symptoms lack specificity.

Confirming iron excess is the diagnostic cornerstone. Plasma iron and transferrin saturation are increased in patients, reflecting the basic metabolic dysregulation of the disease. Increased plasma ferritin concentration reflects intracellular iron overload and is the most frequent surrogate marker for tissue iron overload. Magnetic resonance imaging (MRI) is a valuable tool for confirming hepatic iron overload as it shows a characteristic hyposignal that is correlated with the degree of iron excess. By contrast, no iron overload is observed in the spleen. In addition, the T2-star MRI technique has been developed for the assessment of cardiac iron overload. Liver biopsy to evaluate iron excess is performed less and less, considering the combined value of the ferritin assay and MRI. The main use of biopsy is to evaluate possible cofactors of hepatotoxicity (fatty infiltration or signs of alcoholism) and to search for cirrhosis which exposes the patient to the development of hepatocellular carcinoma, especially when associated to iron-free foci. Deducing iron overload from the amount of withdrawn iron required to reach iron depletion remains a valuable, although retrospective, method.

The third step is molecular diagnosis via genetic tests that detect the presence of p.C282Y homozygosity in the HFE gene. It should be emphasized that p.C282Y heterozygosity cannot be considered, alone, to be responsible for clinically significant body iron excess. This is true even for HFE compound heterozygosity, which is commonly the association of heterozygosity for p.Cys282Tyr and heterozygosity for the other frequent mutation, p.His63Asp (p.H63D), which can only lead to a limited increase in plasma transferrin saturation and ferritin. Likewise, p.H63D homozygosity, despite some experimental data and rare case reports, is not generally considered to account for significant iron excess. In practice, the search for the p.H63D mutation is no longer recommended in France and should be confined to clinical research. The same holds true for other HFE protein mutations, such as p.Ser65Cys (S65C), p.Val59Met (V59 M), p.Arg66Cys (R66C), p.Gly93Arg (G93R), p.Ile105Thr (I105T), p.Arg224Gly (R224G) and p.Val295Ala (V295A). Whenever a p.Cys282Tyr mutation in the heterozygous state is associated with significant visceral iron overload (hepatic iron concentration more than 3-fold the upper normal limit), one must evoke an associated rare HFE mutation , a homozygous deletion of HFE, or associated non-HFE mutations. In practice, testing for mutations other than p.CysC282Tyr (and p.His63Asp) remains confined to specialized laboratories.

Treatment for type 1 hemochromatosis consists of repeated venesections on the principle that removing red blood cells, which are iron-rich, obliges the body to compensate for this erythrocyte loss by mobilizing iron from its storage locations. Provided this therapy is started before the development of severe complications (cirrhosis, insulin-dependent diabetes or cardiomyopathy), the efficacy is excellent, and patients recover both an overall good quality of life (except for arthritis) and a normal life expectancy. Oral chelation might be used, particularly in the case of contraindications of phlebotomies, such as poor venous access or patient unwillingness. Future therapy might consist of normalizing hepcidin levels to prevent absorption of additional quantities of excess iron and excessive iron release from macrophages.

Non-HFE-related genetic iron overload diseases are rare but are distributed worldwide. Type 2 hemochromatosis (juvenile hemochromatosis) is linked to mutations in the hemojuvelin gene (HJV, located on chromosome 1 or the hepcidin gene (HAMP, located on chromosome 19, which correspond to hemochromatosis types 2A and 2B, respectively. Type 2 hemochromatosis produces massive iron overload, specifically targeting the heart and the endocrine glands, and is mainly expressed, in individuals under 30 years old, as cardiac failure and/or hypopituitary hypogonadism. Repeated phlebotomies are the mainstay of treatment, possibly combined with oral iron chelation. Genetic testing, which is not routinely available, would find hemojuvelin or hepcidin mutations, either as homozygous mutations (for HAMP[30] and most often for HJV but also as compound heterozygosity. The hepcidin promoter is also studied by sequencing, as mutations have been described in this region.

Type 3 hemochromatosis is due to mutations in the transferrin receptor 2 (TFR2) gene. When TFR2 is mutated, hepcidin production by the liver is decreased, leading, in turn, to body iron excess. The clinical picture mimics type 1 hemochromatosis; however, cases have also been reported in young patients that resemble juvenile hemochromatosis. Molecular diagnosis, if available, would identify homozygous TFR2 mutations, but compound heterozygosity has also been reported. Genetic testing is performed as for HJV and HAMP.

Type 4 hemochromatosis is due to mutations of the ferroportin gene (SLC40A1) and is also called ferroportin disease. It has a dominant pattern of transmission and incomplete penetrance. Typical ferroportin disease (‘loss-of-function’ or type A), the most frequent form of non-HFE genetic iron overload, is due to mutations affecting iron export capacity. The ‘loss-of-function’ profile is that of a predominantly macrophagic iron overload with normal or low plasma iron (and transferrin saturation). Ferritin levels are often high (>1000 μg/l) contrasting with normal or low plasma iron and transferrin saturation levels. MRI shows marked splenic iron excess and relatively less pronounced hepatic iron overload. Clinical symptoms are rare and this disease does not seem to have, at the time of diagnosis, significant morbidity in the absence of acquired or genetic cofactors. Genetic testing is not routinely available, but identified mutations are mainly located on the cytoplasmic portion or transmembrane segments of ferroportin [including p.Val162del, p.Asp157Gly (D157G), p.Gly80ser (G80S) and p.Gly490Asp (G490D). The p.Gln248His (Q248H) mutation might be associated with iron overload in male African Americans. Phlebotomies remain the basis for treatment but, given the impaired iron recycling process, are less well tolerated than in the case of hepcidin deficiency related iron overload (hemochromatosis types 1, 2 and 3). Atypical ferroportin disease (‘gain-of-function’ or type B) is rare, and by generating a hepcidin resistance phenotype it mimics type 1 hemochromatosis. Several mutations linked to this phenotype have been reported: p.Asn144Asp/Thr (N144D/T), p.Tyr64Asn (Y64N) and particularly p.Cys326Ser/Tyr (C326S/Y).

Hereditary aceruloplasminemia is a rare but widely distributed recessive disease arising from mutation of the ceruloplasmin gene located on chromosome 3. Plasma ceruloplasmin, through its ferroxidase activity, is involved in cellular iron egress. It is required for oxidizing ferrous iron, the redox iron species that crosses the membranes, into ferric iron, the iron species transported by circulating transferrin. In the absence of plasma ceruloplasmin, which is related to mutations in the ceruloplasmin gene, the process of cellular iron release is impaired because of subsequent alterations in ferroportin functioning. Therefore, cellular iron overload develops in a way similar to that observed in ferroportin disease, namely iron trapping within the cells associated with decreased iron release into the plasma, accounting for hyposideremia and low transferrin saturation levels. However, aceruloplasminemia is more severe than ferroportin disease, with marked anemia and brain involvement, suggesting that further mechanisms not yet fully elucidated are involved. The clinical picture is peculiar, combining, in an adult individual, anemia with low plasma iron and transferrin saturation, high plasma ferritin levels and neurological symptoms. Iron overload is found by MRI not only in the liver and spleen but also within the basal ganglia. The diagnosis rests first on biochemical assessment of plasma ceruloplasmin and plasma ferroxidase activity, which show no detectable activities in affected individuals. Genetic testing, if available, serves for diagnostic confirmation in a given individual and as a diagnostic marker for family members, and mutations are predominantly identified in the homozygous state. Phlebotomies are contraindicated because of pre-existing anemia, and treatment is therefore primarily based on iron chelation, with uncertain results on the brain iron load.

Hereditary atransferrinemia is a rare recessive disease affecting young individuals. It is responsible for severe anemia (the normal fate of transferrin iron is to provide bone marrow for red blood cell production) associated with cellular iron overload, which is related to plasma NTBI because transferrin is absent. The diagnosis rests on the fact that affected individuals show no detectable plasma transferrin. Molecular diagnosis, if performed, will identify either homozygosity or compound heterozygosity and serves both as an individual confirmation and as a family marker.

Divalent metal transporter1 (DMT1)-related iron overload is due to the fact that DMT1protein is not only involved in dietary iron uptake at the apical membrane of duodenal enterocytes but is also involved in the release of iron from acidified endosomes into the cytosol. Therefore, mutations in the SLC11A2 gene encoding DMT1, as first shown in Belgrade rats and mk/mk mice, give rise to a rare recessive disease expressed as microcytic anemia that is present from birth, is refractory to oral supplementation and is associated with visceral iron overload with only mildly elevated plasma ferritin. Molecular diagnosis, showing either homozygosity or compound heterozygosity, is the key diagnostic approach, although it is not feasible in routine practice. Treatment is mainly based on iron chelation therapy, but can be augmented with erythropoietin.

Finally, genetic sideroblastic anemias are characterized by iron accumulation in perinuclear mitochondria of erythroblasts and combine microcytic anemia with iron excess. They encompass two X-linked forms, delta-aminolevulinic synthase 2 acid mutations (in the ALAS2 gene) and ATP-binding cassette B7 deficiency (related to mutations in the ABCB7 gene), and two recessive forms, one related to SLC25A38 mutations and the other due to mutations in the glutaredoxin X5 gene (GLRX5).

Iron deficiency of genetic origin is essentially represented by iron-refractory iron deficiency anemia (IRIDA). It is a recessive disorder due to mutations in the gene TMPRSS6, which encodes the enzyme matriptase-2. The mutations relieve a form of inhibition on the HJV–BMP–SMAD signaling pathway, resulting in chronic elevation of plasma hepcidin levels. This elevation impairs duodenal iron absorption as well as iron release from the spleen. This process is close to that observed in the anemia of chronic disease, where increased plasma hepcidin levels are related to STAT3 pathway activation by interleukin 6 (IL-6). IRIDA is characterized by severe microcytic anemia with very low transferrin saturation and normal or high plasma ferritin. Hepcidin levels are normal or high, which is strongly abnormal in the setting of profound anemia, which, ‘physiologically’, should result in low plasma hepcidin levels. Anemia is more pronounced in children than in adults. Oral iron supplementation is ineffective and parenteral iron is only partially effective as iron recycling from macrophages – the first site of deposition of parenteral iron – is hampered by ferroportin deficiency subsequent to increased plasma hepcidin levels. Decreasing hepcidin levels, through the use of hepcidin antagonists, represents an important area of translational research.

