A randomized trial of FA v F.

The Lancet Oncology reports and randomized phase 3 trial comparing fludarabine plus alemtuzumab with fludarabine alone in relased or refractory patients with CLL who have had no more than one previous line of chemotherapy. They were allowed to have had either of the agents alone previously as long as the duration of response had been greater than 12 months, but they were not allowed to have previously received the combination. I have reported this trial in some detail since it differs from other FA combinations. There is little to recommend FA as first line therapy, but since we know that p53 abnormalities are so common after FCR and that alemtuzumab is useless in bulky disease, this report might have something important to say about second line disease. It also gives a lot of detail about what it is like to receive alemtuzumab.

The study was done in five centres in North America and 43 in Europe. 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 positive Coombs test and active haemolysis; absolute neutrophil count (ANC) of less than 1·5×109 cells per L or platelet count of less than 75×109 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.

During the first treatment cycle, patients in the combination group were given escalating doses of alemtuzumab. 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 (or equivalent) 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.

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.

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. 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.

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.

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 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 (= death) [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 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 (data not shown). 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 (data not shown). 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 (data not shown). 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.

Comment

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, the authors designed this study for further assessment of combination treatment.

The findings of this 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, 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. Robak and colleagues 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. (I was one of those who participated in the Independent Review). The results presented in this report are comparable to those of Robak and colleagues' combination chemotherapy and immunochemotherapy regimens in previously treated patients with relapsed or refractory CLL. 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, 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 FDA 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.




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Blowing our own trumpet

I had my first dose of my second course of my third line of chemotherapy this morning. Once again I was impressed by the set-up at the Royal Bournemouth Hospital. I learned today that it received the accolade of NHS Hospital of the Year in 2009. And in 2010 it was awarded Safe Hospital of the Year status. It is now 21 months since there has been a case of hospital acquired MRSA.

To continue blowing our own trumpet may I direct you to our new website set up by our new colleague, Dr Renata Walewska. http://www.rbch.nhs.uk/index.php?id=616 Please browse. You will see that we have had nearly 800 scientific publications over the past 30 years.

The role of CD38 in affecting CLL migration

In vitro activation of CD38 caused by stimulating mAbs induces a portion of the CLL clone (10%-30%) to proliferate, giving rise to an immunoblast-like component that does not secrete Igs; these effects are dependent on significant amounts of soluble IL-2, in keeping with the observation that T lymphocytes and accessory cells are needed in vivo. This was a first indication that CD38 transduces signals, leading or contributing to CLL cell growth, even in the absence of stimuli coming from the BCR.

First indications that CD38 acts as a molecular signpost that routes leukemic cells to specialized niches arose from in vivo findings that the number of CD38 molecules expressed in BM and LN is higher than in circulating lymphocytes. In addition, nurse-like cells, differentiated in vitro from circulating CD14+ cells and also presumably present in solid lymphoid tissues in vivo, express CD31, the CD38 ligand. Interactions between CD38 and CD31 in this system promote proliferation and survival through a molecular circuit that can be interrupted by blocking anti-CD31 or anti-CD38 mAbs. CD38/CD31 interaction results in a genetic signature that includes more than 1500 modulated sequences. Pathway analysis drastically reduces this complexity, with proliferation and migration emerging as the main elements characterizing this receptor/ligand system.

CD38 signaling may be influenced by the presence of ZAP-70. Patients with CD38+ZAP-70+ clones are more responsive to activation of intracellular proteins than CD38+ZAP-70− persons. This may explain why the simultaneous expression of the two molecules offers a more efficient identification of the high-risk patient subset. CD38+ZAP-70+ CLL cells also migrate better in response to the CXCL12 chemokine and exhibit a genetic signature primarily consisting of genes involved in cell locomotion. A functional cooperation between CD38 and CXCR4 was demonstrated by showing that binding of stimulating anti-CD38 mAbs and de novo expression of CD38 by lentiviral infection increases chemotaxis in response to CXCL12.

These effects on proliferation and chemotaxis are altered by blocking reagents, which interfere with CXCL12-mediated migration in vitro and block CLL homing in an NOD/SCID mouse model. A possible explanation is that CD38 and CXCR4 are associated on the same membrane patches; and hence, stimulating and blocking anti-CD38 mAbs have the potential to interfere positively or negatively with CXCL12 binding to the CXCR4 receptor, changing responses. Recent data indicate that this signaling platform of molecules is more complex and includes adhesion molecules, such as CD49d and matrix metalloproteases, such as MMP-9.