In conclusion, several novel genetic iron-related disorders have been recently identified, corresponding either to primary hepcidin disorders or to disorders implicating iron transport, utilization and recycling. From a diagnostic viewpoint, molecular confirmation is easy for HFE-related hemochromatosis, but for all other genetic entities highly specific laboratories are needed due to the high cost of time-consuming techniques that are used infrequently given the rarity of these diseases, so that, in practice, only countries that have set up Reference Centers are able to provide clinicians with molecular confirmation. From a therapeutic viewpoint, the improved mechanistic understanding of these various disorders opens the way for the development of innovative treatment approaches.

Questions for future research

Iron metabolism

• What is the precise pathway whereby HFE regulates hepcidin transcription?

• Identification of new candidates for therapeutic targets in iron metabolism diseases among the signal transduction cascade involved in hepcidin transcription.

• Can cellular iron egress be regulated independently of the hepcidin–ferroportin interaction?

• How is iron metabolism controlled in the brain?

Diagnostic aspects

* What are the acquired and/or genetic cofactors accounting for phenotypic variability in the various forms of hemochromatosis?

• Evaluation of plasma hepcidin determination as a diagnostic and/or prognostic tool in the management of hemochromatosis and iron related diseases.

• Development of genetic, functional and metabolic tools to optimize quick diagnosis of iron overload diseases.

Therapeutic aspects

• Determination of the most appropriate means for normalizing hepcidin levels in patients with hepcidin-deficient hemochromatosis.

• Finding ways to manipulate iron metabolism in the brain.

New treatment for DLCBL.

2011-11-25T11:52:00.003Z

For a long time it has been accepted wisdom that R-CHOP is as good as anything else for diffuse large cell lymphoma. More intensified regimens are possible, but a meta-analysis of some years ago found no advantage for them.

In today's Lancet there is a paper from France reporting a trial that suggests that this is no longer true. Here is the abstract:

We did an open-label randomised trial comparing dose-intensive rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone (R-ACVBP) with subsequent consolidation versus standard rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisone (R-CHOP). Random assignment was done with a computer-assisted randomisation-allocation sequence with a block size of four. Patients were aged 18–59 years with untreated diffuse large B-cell lymphoma and an age-adjusted international prognostic index equal to 1. Our primary endpoint was event-free survival. Our analyses of efficacy and safety were of the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00140595.

One patient withdrew consent before treatment and 54 did not complete treatment. After a median follow-up of 44 months, our 3-year estimate of event-free survival was 81% (95% CI 75–86) in the R-ACVBP group and 67% (59–73) in the R-CHOP group (hazard ratio [HR] 0·56, 95% CI 0·38–0·83; p=0·0035). 3-year estimates of progression-free survival (87% [95% CI, 81–91] vs 73% [66–79]; HR 0·48 [0·30–0·76]; p=0·0015) and overall survival (92% [87–95] vs 84% [77–89]; HR 0·44 [0·28–0·81]; p=0·0071) were also increased in the R-ACVBP group. 82 (42%) of 196 patients in the R-ACVBP group experienced a serious adverse event compared with 28 (15%) of 183 in the R-CHOP group. Grade 3–4 haematological toxic effects were more common in the R-ACVBP group, with a higher proportion of patients experiencing a febrile neutropenic episode (38% [75 of 196] vs 9% [16 of 183).

Compared with standard R-CHOP, intensified immunochemotherapy with R-ACVBP significantly improves survival of patients aged 18–59 years with diffuse large B-cell lymphoma with low-intermediate risk according to the International Prognostic Index. Haematological toxic effects of the intensive regimen were raised but manageable.

Here is an editorial from Julie Vose on the trial

In The Lancet, Christian Récher and colleagues report the findings of their randomised trial of dose-intense chemo therapy with rituximab, doxorubicin,
cyclo phos pha mide, vindesine, bleomycin, and pred nisone (R-ACVBP) versus rituximab, cyclophosphamide, doxo rubicin, vincristine, and prednisone
(R-CHOP).

379 patients aged 18–59 years with diffuse large B-cell lymphoma and an age-adjusted International Prognostic Index of 1 were randomly assigned to receive either dose-intense chemotherapy with four cycles of R-ACVBP with a subsequent sequential consolidation with two cycles of methotrexate and calcium folinate rescue, four cycles of rituximab with etoposide and ifosfamide, and two cycles of cytarabine or to receive eight cycles of R-CHOP at intervals of 21 days. On the basis of previous studies in this population of patients, 3-year event-free survival would be expected to range from 70% to 80%.3 The study by Récher and colleagues had a 3-year event-free survival of 67% (95% CI 59–73) in the R-CHOP group, which seems slightly low.

In terms of the trial’s primary endpoint, event-free survival, there was an advantage to R-ACVBP versus R-CHOP (hazard ratio 0·56, 95% CI 0·38–0·83, p=0·0035). The dose-intense R-ACVBP regimen with sequential consolidation has an expected higher rate of toxic effects, with significantly increased haematological toxic effects over R-CHOP identified in this and previous trials. Also, the additional chemotherapeutic drugs, higher haemopoietic growth factor use, and higher neutropenic fever rate would lead to higher health-care resource consumption. Therefore, this dose-intense regimen should only be used in patients in whom the expected relapse rate is sufficient to justify the higher toxic effects and cost profile.

Possible risk stratification factors for the use of more dose-intense treatments include: International Prognostic Index, bulky disease, gene expression profiling results (eg, activated B cell v germinal centre B cell), oncogenic profile (eg, MYC positive or so-called double hit lymphomas), or interim PET positivity. Clinical features, such as International Prognostic Index or bulky disease, are the easiest to use in clinical practice. However, more biologically relevant assays, such as genetic profiles, interim PET, or a combination approach, might be more accurate in predicting which patients are at higher risk. Once patients at higher risk are identified by biologically relevant assays or procedures, future study designs will address the use of these biological prognostic factors for direction of treatment by dose intensification or pathway-directed drugs.

Some of the newer pathway-directed drugs seem to be less toxic and, if earlier-phase studies show that they can be combined with standard chemotherapy, this might represent a more directed treatment for patients at higher risk. Examples of drugs tested in this manner include lenalidomide, bortezomib, or drugs directed at
the B-cell signalling pathway. In the meantime, who should receive dose-intensified
treatment? Récher and colleagues report convincing evidence that patients younger than 59 years with an International Prognostic Index of 1, who can tolerate the
additional toxic effects of R-ACVBP with consolidation, do have a better 3-year event-free survival. Unfortunately, some of the drugs in the regimen are not available in all countries and testing of substitute drugs or modifications would be needed. Furthermore, a direct comparison of other dose-intensive chemo therapy regimens such as a dose-adjusted regimen of rituximab, etoposide, vincristine,
cyclophosphamide, and doxorubicin (R-EPOCH) versus the R-ACVBP regimen is needed, pending the results of the present R-CHOP versus dose-adjusted R-EPOCH protocol being done by the United States Cooperative Group Mechanism (registered with ClinicalTrials.gov, number NCT00118209). Although we continue to identify subsets of patients at higher risk, further international clinical trials are needed to assess the best individualised approach to treatment for these patients.

Of course for CLL patients, we have to question whether the standard treatment for Richter syndrome should remain R-CHOP, but I fear that patients with Richter Syndrome may not be able to withstand this intensity of treatment.

BBC unfair?

2011-11-24T18:00:00.002Z

The BBC are a one-eyed bunch of left wingnut clowns who have lost all credibility. Worse though, they are parasites, demanding unearned income with threat of fines and inprisonment. Disband them and sell the bits to real corporations.

So says one commentator on the news that the BBC has apologised to a local council after it complained about a One Show report on the travellers' site at Dale Farm. A BBC report said that the programme had ‘failed to clarify that the site had been developed on green belt land’

It also said it had been ‘unfair’ to the council in allowing a traveller to allege the local authority was ‘throwing us out on the road’ with ‘nowhere to go’ without giving it a right of reply. The committee also found a studio discussion between presenters Matt Baker and Alex Jones and actor Neil Morrissey, who was a guest on the show, created an ‘overall impression’ that was ‘unfair’ to the council.

The report went on to say that Morrissey, who speculated whether the land had been ‘earmarked for development’, had ‘been placed in a very difficult position’ when he was asked to comment.

A BBC spokeswoman said: 'We note the findings of the ESC bulletin, which we have taken very seriously. 'Moving forward, The One Show has reviewed and will continue to strengthen its editorial procedures to ensure accuracy, fairness and due impartiality on all the programme's output.' In response Tony Ball, Leader of the Council, said:

'We are satisfied with the findings. 'The site clearance of Dale Farm has always been about the protection of the green belt, but this was not accurately portrayed by The One Show report, nor the fact that we had made several offers of housing to traveller families.

'Since we made the complaint, these key facts have been more accurately
broadcast, helping to aid the public understanding of what the whole issue
was about.'

The six-acre site in Crays Hill was cleared earlier this year following a decade-long row over unauthorised plots. Tensions centred over 51 plots which had been created on green belt land not authorised for development.

John 8:14: The testimony of the Father.

2011-11-24T14:21:00.003Z

Jesus answered, “Even if I testify on my own behalf, my testimony is valid, for I know where I came from and where I am going. But you have no idea where I come from or where I am going.

Count the I AMs. Jesus retained the knowledge of his life in heaven with the Father. The Jews did not even know of his birth in Bethlehem, let alone his pre-existence in heaven.

Some sects believe that Jesus was a created being, others that he was never divine, yet others that he 'became God', but the testimony of this Gospel is that he was 'with God in the beginning'. We have the wonderful testimony that he who has seen Jesus has seen the Father, for "I and the Father are one."

Unfairness at the GMC

2011-11-24T11:56:00.004Z

It is very dangerous to touch on the subject of sudden infant death syndrome (SIDS) and Munchausen-by-proxy. A very powerful vigilante group patrols the web seeking out postings from bloggers on the subject. They are in denial over the possibility that a parent could harm a child. So I was surprised to see that two pediatricians had raised their heads above the parapet and commented on the subject in the BMJ. The only time I deigned to comment on the subject I was subject to vile invective which can still be traced on Google.

This is what Leonard Williams wrote:

Professor David Southall must have been investigated more than any other doctor. He has appeared before the General Medical Council on five separate charges, and has been investigated by the police, his trust, and his strategic health authority. He has been cleared at every stage. He has been compared to Dr Mengele in parliament and vilified by the media, and a website is devoted to his downfall. Yet he is highly respected by pediatricians throughout the world. How is this possible?

His reputation was forged through his work on SIDS. His investigations led him to believe that some infants were being smothered, which he confirmed by covert video surveillance. His team videoes 30 mothers smothering their babies. Each episode was interrupted and no baby was harmed. Most important of all, these babies had 41 older siblings, of whom 12 had died suddenly with 11 of them being certified as SIDS. It is clear that in retrospect that they were likely to have been killed.

A vigilante group began to co-ordinate assistance for parents charged with abuse and to orchestrate multiple complaints to the GMC and other authorities, Professor Southall was prevented from working while these many investigations took place.

Even more importantly, the use of covert video surveillance was almost completely stopped. But there is no reason to believe that the smothering has ceased. Southall's analysis of the siblings showed that smothering is highly dangerous, but the actions of the GMC and other authorities have prevented use of a means of detection. One is left to wonder, how many babies have died and will die because of these actions.Derek Summerfield has written:

As an observer of the story of Professor Southall and the General Medical Council over many years, I entirely endorse Bridson’s reflections. GMC decisions at Southall’s hearings have seemed so perverse and devoid of natural justice that each time I have predicted that they would be overturned at a higher level, and they have been.

I recall that one of the GMC's judgments described Southall of having a deep-seated "attitudinal problem", but the GMC seems to have the attitudinal problem. The judgments in Southall's favor at the Court of Appeal and the like attest to the GMC's persistently prejudiced and unprofessional behavior towards him. I believe that Southall has grounds to bring a case against the GMC for a persistent breach of the duty of care it has towards him, as it has to all UK doctors.

My comment on this story is less to do with the actual story, since I am no expert on its content. What I object to is unfairness. I think that the GMC is a corrupt institution. It was once a regulatory body that kept a register of doctors and struck doctors off the register for behaving inappropriately, like performing abortions, having affairs with patients, getting into trouble with the law etc. Doctors funded it with a registration fee of £5 and doctors were judge and jury. Today doctors still fund it with an annual retention fee of over £400, but they no longer act as judge and jury - lay people form a majority on fitness-to-practise 'courts'. It has taken on a lot of extra work for the government (for which the taxpayer pays nothing) and retired doctors are expected to relinquishing their license to practise. They can't even write up a script for acyclovir for a granddaughter with a cold sore.

The GMC having been over-ruled by the Court of appeal over both Meadows and Southall, it seems that they are subject to influence by lay-pressure groups in a way that is unfair. There is a lot of unfairness about who has access to information and how the press presents it. Keep watching the Levenson Inquiry.

del 13 q14: size matters

2011-11-23T16:08:00.001Z

In Leukemia Research on line

Chronic lymphocytic leukemia (CLL) is a highly heterogeneous disease which has proven amenable to subtyping through genomic microarray analysis. Initially, 13q14 deletions as an isolated finding were associated with a favorable prognosis. However, recent evidence has revealed significant heterogeneity within the 13q14 deletion subtype, thus, there is a clear clinical need for more precise stratification of 13q14 deletions at the genomic level. The minimal deleted region (MDR) includes: DLEU2, DLEU7, MIR15A/MIR16-1 and part of DLEU1. Recent studies suggest that in addition to the MDR, the size of the deletion and the involvement of the nearby tumor suppressor gene RB1 serve as an independent prognostic biomarker for disease progression. Nine individuals in whom a 13q deletion had previously been identified by bacterial artificial chromosome (BAC) array were re-analyzed using the Cancer Cytogenomics Microarray Consortium's consensus design on an Agilent (Santa Clara, CA) 180K oligonucleotide platform. Based on the size and location of the 13q14 deletion, cases were further classified as having type (smaller, not including RB1) or type II (larger, including RB1) deletions, as described by Ouilette et al. (Cancer Res, 2008). Type I deletions were seen in 77% of cases, and Type II deletions in 22%. There was a single case of a biallelic 13q14 deletion. Deleted regions ranged in size from 1.0 to 9.8 Mb. Unlike older BAC technologies that are subject to limited resolution, the CCMC 180K oligonucleotide array allowed for further clarification of 13q deletion cases, providing valuable clinical and prognostic information for CLL.

anecdotes about non-hemic autoimmunity

2011-11-23T14:51:00.002Z

Unusual Autoimmune Complications in Chronic Lymphocytic Leukemia
Moonjung Jung1, Lawrence Rice1The Methodist Hospital, Weill Cornell Medical College, Houston, TX

1. Myasthemia Gravis (MG)

A 56-year-old man was recently diagnosed with MG. His muscle weakness and difficulty swallowing had improved only moderately with weekly plasmapheresis, azathioprine and mestinon. Following a diarrheal illness treated with ciprofloxacin, he was admitted to the ICU for respiratory failure from respiratory muscle weakness. Hemoglobin rapidly fell to 6.7 g/dL. His peripheral blood smear, flow cytometry and Coombs' tests revealed CLL and autoimmune hemolytic anemia. After chemotherapy, his blood counts normalized and his symptoms of MG resolved; he remains in clinical remission of CLL and MG off therapy.

2. Von Willebrand's Disease (vWD)

A 48-year-old man presented with severe headache and was found to have a spontaneous subdural hematoma by CT scan. He had experienced weight loss, easy bruising and epistaxis recently. There was lymphadenopathy on exam. Blood counts, flow cytometry, and coagulation tests revealed CLL and type IIA vWD with a circulating vWF inhibitor. After chemotherapy, the CLL remitted and coagulation studies normalized. With relapse of CLL four years later, the bleeding diathesis re-emerged

3. Aquired Angioedema

Three patients with known stable CLL for years, presented with episodes of severe abdominal cramping, nausea and vomiting. This led to numerous Emergency Room visits, hospital admissions, invasive diagnostic tests, and disability. A deficiency of C1 esterase inhibitor was discovered in all cases. With danazol and chemotherapy for CLL, the patients had response of CLL, normalization of C1 esterase inhibitor, and no recurrence of abdominal pains.

In some of our patients, signs and symptoms of CLL were neglected at the onset of the autoimmune problem. Earlier consideration of underlying CLL would have facilitated earlier effective treatment. In all our patients, the activity of the autoimmune complications closely correlated with the activity of CLL. Immune dysregulation characterizes CLL, and effective treatment offers the possibility of reversing the environment ripe for autoimmunity.

These are more anecdotes. The plural of anecdote is not evidence. I would dismiss these cases as coincidence.

More on scientific fraud

2011-11-23T12:34:00.002Z

In last week's BMJ they drew attention to an outbreak of scientific fraud. There was mention of the pharmaceutical company GSK, paying $3 billion to settle a dispute with the US government over the incorrect marketing of Rosiglitazone (Avandia) and bupropion (Wellbutrin), a London GP was struck off the register by the GMC for using inappropriate tests and treatment for chronic fatigues syndrome, The Fraud Agency investigated conflicts of interest at the European Medicines Agency over the use of benfluorex (Mediator) as an appetite suppressant, the Dutch Health Minister was quizzed about excessive contacts with the tobacco industry, US organizations challenged the financial interests behind the recommendation of the use of HPV vaccine for boys and a Dutch psychologist was shown to have falsified data in dozens of studies in one of the biggest cases of scientific fraud on record. Diederik Stapel from Tilburg was responsible for 150 papers.

Then there was ongoing coverage of the MMR fraud committed by Andrew Wakefield, indicating that several of his colleagues were also culpable and that there seems to have been an ongoing cover-up at University College, London.

There is a good article by Elizabeth Wager of COPE detailing the ways of coping with scientific misconduct.

John 8:13. The testimony of one.

2011-11-23T12:25:00.003Z

The Pharisees challenged him, “Here you are, appearing as your own witness; your testimony is not valid.”

On a technical Jewish point of law, the self-testimony of a single witness was not valid. But they make a mistake in who was doing the testifying. This was not a mere man; The "I am" makes a claim of divine authority as does the mention of light. Light is Yahweh in action - Ps 44:3

The racism scandal in football

2011-11-23T12:07:00.003Z

A judge in the Court of Appeal had stated that a policeman in London should not be offended by being aggressively sworn at by a criminal. This should not be construed as 'resisting arrest'.

I wonder how the judge would feel if the same criminal addressed him in court? No doubt the accused would be held in 'contempt of court'. Suppose such a person were to let off a stream of invective in an old person's home populated by old ladies born in the 1920s? My mother would be offended and so would I.