Health update

I have a week off chemotherapy and I am feeling better. Last week we had some sunshine and I was able to go for a walk on the beach at respectively Bournemouth, Poole and Highcliffe, depending of where the cusp of the cold front encroaching on the British Isles was exactly situated; 15 minutes walking and 30 minutes sitting in the sun.

I saw the oncologist this morning and had the good news that my carcinoembrionic antigen had fallen. It had always been in the normal range until before the last lot of chemotherapy began, when it had risen to 32. After this course it has fallen to 24 which is obviously in the right direction. Enough anyway to encourage them to restart the same type of chemotherapy tomorrow.

I am due a CT scan this afternoon. I met a new registrar this morning; a very pleasant young woman from Bangalore.

CD38 and the BCR

Clones with higher numbers of CD38+ cells are generally those more responsive to BCR signaling in vitro, whereas CD38− clones are generally anergic, although exceptions exist. The same phenomena are observed at the intraclonal level as CD38+ cells respond more readily to BCR stimulation than CD38− cells of the same clone. However, evidence for involvement of CD38 in the BCR signaling pathway is indirect and linked to lateral associations with CD19 and CD81 (in turn part of the BCR complex) and colocalization in the same lipid rafts as the BCR.

The most favorable conditions for expansion of CLL clones exist in discrete anatomic sites, such as Proliferation Centers (PC) in Lymph Nodes (LN) and in the Bone Marrow, where leukemic cells come into contact with accessory cells and the appropriate array of cytokines and chemokines. These sites contain more CD38+ CLL cells than detected in the blood, implying that CD38 is involved in the expansion process and/or results from it.

These findings may indicate that a trafficking fraction of CLL cells may enter PCs of peripheral LNs, become activated, and express (more) CD38 as well as ZAP-70 and other activation markers. Additional stimulatory signals may also be delivered directly via CD38. The degree of activation would influence a cell's capacity to up-regulate the number of markers per cell and the percentage of positive cells. On re-entry into the peripheral circulation, CLL cells may express more activation markers (CD38, ZAP-70, CD49d, and others), thereby representing important predictors of disease outcome. Besides the BCR, CD38+ cells also respond better to signals coming through chemokine and other receptors (eg Toll-like receptors). Therefore, signals emanating initially and subsequently from this pathway probably provide molecular bridges to the extended CLL microenvironment, thereby favoring survival/proliferation of CLL cells.

What do we have but the Bible?

There is an extreme view of the origin of the gospels contaminated by the German higher critics of the nineteenth century, that holds that the Gospels were late documents cobbled together by people in the second century who did not know Jesus.

Modern scholarship suggests that all 4 evangelists were contemporaries of Jesus and the three synoptic gospels were written within 20 years of the death of Jesus. The incident of the young man who lost his clothes puts John Mark at the arrest of Jesus, Matthew was himself a disciple, Luke was a confidant of both Mary the mother of Jesus and Peter and he was later a companion of Paul whose own writings predate the gospels, even though he never met Jesus in His earthy lifetime. John's gospel is later but he was a very old man when he wrote it and there is no reason to believe it was written by anyone other than John the beloved disciple.

As for Jesus' own sayings, he claims to have come not to negate the Law but to fulfill it. The Old Testament apparent anomalies were pictures of the Christ to come. This same Jesus speaks more about the Hell to come than any other person in either testament and will come to judge the world. He is not the milksop that liberal Christians claim him to be and though for now he offers salvation, that offer is not for all time. After we die there will be no second chance and then if not covered by his death and resurrection, our sins will surely find us out. It is then that he will confront us with, "I was hungry and you gave me nothing to eat, I was thirsty and you gave me nothing to drink, I needed clothes and you did not clothe me, I was sick and in prison and you did not look after me. ... I tell you the truth, whatever you did not do for one of the least of these you did not do it for me ... then they will go away to eternal punishment."

John 7:19. Falling short.

"Has not Moses given you the law? Yet not one of you keeps the law. Why are you trying to kill me?”

The inadequacy of the Law; it points out our faults but it does nothing to help us to keep it. Truly, all have sinned and fallen short of the glory of God

Royal Wooton Bassett

In a moving ceremony this afternoon the small town of Wooton Bassett received the Letters patent to be able to prefix the town's name with "Royal". This was only the third occasion that this has happened and the first time for over 100 years.

The other two towns are Royal Tunbridge Wells and Royal Leamingston Spa which are both watering holes favored by previous monarchs. For Tunbridge Wells the prefix "Royal" dates to 1909, when King Edward VII granted the town its official "Royal" title to celebrate its popularity over the years amongst members of the royal family. It is a Spa town, incorporated as a municipal borough in 1888. In 1909 Edward VII allowed the prefix "Royal" in recognition of the town's connections with the royal family since the Stuart dynasty. The Borough of Royal Tunbridge Wells was abolished in April 1974, and charter trustees were briefly appointed to preserve the mayoralty of the town. The trustees, who were themselves abolished in December 1974, obtained letters patent reauthorising the prefix "Royal" to the name of the town

Leamington was granted a "Royal" prefix in 1838 by Queen Victoria, who visited the town as a Princess in 1830 and as Queen in 1858. There are other Royal counties and boroughs recognized because there are Royal palaces in them. The following places have been explicitly granted or confirmed the use of the title "royal" by royal charter, letters patent or similar instrument issued by the monarch. Berkshire, Greenwich, Kensington and Chelsea, Kingston on Thames, Windsor. Since 1926 the entitlement to the title "royal borough" has been strictly enforced. Devizes in Wiltshire, which had previously used the title without sanction was forced to end the practice.

The title "regis" (of the king) has also been granted to one town - Bognor. Tourism gradually took off in Bognor during the 19th century, with the area being chosen as an ideal location for King George V to convalesce during 1929, the King and Queen actually staying at Craigwell House in Aldwick. As a result, the King was asked to bestow the suffix "Regis" ("of the King") on "Bognor". The petition was presented to Lord Stamfordham, the King's Private Secretary, who in turn delivered it to the King. King George supposedly replied, "Oh, bugger Bognor." Lord Stamfordham then went back to the petitioners and told them, "the King has been graciously pleased to grant your request. There are 13 other Regis-es in the UK, but it generally signifies nothing more than that the Crown originally owned the manor. Among them are Houghton Regis in Bedfordshire, Salcombe Regis in Devon, Bere Regis and Lyme Regis in Dorset, Milton Regis in Kent, Beeston Regis in Norfolk, Grafton Regis in Northamptonshire, Brompton Regis in Somerset, Newton Regis in Warwickshire and Rowley Regis in the West Midlands.

The prefix King---- signifies something similar and there are more of these: Kingham, Kingsclere, King's Heath, Kingskerswell, Kings Langley, King's Lynn, King's Norton, King's Sutton, Kings Tamerton, Kingstanding, Kingsteignton, Kingston by Ferring, Kingston upon Hull, Kingston upon Thames, Kingswinford Winterborne, Kingston, Kingsbridge, Kingsbury Episcopi, Kingsdon, Kingston Seymour, Kingston St Mary, Kingstone, Kingweston, Kingswood, Queen Adelaide, Cambridgeshire, Queen Camel, Queen Charlton, Queen's Park, Princes Risborough, and Princetown.

Royal Wooton Bassett is different. It is the closest town to the RAF base at Lyneham. In 2005 a Hercules aircraft from Lyneham was lost in Iraq with all its crew. As they were repatriated people from the town spontaneously lined the streets to honor the servicemen as their hearses drove through the town. After 2007 servicemen killed in Afghanistan were routinely repatriated through Lyneham and again the town stood in silence as the funeral corteges drove through. Eventually several thousand people lined the streets, distributing flowers on the funeral vehicles. This was a spontaneous gesture of respect and honor for our servicemen. They performed this ceremony for 365 soldiers, marines, sailors and airman. It is for this act of honor that they have been honored. In future repatriation flights will be through a different RAF base at Brize Norton.

Model of role of CD38

CD38+ CLL cells are more sensitive to chemokine (CXCL12) signals, with a higher likelihood to home to lymphoid tissues than the CD38− cells. Once inside the Lymph Node Proliferation Centers, CLL lymphocytes come into contact with accessory cells, such as nurse-like (NLC), follicular dendritic (FDC), stromal, endothelial, mesenchymal (these may be different names for the same cells in some circumstances), and T cells. The presence of antigen and accessory signals leads to proliferation which runs the risk of causing the acquisition of novel genetic lesions (like del 11q or del 17p) that promote clonal evolution and disease progression. These events are more apparent in the CD38+ subsets.

Other characteristics of the CD38+ and CD38− CLL subgroups are variable telomere lengths, telomerase levels, expression of the COX-2 enzyme, and in vivo incorporation of heavy hydrogen into DNA of dividing leukemic cells. Lastly, they differ in high-risk genomic abnormalities, in the development of new DNA mutations and copy number changes over time.