One of the current cases being considered by the Football Association concerns the English Football captain, John Terry, who it is alleged, abused the Queen's Park Rangers' defender, Anton Ferdinand, by the words, "F---ing black c---". Excuse me if I do not spell it out. Anton Ferdinand is a member of a large footballing family which includes Rio, a former England captain and well known twitterer, and Les, a previous England centre forward who is now a coach at Totenham Hotspur. He is also an evangelical Christian who has led prayer groups at his former clubs. Who would not be offended by being described by such an epithet?

John Terry is a yob who cuckolded former full back, Wayne Bridge, (a rather intelligent Southampton lad, who happened to play as a schoolboy against my son), and who withdrew from the International game because of the incident. Terry's elder brother, recently had an affair with another footballer's girlfriend, leading to the footballer committing suicide.

There are plenty of decent minded footballers around. I hope we have seen the last of Terry and his kin. Cappello, the England manager, has a reputation as a strictly moral boss who stands no nonsense. Let us hope he does not let us down.

Cancer survival

2011-11-22T14:08:00.002Z

There is a report in today's newspapers in the UK about progress in cancer survival. There has been some improvement but it is not a record of magnificent success. Most of the improvement has come from surgery, particularly with breast and colon surgery - often when combined with adjuvent chemotherapy. Some of the improvement has been because of early diagnosis - not that patients are living longer than they did, merely that are living with the diagnosis for longer. This is particularly true for breast and prostate cancer.

Hormones have made a great impact on cancer survival, particularly for breast cancer.

Chemotherapy has made a great impact on Hodgkin disease and childhood acute leukemia but limited impact elsewhere except in the adjuvent setting. Adult AML has shown little if any benefit from chemotherapy

Monoclonal antibodies have made an impact in CLL, diffuse large cell lymphoma and follicular lymphoma (actually it's all rituximab).

Targeted therapy ahs made an impact on CML, and possibly kidney cancer and a rare form of adenocarcinoma of the lung in Indian female non-smokers. There is some promising news about melanoma.

Bone marrow transplantation has saved some lives but the risk is so great that the butcher's bill is hard to calculate.

Longer survival may come from better disease definition as in some skin cancers and lymphomas.

As for the common solid tumors like lung cancer, pancreatic cancer, brain cancer and the rest, there has been very little improvement since I became and oncologist 37 years ago

John 8:12: The Light of the World

2011-11-21T15:31:00.003Z

When Jesus spoke again to the people, he said, “I am the light of the world. Whoever follows me will never walk in darkness, but will have the light of life.”

This is another of the great 'I AM' statements where Jesus is declaring himself to be God. We go right back to the start of the Gospel, "That life was the light of men".

We now know that light is a form of energy. To the Jews, the main source of life was the sun, which gave light, heat and energy. It was the source of life. Not only that, it permits no dark corners, for men love darkness rather than light. With light there is nowhere to hide.

Jesus is claiming to be the source of all life and the dismisser of darkness.

Syria

2011-11-21T15:08:00.003Z

Syria is proving a harder nut to crack than the Western Media imagined. The uprisng is largely confined to a few towns where there has been trouble in the past and generally the Syrian army is in control.

If there were elections who would win? And if Assad won would the elections be declared by the Western Media as corrupt? Are America and the EU opposed to Syria because Russia and China support it? Or is it the other way round?

Syria is Israel's implacable enemy, giving aid to Hamas, Hezbollah and Iran.

But Syria is also a safe haven for Christians. Many Iraqi Christians have found sanctuary there.

It is a conundrum.

The remedy for the ills of the world

2011-11-21T13:57:00.004Z

What has happened this year politically? The 'Arab spring' has toppled a few dictators, but has it been a real victory for militant Islam? We have seen the deaths of Ghaddafi and Bin Laden, but were there really 'players' in any meaningfull sense? Financial markets have collapsed, but why? The polarization between the Senate and the House in America? The Chinese currency inequality> The folly of the European single currency? WE are watching the failure of democracy. People no longer vot for something, but against something. They no longer see solutions. Like the Occupy protestors that can only complain but all the proposed solutions have already failed.

We have seen riots in London, buthow does stealing two left-footed luxury trainers help matters? We have seen scandals in the press phone hacking. Neither the police nor politicians can be trusted. At least two journalists have been fired for high level plagiarism or misrepresentation. Global warming is suspected of being a sham. Scientific fraud is rife. Even in cricket the players cheat.

This has been a year when the Devil has taken control.

You know what my remedy is. This is how I became a Christian:

I was 30 years old. I had just been appointed as consultant hematologist in a beautiful seaside town. I had a wonderful wife and two lovely children. I was financially secure for the rest of my life. I was well on my way to making a name for myself as a research scientist. One day I was going to be famous in my field. I was moving into a circle of smart people with every material luxury. I could see that it would soon be mine.

And yet I was profoundly unhappy. Something was obviously missing in my life.

One day (these were the days when doctors did house calls) I visited a patient at home. As he opened the door to me, he greeted me with, “Hello, doctor, I’m a committed Christian, how about you?”

What an embarrassment. I muttered something about being sent to Sunday School as a child, but, in truth, I had given up on religion. I had taken home the message that if you went around doing good, or at least did your best, you would end up in heaven. I was honest enough to know that I couldn’t do good all the time, and indeed, much of the time I didn’t even do my best. Nevertheless, he sent me on my way with, “Why don’t you come to our church. You will find Francis Dixon a wonderful preacher.”

Six months went by and I did nothing. I was sinking into an ever deeper despair, particularly so as all the skills that I had relied on to answer examination questions were letting me down. I could get the diagnosis right and give the right treatment, but my leukemia patients still died.

Eventually my wife cajoled to me to going to my patient’s church. On the first Sunday I tried, I couldn’t find it so I returned home empty. I found it the second time, and looked around, expecting to see at least one friendly face. It was difficult because the church was absolutely packed with hardly a seat to be found, not the way I envisioned churches. The reason I couldn’t find him soon became apparent. He had died the previous Thursday. The sermon that Francis Dixon preached that day was clearly designed to console his widow.

His text was from John 11:25-26. It was the story of the raising of Lazarus. Remember the story, the sisters of Lazarus, Mary and Martha, had sent word to Jesus that their brother was dying. Rather than hurrying to Bethany, where they lived, Jesus stayed where he was across the River Jordan for two more days. Eventually he decided to go. When he arrived at Bethany Lazarus had died and had been in the grave for 4 days. Jesus had deliberately delayed because he was about to perform the miracle of raising Lazarus from the dead. When he arrived Martha scolded him, “Lord, if you had been here my brother would not have died.”

Jesus replied, “I am the resurrection and the life, he that believeth in me, though he were dead, yet shall he live, and whosoever liveth and believeth in me shall never die.” (In those days they used the KJV)

Jesus then asked Martha, “Do you believe this?”

And Francis Dixon points straight at me and asks, “Do you believe this?”

Martha replied, “Yes, Lord, I believe that you are the Christ, the Son of God, who was to come into the world.”

This was the pointed question I was asked. Did I believe that? Now was the time to stop pussyfooting around. This was the real question. Did I believe that Jesus was the Son of God, with power over Life and Death or was he just a prophet or a wise man or even just a good man? If I believed that he was the Christ I would live my life one way; if I believed he was not then I would live my life completely differently.

You cannot figure this out by logic or by examining the world or by any type of science. You have to make a decision, because in not making a decision that he is the Christ you are making a decision that he is not. People talk about a leap of faith. I never knew what that meant. But then I did. To believe that Jesus is the Christ means to live it and only by living it do you discover that it is true.

On that day, I trusted it was true and today I testify that it is true.

I later learned that my patient’s wife and two other women had been meeting every week to pray for the conversion of his doctor.

Latest on Occupy London

2011-11-21T13:26:00.003Z

Occupy London St Pauls has been trying to raise its image. Here what an independent investigation has found: ‘Desecration: graffiti have been scratched and painted on to the great west doors of the cathedral, the chapter house door and most notably a sacrilegious message painted on the restored pillars of the west portico.

‘Human defecation has occurred in the west portico entrance and inside the cathedral on several occasions.’

There have been noisy interruptions during services, foul language directed at staff and the use of alcohol and ‘other stimulants’ that appeared to ‘fuel the noise levels day and night'.

More than half of schools scheduled to visit the cathedral had cancelled since the occupation began on October 15. Drop-in visitor numbers were also down by half.

A further witness statement from a police inspector expressed ‘mounting concern of drugs within the camp’ including ‘what is currently believed to be a liquid class A drug'.

Social workers have also raised concerns the camp is attracting vulnerable people with mental health and substance abuse problems.

Anti-capitalist protesters were served with an eviction notice by the City of London Corporation last week

Another activist admitted there had been problems with protesters urinating on each other’s tents, and called for a ban on drink and drugs, telling the group: ‘Recreational drinking isn’t something we should passionately support — this is a movement trying to overthrow capitalism,’ she said, adding that anyone wanting to have a drink or 'do a few lines’ (presumably of cocaine) could go off-site.

A member of the so-called Tranquillity Team, a roster of protesters who spend the nights trying to quell trouble, says they have been rushed off their feet dealing with problems, and that people carousing on the cathedral steps have been keeping everyone awake until dawn.

Meanwhile, a member of the finance team implored people to stop asking for money that has been donated to the camp. 'We won’t give out money for cigarettes or booze,’ he said, clearly exasperated. 'Please don’t even bother asking.’

Legal notice was served on the camp on Thursday, a day after U.S. police cleared the Occupy Wall Street camp in New York. The Corporation had halted earlier court action to hold talks with protesters. But policy chairman Stuart Fraser said the negotiations went ‘nowhere’.

Naomi Colvin, for Occupy London, insisted the threat of eviction ‘was not something we need to be remotely worried about’. She added: ‘It could take months. We will contest it.’

Apparently 'The Great Unwashed's' 'headquarters' is the nearby Starbucks because there's free WiFi, its warm and dry and they need somewhere to spend their job seekers allowance (paid for by us tax payers who include a few capitalists I imagine!).

The Incredible Journey: Christmas from Genesis to Jesus

2011-11-20T15:59:00.002Z

Steve Brady visited me on my sick bed a little while ago and left me a copy of this book. Although it is book of daily readings, I couldn't put it down and finished it in three days. It is known as an advent book with a reading from Genesis to Revelation for every day of the Advent period. Steve is fun to read with an irrepressible sense of humour (he'd have to be like that, he is an Everton supporter).

The whole Christian message is here in this book and since Steve is an expert on the Last Things (he wrote his PhD on the Intermediate State) he gets Revelation right. If you are wondering what you should read in December, read this.

Correctly dividing the Word of God

2011-11-20T15:31:00.003Z

One of the great temptations in preaching a sermon is to find a political point you wish to make and then find a story from the Bible with which you wish to illustrate it. over the past few weeks preachers have been seizing on the story of Jesus overturning the tables of the moneychangers in the Temple to preach a sermon about the unfairness of the inequality in the financial sector - quite out of context. Pick a text out of context and use it as a pretext.

Equally invalid is to preach systematic theology, using illustrative passages. This is practised by Evangelical preachers throughout the world. Proper preachers should be preaching Biblical theology - preaching what actually comes out of the passage.

To do this well it is necessary to properly divide up the word of God. There is a structure that the original authors applied to Scripture and it is necessary to sort this out from the chapters, verses and paragraphs that later editors have imposed.

You can find a superb example of how to divide up Scripture in the preaching of Chris Kelly, particularly in the Gospels of Mark and John. and I thoroughly recommend it.

What happened to the Respect Trial?

2011-11-19T15:35:00.002Z

Trials for patients with early stage CLL approved by the British NCRI
RESPECT – (CLL203)

This is a 40 patient single arm study to investigate the use of Lenalidomide in patients with early stage CLL with 2 or more poor prognostic factors. Christie Hospital is managing the trial. There are stringent stopping rules. Screening conducted by HMDS in Leeds. Biobanking samples will be collected from all screened patients.

Current Status

The trial opened and recruited 2 pts but recruitment is currently suspended following the release of 2nd malignancy data following the use of Lenalidomide. Recruitment had been slow prior to suspension of recruitment. It was asked whether the group if they were still interested in the trial and whether the design was still viable. These issues were discussed by the group; problems include: there is limited data on the use of this toxic treatment (lenalidomide) in patients who may otherwise not require treatment; the variable rate of progression of Stage A patients, even those with a poor prognosis and many stage A are treated in DGHs. However, it is still an interesting question. To wait for official feedback from Celgene before assessing the full impact on the protocol, the risk-benefit analysis and the re-opening the study.

Why a Tobin Tax would not work

2011-11-19T15:10:00.002Z

This from a Leader in Today's Times:

As bad economic ideas go, a European financial transactions tax is hard to beat in any circumstances. When the continent is mired in a crisis of indebtedness and weak growth, in which the inflexible monetary arrangements of the eurozone render any solution far more difficult, its irrationality possesses a particular grandness.

Yet EU policymakers, with President Sarkozy and Angela Merkel principal among them, are seriously considering just such a scheme. The British Government should respond that if the tax proceeds, the UK will assess dispassionately the economic benefits of belonging to the EU against the economic benefits provided by the City of London, and unhesitatingly choose the latter.

The principle of a tax on financial trading, as the European Commission envisages it, is that it might deter disruptive short-term speculation while raising money to ameliorate Europe’s budgetary needs. The reality is that it would not work. By raising the costs of trading, its main and entirely foreseeable effect would be to drive securities business out of Europe to other financial centres. Ill-judged financial regulation has a long history. The very success of London as a modern financial centre partly derives from it.

In the 1960s, the City was in relative decline in common with the rest of the British economy. The US Government then introduced legislation that limited the amount of interest payable on dollar deposits by banks in America. Investors promptly moved their dollars abroad and London became a magnet for international banks. More recently, in the 1980s, Sweden introduced a tax of 0.5 per cent on equity purchases. It raised far less revenue than its proponents had predicted, and within a few years more than 50 per cent of Swedish equities had moved to London.

A financial transactions tax applied in the EU would do the same on a bigger scale. Traders would avoid paying it by booking deals in other financial centres. Even if, with magnificent improbability, the tax were agreed also by financial authorities in the US, China and other leading economies, that would still leave offshore tax havens, which would have a huge incentive not to follow suit. Even then, the tax would have to apply to every transaction without exception, or traders would reclassify one type of deal to something else — a bond transaction might, for example, be reclassified as a foreign exchange deal. The ease with which a tax can be avoided is not always a conclusive argument against levying it. The problem with an EU transactions tax, however, is not primarily its futility but its destructiveness. Securities business would migrate from Europe to other parts of the world.

George Osborne, the Chancellor, has rightly described such a predictable outcome as economic suicide for Britain and Europe. But he is too polite. There is an implicit but unmistakable aim in the proposal to erode the importance of London as a financial centre. Mr Sarkozy has made no secret of his aversion to the “free-wheeling Anglo-Saxon” model of financial markets. This is an economically damaging aim, but most particularly for the UK. The City accounts, among much else, for more than a third of global foreign exchange turnover. Its earnings are crucial to Britain’s economic recovery. If European leaders push this tax, they are simply pushing Britain out of Europe.

John 8: 9b-11. A temporary reprieve?

2011-11-19T12:20:00.003Z

Only Jesus was left, with the woman still standing there. Jesus straightened up and asked her, “Woman, where are they? Has no one condemned you?” “No one, sir,” she said. “Then neither do I condemn you,” Jesus declared. “Go now and leave your life of sin.”

It should not be taken to believe that Jesus will never condemn us. On this visit to Planet Earth, Jesus' purpose was to provide the means by which we could we could go uncondemned (his death and resurrection) and to tell the world the good news. But when he comes again it will be for judgement. He told us that all fall short of the glory of God and that the wages of sin is death. No wonder he told the woman, “Go now and leave your life of sin.”

Racism in Sport

2011-11-19T10:33:00.003Z

South Africa-born former England cricket all-rounder Basil D'Oliveira has died at the age of 80. Fifty years ago South Africa was in the grip of Apartheid and Basil, by far the best cricketer in that country was, as a 'cape-coloured', not allowed to play cricket officially. He wrote to the English Cricket commentator, John Arlott, in green ink to ask if it was possible for him to play in England. Within 2 years he was an England international. He finished with a Test batting average over 40 an unusually high average for an all rounder.

Eventually Basil was a major catalyst for the ending of apartheid in South Africa, still the greatest success for the anti-racist movement worldwide.

This all sets the current 'crisis' about racism in football.

In a sense the racism battle has already been won. When I was married in 1967 I caused a little bit of squirming by choosing an ethnic Indian as my best-man. He was actually a Kenyan whose parents had left Goa, a former Portuguese colony on the west coast of India. He was also a Christian.

In Switzerland Sepp Blatter, the FIFA president has upset some English footballers (and David Beckham) by suggesting that racial insults on the pitch should be forgiven and forgotten with a handshake at the end of the game. Blatter has since apologized and withdrawn his statement. It goes to show that it is unwise to comment on a situation that you are not really part of.

FIFA was already in bad odour because of widespread belief that delegates within the inner circle are irredeemably corrupt and by a silly refusal to allow English and Welsh players to wear embroidered poppies on their shorts for international matches played over Armistice weekend.

There are two current issues in the English Premier League under consideration. In one the Liverpool player Soares, who is Spanish is accused of calling the Man U, French player, Patrice Evra, a 'nigger', though this may be a language problem between French, English and Spanish. I did watch this match, though, and felt that Saurez spent the whole match trying to niggle Evra including with foul tackles from behind which went unpunished.

The other case involves John Terry who reportedly was abusive to Anton Ferdinand, the brother of former England captain Rio Ferdinand. Both the Ferdinands are of mixed race and I don't thing it is the racial content of the insult that is the greatest offence of it. Terry reportedly used the 'C' word to describe Ferdinand. Terry is a London lout with a history of bad behavior; it runs in his family. Since both Terry and Rio Ferdinand are reaching the end of their careers and have been vying for the England captaincy, one can easily see where the tensions lie.

I suspect most readers, unless vehement supporters of the various clubs that the players are attached to, will regard this as a storm in a tea cup. I remember the days when fans used to take inflatable bananas to football matches to imply that black players were descended from monkeys. Things have greatly improved in England, though no doubt there are still places where racism persists. The number of black faces that one sees on television and in parliament suggests that the great prejudice about race that did exist when I was a boy has largely been dissipated with succeeding generations.

There is no doubt that prejudice does still exist. In London we are seeing a trial of two white guys who allegedly murdered a black man at a bus stop. That was 19 years ago and at the time the London Police Force was declared to be 'institutionally racist'.. With large waves of ethnically different immigrants, particularly in London, since then, one might have expected the situation to get worse. Yet it is difficult to make that judgement honestly. Police are prejudiced against criminal and large numbers of young black men are criminals, as the London riots in the summer have confirmed. It is clearly wrong to racially stereotype people, but then it is probably inevitable. Stopping and searching old white (or black) ladies would be a waste of police time. Topping and searching young men in parts of East London makes more sense if applied to white youths (there are very few black youths there) but in West London, most young men are Asian and in South London, Afro-Caribbean or Nigerian.

In Scotland the main divide is sectarian between Catholic and Protestant. This too spills out onto the football pitch. The recent fine of £34,000 that EUEFA imposed on the Bulgarian Football Association for chanting abuse at black England footballers at a EUEFA qualifier demonstrates that Racism has not been eliminated from football, but it has been reduced by a great deal while I have been watching the game.

Miracles

2011-11-17T13:12:00.002Z

I believe in miracles. Some people think it crass of me as a scientist to admit to this, but as a Christian, it seems to me that to deny things like Jesus turning water into wine or walking on water, while insisting that he was raised from the dead is straining at a gnat while swallowing a camel.

I know that many of my readers are praying for me, and while some are praying that I have strength to suffer my illness, many will be praying for a miraculous recovery. But do such miracles happen today. Miracles in Scripture tended to occur at specific times: at the times of Moses, Elijah and Elisha, in Daniel's time and at the time of Jesus and the Apostles. Early in Acts, an Apostles shadow or handkerchief could effect a cure, but later in Paul's lifetime he was advising Timothy to use medicine (Take a little wine for your stomach's sake) rather than have the Elders lay hands on him.

Today, most reports of miracles come from rather primitive communities, where they cannot easily be checked up on. An evangelical Christian GP in Southampton, Dr Peter May has spent most of his life trying to authenticate medical miracles and hasn't found a single incontrovertible case. I am also for the most part a sceptic, especially about all those stories from Lourdes in France.

Looking objectively at what would have to happen, any medical miracle would have to be a major feat in engineering. "Prepare ye a highway for the Lord" says Scripture. So there would be Biblical warrant for a new dual carriageway between Bournemouth and Dorchester to appear overnight. Of course, this would involve clearing the route, laying down foundations, packing down the hardcore and then tarmacadaming the road. For it to happen overnight would be astonishing, and it ain't going to happen. What people don't realise is that to cure cancer is an even more complicated feat of engineering.

But we should not limit God in any way. He is omnicompetent. He will do whatever he wants. But He usually limits himself. If miracles were regular happenings, they would not be miracles. God has ordered the Universe in a particular way - if miracles were common then we would not be able to rely on the normal laws of Physics.

Most medical miracles in Scripture are instantaneous. But there is one where Jesus uses means to heal. He mixes up mud and spittle to heal a blind man, but the healing is in two parts. Does this give us warrant for asking that The Lord aids in medical healings? It would then be valid to pray for my medical treatment to work.

The nearest I have seen to a medical miracle was with my friend and patient Dr Waribo Urum from Nigeria. This began 19 years ago. Waribo was a young dostor from Nigeria who had become very anemic. In Nigeria he had received 76 units of blood by transfusion and surprisingly had managed to avoid any virally transmitted disease. He was referred to me for a marrow transplant for aplastic anemia. This itself was a minor miracle. He would need to provide funds for this procedure. It so happened that we had in the hospital a registrar in Geriatrics from Nigeria who brought him to my attention. There seemed no possibility of getting the funds, but at that time there was a coup d'etat in Nigeria and the Registrar's husband became Minister of Health for 6 weeks ans found the money for Waribo.

When he arrived we swiftly discovered that the diagnosis was wrong. He had multiple myeloma and pure red cell aplasia. Although there is nothing in the medical literature that relates these conditions, I felt sure that they must be related. We applied several different treatments including a stem cell autograft. Although his myeloma went into remission we could not cure his red cell aplasia. He remained dependent on blood transfusions, mostly on a weekly basis for 16 years. Then suddenly, three years ago he no longer required them. Moreover his blood group changed. I have no explanation for what has happened.

Today he is settled in this country, he is married to a Christian girl, singing in a local choir and preaching regularly at the local evangelical Anglican church.

Is it a miracle? I have no other explanation, but it is one of those 'Men like trees walking' types of miracles.

Why is the Eurozon failing.

2011-11-17T13:06:00.002Z

This leading article from Charles Crawford, former British Ambassador to Yugoslavia and Poland says all you need to now about the problems of the Euro.

We mere mortals cannot get our heads round the astounding phenomenon of Compound Interest. Thus the amusing school maths puzzle:

A lily-seed is dropped in the middle of a circular pond 64 feet in diameter. The seed starts to grow. The new lily-pad doubles in size every day. It takes 100 days to cover the pond fully. How long does it take to cover half the pond?

The average adult’s eyes glaze over. The hesitant reply comes: “Er… 50 days…?”

NO. If it doubles in size every day and covers the pond on the 100th day, it must have taken 99 days to cover half the pond. Duh.

In this imaginary example the lily pad has been actually invisible for most of the 100 days, but suddenly in the final few days it doubles and doubles and doubles up to previously unexpected – if not unimaginable – proportions.

This metaphor helps explain phenomena like al-Qaeda: they lurked below the consciousness horizon of Western opinion, quietly growing their networks, before launching into destructive action. They were playing on the tendency of busy Western leaders to say that if AQ were a problem at all, they were tomorrow’s problem: today’s problems are always more pressing.

In Italy’s case now, the country’s economic fundamentals are quite strong. Italians (unlike, say, Greeks) actually make stuff we all buy. But Italy is a sizeable country. This means that if the rest of the world’s confidence in Italy edges downwards, and interest rates for Italy’s bonds edge up, the absolute sums of money which Italy needs to pay back quickly soar to previously unexpected, startling levels.

Since no one is prepared to lend Italy the money to pay back these debts at affordable rates and Italy cannot quickly grow its economy to create the wealth to repay them (or devalue its currency), options dwindle fast. Italy must spend less on government programmes and divert that money to debt servicing. It must also cut spending, mainly by sacking expensive state employees. But since these measures – even on the toughest and most optimistic scale – won’t be enough to deal with the absolute scale of the problem, the euro system has to print money to pay back these debts.

Which brings us back to the Germans, who insist that that printing can’t happen: unwise in principle and/or unlawful under the EU’s treaties, they say. Dishonourable too. When the eurozone came in being, German leaders and officials (all with long family memories of savings being wiped out by inflationary mismanagements earlier in the twentieth century) toured Germany promising explicitly "no bail-outs for profligate eurozone members!"

That was the very point. Germany would surrender control over its beloved deutschmark but insist on (and get) tough rules to avoid being lumbered with other Europeans’ fecklessness.

Nice try. But right at the start of the eurozone project the Germans sold the pass, loosening the criteria to allow heavily indebted Belgium to join, as it was "politically unthinkable" that Belgium as one of the original European Economic Community founders should be embarrassed by being left out.

So, will the Germans now fold in the face of the potential horror of the eurozone’s possible collapse, and allow the ECB to "create" money as the lender of last resort to stop the markets gnawing away at eurozonic contradictions?

They insist noisily and repeatedly that they won’t. But that is consistent with (a) the Germans really meaning it and letting the chips in the inevitable disaster lie where they fall; and with (b) the Germans doing everything they possibly can to squeeze the last brutal droplets of reform and austerity from more profligate eurozone countries before completely changing course. Because (think the Germans, and they are right) if the Germans even hint at allowing the euro printing-presses to roll, all pressure on the worst-run eurozone countries to work responsibly immediately stops.

Meanwhile the interest-payment effect works in Germany’s favour. Germany is making significant "savings" by being seen as a safe borrower worthy of lower long-term interest rates. The UK too looks like one of the saner places to lend money – billions of pounds which would be spent on repaying loans can be earmarked for other purposes. France’s Finance Ministry, by contrast, must be aghast as the cost of borrowing piles on billions of Euros of French taxpayers’ money every time the market twitches in unease about France’s credibility.

Yet Germany is, basically, in a hopeless position, for all its fine work in responding to the previously over-valued DM by moving up the global competitivity rankings and managing costs and labour unions skilfully. Because the more the credit-ratings of other eurozone member countries erode, the more exposed sooner or later must be Germany’s own credit-rating.

Germany created a single monetary space. It can’t escape the inexorably compounding consequences.

Health update.

2011-11-16T15:31:00.003Z

I have not been very well since I came off the Capecitabine. I did not have the recovery that I had had last time. It will be at least 3 weeks until I get the monoclonal antibody. I reasoned that I ought to have some maintenance therapy to tide me over the gap and decided after two weeks without any treatment to take half dose Capecitabine. This was a mistake. The abdominal pain and bloating kicked in with a vengeance.

To remedy this I have had a couple of days on clear fluids, more bed rest, dexamethasone 6mg, and I've bought some bigger shirts to accommodate my expanded waistline. Things are gradually getting better, but I shall have to start eating again soon.

Beyond the Poison; Peter Robinson

2011-11-16T14:54:00.003Z

We have watched a few of the DI Banks films on TV. He is a fairly miserable detective from Yorkshire with all the usual character flaws. The books are written by Peter Robinson; there are about 20 of them. I have been reading Beyond the Poison, his latest book and one of the three that doesn't feature DI Banks.

A composer of film music returns to Yorkshire from Holywood after his wife dies (sounds like breast cancer). He buys a remote manor house and discovers that in 1953 the wife who owned it then was hanged for killing her husband. He becomes intrigued by the case and is convinced that she wasinnocent; her conviction being due to fifties' moral prejudice. She was having an affair with a young artist only half her age. Her husband oribably died of natural causes. But as he traces the old men who impacted on her life, was there a more sinister story behind it all?

As we discover the background, we disover the history of North Yorkshire in the war and read a vivid account of what it was to be a nurse in the QA in Singapore when the Japanese attacked. The Japanese never signed the Geneva convention and their treatment of prisoners of war was vile. The German use of chemical warfare in WWI prompted the setting up of a British chemical and biological warfare defence establishment at Porton Down. Or was it a chemical and biological warfare attack department?

The book is well written being full of references to the films and music that I admire and is very up=to-date. culminating in the summer of 2011.

John 8:8-9. Keep on writing.

2011-11-16T13:36:00.002Z

Again he stooped down and wrote on the ground. At this, those who heard began to go away one at a time, the older ones first, until only Jesus was left, with the woman still standing there.

What did Jesus write on the ground the second time? One suggestion is "have nothing to do with a false charge and do not put an innocent of honest person to death, for I will not acquit the guilty." (Ex 23:7) But perhaps in his omniscience he just kept writing down the sins and the sinful thoughts of the younger members of the mob. Perhaps he was reminding them of the Serman on the Mount where Jesus identifies lust with adultery?

Straights fight back against gay pride

2011-11-15T13:37:00.003Z

In recent time the Gay Pride lobby has become more strident, even arranging prosecution of people going about their normal behavior.

I post here an e-mail that I received today from Davis Skinner:

Dear Friends,

I recently wrote to ask that you protest against Tesco sponsoring London Pride 2011 and World Pride 2012.

I wish to thank all those who have responded and those who have written to me with advice and encouragement as to how to motivate more people to engage with issues that threaten us in these perplexing times. You may have seen the result of our letters in the Daily Mail:
Well done and God bless you all. However, Tesco is totally unrepentant, preferring instead to shift attention away from their evil and wicked sponsorship to the charities that they can more than afford. No doubt many of you may have received a Tesco letter such as this:

“Thank you for your email addressed to Andrew Higginson, our Chief Executive of Retailing Services, to which I have been asked to respond. ………We believe that everyone should be welcome at Tesco. This is reflected in the people we employ and the customers we serve. It is also reflected in the broad range of organisations and causes we support…………Last year we donated over £64 million to charities and good causes across the world. This amounted to 1.8 percent of pre-tax profits; nearly doubling our goal for 2010. ……Each year in the UK we select a national charity as our Charity of the Year which represents a cause our customers and staff care about……….. We are proud to support this wide range of charities and community initiatives and look forward to continuing to do so…… trust that I have clarified our position on this matter.

Kind Regards

Frances Hickling

Chief Executive’s Office”

Below is my letter in response, explaining that World Pride 2012 will be a moment of national shame, not pride. I would urge you to keep up the pressure on Tesco. Please write back to them in your own words or using part of my letter. Please make your voices heard before this freedom of speech is taken away, as the previous government has threatened to do, if it returns to power.

Contact details: philip.clarke@uk.tesco.co; or customer.service@tesco.co.uk;
or ceo.customerservice@tesco.co.uk; or cr.enquiries@uk.tesco.com For comments or questions on Tesco's Corporate Responsibility Report please contact Sir Richard Broadbent, Chairman, Tesco, PLC, Delamare Road, CheshuntEN8 9SL
also see:

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TO CUSTOMER SERVICES TESCO
To whoever it may concern
Dear Sir/Madam,

It is with regret that it seems to me that Tesco have come under the domination of OUTatTESCO and that though it might donate 1.8% of its gross profits to good causes (which for a company of this size is a modest amount; I personally donate 20% of my net income) this can in no way compensate for its sponsoring such shameful, dehumanising and degrading events as London Pride or World Pride 2012.

Perhaps I am being unfair when I say that I anticipate that your reply to my concerns might be something along the lines of, “Dear Sir/Madam, Tesco is striving to achieve a fairer, 21st century, multicultural society where there is great diversity of lifestyles ……… and that consequently this case is now closed.” And indeed, absolutely on queue I have just received such an answer that says, “I understand that you are unhappy about this situation and your comments have been duly noted. However, I have nothing further to add to the comments in my previous correspondence and our position on this matter remains unchanged.

Kind Regards
Gary Menzies
Customer Service Executive”

If that should be the case, I have to emphasise that the rapidly degenerating state of our once great Nation, being in as much danger, if not more, than the one it faced in World War 11, especially if the genuine concerns of the public are treated with such contempt, also remains unchanged. This issue will not go away.

I need to say at the outset that I wish in no way to attack those vulnerable and fragile men and women, boys and girls who possibly, through no choice - initially - of their own, have developed an emotional disorder or sexual addiction - not through genetics but through environmental influences - even sexual abuse - coupled maybe with temperamental weakness. These require our love, compassion and assistance - not condemnation. Indeed there but by the grace of God go I. However, with regard to the out-proud, militant and proselytising homosexuals, who, with the support of Tesco and the British government, have visited their cruelty on Peter and Hazelmary Bull, an elderly Christian couple, who run a bed and breakfast business in their own home, in Cornwall, I can only say that by using ambiguous laws, fear, oppression and tyranny, the government and Tesco have declared war on the people of Britain.

Peter and Hazelmary, like Tesco, are in the business of providing goods and services. But, unlike Tesco, they refused to bow to the dictats and bullying of gay pressure groups. At the beginning of 2011 they were informed that they had contravened the Sexual Orientation Regulations (SORs) because they had discriminated against two gay men, Steven Preddy and Martyn Hall, by refusing them a double bed.

In addition to having to pay damages of £3600 to them, homosexuals then besieged their guesthouse with demands for double rooms, seemingly in a bid to destroy the business. Mrs Bull, 66, also received abusive and menacing phone calls, whilst her 71-year-old husband lay critically ill in hospital. Does Tesco support such behaviour?

I have generated a government e-petition, in support of Mr and Mrs Bull, asking for the repeal or drastic amendment to the Sexual Orientation Regulations (SORs) which like the outlet of an effluent pipe, continues to pump its toxic waste into British society:

With homosexuals, Steven Preddy and Martyn Hall, there is no “live and let live”. They knew perfectly well how deeply offensive it would be to Mr and Mrs Bull to have anyone performing sodomy under their roof - whether married or unmarried, male or female. The men could have respected how they felt and gone elsewhere. They had a choice of many double beds in Cornwall catering for their “special tastes”, but no; the evidence points to their having been emboldened in their action by Stonewall, the homosexual bullying lobby group.

It is vital that we understand who generated the SORs, the purpose of which is to destroy traditional marriage and family life. This might sound and extreme claim, but read Peter Tatchell’s vision for the future just a few paragraphs further down.

The SORs were not handed down from heaven; neither are they based upon self-evident and universal truths. They were spawned in the imagination of Stonewall’s former chief executive, Angela Mason et al who is a commissioner of the Equality and Human Rights Commission (the outfit responsible for hauling Mr and Mrs Bull through the courts). Not only was she responsible for setting up the Equality and Human Rights Commission (ECHR),she was responsible for overseeing the Sexual Orientation Regulations when she headed up the Women’s Equality Unit from 2003 to 2007. She is also a Marxist, lesbian, IVF mother, ex-member of anarchist group, the Angry Brigade (who in 1971 conducted a campaign of terror bombings in London). She also chairs the feminist organisation, the Fawcett Society (whose former chair, Dr Katherine Rake said “We want to transform the most intimate and private relations between women and men.”)

For Tesco to throw itself with such enthusiasm into this experiment in social engineering, by promoting sterile ‘different families’, who are unwilling to reproduce in the natural way, that come in all shapes and sizes, where there is no recognisable parentage, and where children are treated as commodities and trophies to be used as human shields to infiltrate our schools, sports clubs and scouting associations with gay propaganda, can only be described as an act of wanton anarchy – beyond anything we saw this Summer on the streets of London.

When law abiding members of the public like foster parents, Mr and Mrs Johns, the housing officer Adrian Smith, and a growing list that includes teachers, therapists, councillors, counsellors, magistrates, paediatricians, registrars, nurses, firemen, policemen and clergy - people from every walk of life - are publically humiliated, fined, forced out of their occupation, forced to close down their business, dragged through the courts, threatened with violence by gays, and compelled to pay for their own oppression through their taxes (for simply trying to halt this anarchy and to defend the values and morality of traditional marriage and the family) and presumably with the approval of Tesco, this is not likely to improve your ratings with the general public either.

To see the kind of vision for Britain that Tesco is promoting, let us have it from the horse’s mouth. Peter Tachtell in “Beyond Equality” writes:

“In many ways, our transcending of heterosexual mores is a positive and immensely liberating experience. Compared with most straights, queers tend to be more sexually adventurous with a wider repertoire of sexual behaviour, less bound by the strictures of traditional morality, and more experimental in terms of relationships. We don't need a marriage certificate to validate our partnerships.”

“Although getting rid of homophobic discrimination is a laudable aim, it doesn't go far enough. Ending anti-gay bias will not resolve all the problems faced by lesbian and gay people. Some of our difficulties arise not from homophobia, but from the more general eroto-phobic and sex-negative nature of contemporary culture.”

“We get equality, but at a price. The cost to our community is the surrender of our unique, distinctive queer identity. The unwritten social contract at the heart of law reform is that lesbians and gays will behave respectably and comply with the heterosexual moral agenda. No more cruising, orgies or sadomasochism!”

In “Teenage Sex-What Should Schools Teach Children?” he writes:

“Until very recent times, all sex education was overwhelmingly biased towards promoting heterosexuality, marriage, parenthood and traditional family life. Anything outside this exclusive framework was either ignored or condemned”……“This old-style monocultural sex moralism is now totally out of sync with our modern multicultural society where there is a great diversity of cultures and communities, lifestyles and love-lives.”…..” Nothing must be off limits”…..“Sex education, to be effective, needs to start at a very early age, beginning gently in the first year of primary school and gradually becoming more detailed and explicit at secondary level”……“The best way to persuade teenagers to adopt oral sex and mutual masturbation is by making them look and sound sexy.”

But Tatchell, in “Insignificant Other” wants to go beyond to something called the Civil Commitment Pact, where any kind of relationship is given social and legal recognition.

“For these reasons, I have suggested a new legal framework – Civil Commitment Pact. It would allow people to nominate as their next-of-kin and beneficiary any 'significant other' in their life. This could be a partner or lover, but it could also be a sister, carer, house-mate, favourite nephew or life-long best friend. “Any new partnership legislation should allow people to select from a menu of rights and responsibilities. This flexibility would enable them to devise a tailor-made partnership agreement suited to their own particular needs.”

It's clear to see where Tatchell is taking us with “any kind of relationship”.

I now draw your attention back to Tesco's World Pride 2012 sponsorship. Without doubt, as each year passes, and the gay lobby become more emboldened, this will become more extreme until it begins to resemble the obscene Folsom Street Fair in California which was described this year as being like “nothing in the world.. with 400,000 kinky friends spread out over 13 city blocks of adult entertainment”: BEFORE viewing these links, I apologies in advance and give a strong warning about the outrageous and highly explosive nature of this GayPride material.

TESCO PROMOTIONS : SCENES FROM LONDONANDMANCHESTER PRIDE (note man and his dog at 3min50 seconds) (note sex workers marching in parade)

GAY HEALTH AND SAFETY PROMOTED BY TESCO

The 1% of the population who identify themselves as gay or bi-sexual are responsible for almost 50% of sexually transmitted diseases.
The Pink News reported,“New figures from the body show that men who have sex with men and young adults are the most at-risk groups for infections.
The HPA said that in cases where sexual orientation was recorded, 64 per cent of new syphilis infections and 40 per cent of new gonorrhoea infections were found in gay or bisexual men.”

It also said,

“More than 100,000 people are expected to be living with HIV by next year, at an annual treatment cost of almost £1 billion. In 2010, 45 per cent of those diagnosed were gay or bisexual men.”

Other sponsors of London and World Pride are the Terrance Higgins Trust, supposedly an HIV and sexual health charity that has been granted £203,528 government funding to run a sex education programme in English schools and youth clubs. This outrageous programme, called the Sexual Health Champions Programme (SHCP), will allow 100 disadvantaged children aged between 14-19 to be trained as ‘Sexual Health Champions’. They will then lead peer-to-peer sessions for 2,000 more young people, while 40 young people who are deemed most at risk of sexual ill-health will receive one-to-one mentoring. This is material from THT that children will no doubt be encouraged to access:

GAY HATRED OF CHRISTIANITY AND THE BIBLE AIDED AND ABETTED BY TESCO

When Tesco proudly states that it is pleased to have been invited to support World Pride 2012, may I cast the spotlight on a similar event held in London's 2006 Europride, when Sir Ian McKellen OBE and Sir Elton John CBE were its patrons and organisers? These same Stonewall champions of diversity may well be integral to World Pride 2012.

In 2006, the Independent on Sunday compiled an annual Pink List of the most influential gay and lesbians in Britain.

Ian McKellen topped the list ahead of singer Sir Elton John in second place. Since September 2008, he has been cruising, virtually unopposed, around British schools, subtly breaking down children's natural reserve towards unnatural behaviour, under the pretext that “we should be kind to each other.” What kind of kindness was it to read out James Kirkup's poem “The Love That Dares To Speak It’s Name” at a Secularist gathering in a London restaurant in 2008, by way of celebrating the repeal of the Blasphemy Laws? This obscene, pornographic poem of homosexual necrophilia, describing in graphic detail a Roman soldier pouring out his lust on the dead body of Christ, was designed to express his visceral hatred of God and Christians. He also demonstrates his hatred of boasting of ripping pages of the Bible – something he proudly confesses to doing whenever he finds one in a hotel room. (look at the video at the bottom of this page of the “comedian, George Carlin, mocking God). DoesTesco applaud this too?

HATRED OF PURITY CONDONED BY TESCO (Warning obscene language)

GAY PAEDOPHILIA ENDORSED BY TESCO

In 2010 the government created a new anti-paedophile database, but McKellen who is patron of the Little Theatre Guild, which represents more than 100 British theatres, said that the Government's new anti-paedophile database was unnecessary for theatres and that "there has never in the last 50 years been any hint of wrongdoing". However, theatre director, Rhys Young who once worked for the Wharf Theatre in Devizes (which is a member of Sir Ian's Little Theatre Guild) was jailed in 2008 for having sex with a 15-year-old boy. He was also jailed for a similar offence dating back to 1996.

Sir Elton John, who came second on this list, put on a show for Cherie Blair and VIPs at the Royal Albert Hall in 1999, in aid of Stonewall, in which he celebrated paedophilia. Six professional teen-age strippers wearing Cub Scout uniforms (for ages 7-11) stripped off their uniforms -- to the song, "It's a sin," by homosexual band, the Pet Shop Boys, and knelt before Elton John in obscene poses while grabbing their crotches.

A Home Office document published in 1998 by Bradford et al suggested reasonably that approximately 20 to 33% of child sexual abuse is homosexual in nature and about 10% mixed (2nd para, p14)

And again, though I am not accusing Peter Tatchell of being a paedophile, his writing is bestrewn with evidence that he supports it. – no matter how much he vehemently denies this. Read your Tatchell.

GAY SUICIDE AND DRUGS PROMOTED BY TESCO

Third in this annual Pink List of the most influential gay and lesbians in Britain was Gary Frisch and Henry Badenhorst who founded the gay online dating agency Gaydar.com, which boasts more than six million subscribers worldwide, and apart from Tesco, is also a proud sponsor of London Pride. .

Gary Frisch committed suicide by leaping from the eighth floor of a block of flats in London, his blood full of ketamine, and shouting “whahee” as he leapt from the balcony.

“Gay singer Elton John revealed that a former lover committed suicide… The star said: “Years back I had a relationship, and I had absolutely no idea in the world he was going to do this… he threw himself under a truck.”

Matt Lucas, Little Britain comedian, who came 9th in this list in 2009, according to the Independent, ‘had been starring in Prick Up Your Ears at the Comedy Theatre, a sombre play about the suicide of the playwright Kenneth Halliwell, who killed himself after murdering his lover and fellow playwright Joe Orton. But the Little Britain star quit after his real-life former partner Kevin McGee was found hanging on Monday in his Edinburgh flat…”

We might also add the names of the many homosexuals, such as Kristian Digby and Kevin Greening, who have committed suicide or died as a result of dangerous sex experiments.

Even within the last few days we hear of Peter Roebuck: cricketer

GAY TYRANNY, OPPRESSION, DOMINANCE AND BONDAGE PROMOTED BY TESCO

Thrown in for good measure, the singer Boy George makes a regular appearance in London Pride. He served only four months of 15 month prison sentence for chaining a male escort to a wall and lashing him with a chain during a sex act in 2009. In this Youtube he believes that Christians should be silenced from making any comment or criticism of homosexual behaviour.

How soon before billboards and posters, proclaiming ‘SOME PEOPLE ARE GAY, GET OVER IT’ are placed in every street, every work place, school, sports club, and church telling us that even to feel uncomfortable with sodomy will qualify us to be forcibly made to attend a diversity course at the national headquarters of the homosexual lobby group, Stonewall in London: - as happened to a Bristol councillor, Chris Windows, when he expressed concern about gay (Sir) Ian McKellen proselytising homosexuality to Bristol schoolchildren ? relevant part of video starts at starts 2hrs 20:56 to 2hrs 28:45)

Clearly a disturbed minority, aided and abetted by our institutions, like Tesco are attempting to impose homosexuality on our children. In all these issues I will gladly go to prison rather than remain silent about this evil or have it forced upon me or my family. I want the right to choose what I teach my children and grandchildren - not be forced to teach them about fornication, adultery and sexual perversions. I will not teach this to my grandchildren, nor stand by and agree to someone else doing so, and sincerely hope that are still people left in Britain who think the same way.

Am I to understand that Gary Menzies of Tesco customer services has the last word?

“I have nothing further to add to the comments in my previous correspondence and our position on this matter remains unchanged.”

In the light of the above overwhelming evidence I ask that Tesco reconsiders its position on this matter?

Yours sincerely

David Skinner

Like most people I tend to regard what people do in private as their own business as long as it doesn't scare the horses, but whan it is spelled out exactly what they do, I find it rather disgusting. I find that the promotion is offensive and the picking on children and young people dangerous. The government and Prime Minister's support for the gay life style has stopped me voting Conservative again and I shall now never shop again at TESCO.

Wolf Hall

2011-11-14T18:05:00.002Z

Thomas Cromwell was only a distant relative of the more famous Oliver Cromwell. I suppose we know most about him from A Man for All Seasons in which Leo Mckern played him as a fat and ugly villain against the saintly Thomas More of Paul Scofield.

Hillary Mantell's 2009 Booker Prize winner, Wolf Hall presents a very different figure. It is historical fiction, of course, but it does fit with my own prejudices. First of all, this is a wonderful read and I must try out more of her books.

Cromwell was the son of a blacksmith who was abused by his father. He left home at the age of 16 after a particularly bad beating. He went abroad and worked in the French Army and for Italian bankers and Dutch merchants before training as a lawyer. He was a very clever man who was fluent in nine languages including Welsh. It was said that he could recite the whole of the Vulgate New Testament in Latin.

On returning to England he made himself useful to Cardinal Worsley, the Lord Chancellor. Worsley himself was of lowly origins, being the son of a butcher. His means of rising in Society was through the Church; he became a Cardinal. Henry VIII got rid of him on the pretence of divided loyalties. In fact, it was because he could not secure him an annulment of his first marriage, something that Cromwell did succeed in, at the expense of divorcing himself from the Catholic Church.

I think that Cromwell was a true Reformer, albeit a pragmatic one. He supported Tyndale's testament in English and looked after, as best he could, the reformers within his merchant colleagues and among Cambridge scholars.

You have to consider Henry's position. It was only 25 years since the end of the Wars of the Roses and his position as King was easily threatened by Pretenders. The succession had to be secured. England was then a small country without the resources of France, Spain or the Holy Roman Emperor (basically Germany). He liked the glamor of war, but he couldn't afford to fight one. Cromwell's power base was his access to foreign loans, but how could they be repaid? Obviously from the dissolution of the monasteries, which were rich, corrupt and useless. Cromwell's Protestant heart was glad to dissolve them. Thomas More turns out to be an evil character, who was jesuitical in his reasoning, cruel to his opponents and unpleasant to his own wife.

The book ends with Cromwell powerful. More beheaded, and Anne Boleyn miscarrying. There will be a sequel.