These findings suggest that cellular proliferation might be at the root of the association between higher levels of CD38, aggressively growing CLL clones, and poor patient outcome. This suggestion is consistent with in vivo labeling experiments using 2H2O (“heavy water”) that demonstrated larger than anticipated rates of CLL birth, especially in patients with poor clinical course and outcome and a several-fold higher percentage of newly born cells in CD38+ fractions of CLL clones than in CD38− counterparts of the same clones.

Furthermore, preliminary results from a large clinical study suggest that the percentage of CD38+ CLL cells strongly correlates with the level of leukemic cell turnover observed in vivo. Finally, a recent study using improved cell surface phenotyping and sorting techniques that incorporate expression densities of CXCR4 and CD5 indicates that the percentage of newly born cells is ∼ 10 times higher in the CD38+ than the CD38− fraction. Thus, the combined kinetic and CXCR4 expression analyses highlight relationships between CD38 expression, in vivo kinetics, cell migration to solid tissues, and clinical outcome.

Therefore, CD38 expression is at least a quantitative reflection of in vivo CLL cell activation. However, the activation status acquired in the PCs of lymphoid tissues may wane over time, leading to the conversion of CD38+ cells to CD38− quiescent cells. The circuit may be restarted when the cells are recruited into lymphoid tissues, where they may be reactivated. The initiating event for this activation is unclear, although the association of higher numbers of CD38+ cells with IGHV unmutated CLL clones that often exhibit biased use and selection for specific IGHV/D/J rearrangements (stereotyped BCRs) suggests that one factor promoting cellular stimulation is BCR signaling.

John 7:18. Content to be second

Whoever speaks on their own does so to gain personal glory, but he who seeks the glory of the one who sent him is a man of truth; there is nothing false about him.

I don't suppose that this is a verse on everyone's lips, yet it is so true. It speaks of the absolute servanthood of Jesus. Despite being co-equal with the Father, he is subject to him. How rare is such an attitude in our human doings. Always trying to strive for the top position. Remember Paul's picture of the body - how we all have our designated roles.

CD38 as a marker in CLL

Like somatic mutations of IGHV, CD38 expression identifies two subgroups of CLL patients with different clinical outcomes; this distinction is based on the percentage of CD38+ leukemic cells within a CLL clone. In the majority of studies, the threshold is considered as ≥ 30% CD38+ clonal members. The 2 patient subgroups that result from this cut-off point differ clinically in several ways, including overall survival, time to first treatment, bias toward male gender, number of leukemic cells with atypical morphology, extent and level of adenopathy, lactate dehydrogenase and β2-microglobulin levels, and absolute lymphocyte counts. These subgroups also differ in responsiveness to various therapies.

Combining CD38 with other prognostic markers, such as ZAP-70 and CD49d, provides complementary prognostic information. Because these molecules are components of the same functional network, their interrelated biologic roles probably explain these observations.

The past decade has highlighted several molecular differences between CD38+ and CD38− members of the same clone, including expression of specific activation markers, which reflect quantitative and temporal differences in response to stimulation. CD38+ CLL cells express high levels of CD69 and HLA-DR, both indicative of recent activation. CD38 also marks a cellular subset enriched in Ki-67+ and ZAP-70+ cells, more efficiently responding to surface IgM cross-linking. Both features are apparently independent of the percentage of CD38-expressing cells within the original clone. In addition, CD38+ CLL clones display enhanced ability to migrate in response to CXCL12, to transduce BCR-mediated signals, and to respond to anti-IgM and anti-IgD antibody-mediated crosslinking. The genetic signature characterizing CD38+ and CD38− members of the same clone revealed higher VEGF and Mcl-1 levels in CD38+ cells, pointing to a survival advantage from microenvironmental interactions.

Which is the best hospital in America?

Which are the best hospitals in America? Most people who make a judgement would pick on the famous ones like: MD Anderson, Duke, Mass General, Stanford, Mount Sinai, Cleveland Clinic, Vanderbilt, the Mayo, University of Michigan, Brigham and Womens, University of Washington, Johns Hopkins etc. There are 17 that make the US News and World Report. These hospitals publish the best research and are most in the news for their innovative work.

But there is another way of looking at things. The Joint Commision for accrediting hospitals in America has released a list of the 450 best performing hospitals in America and none of the 17 makes the cut. This is because the Joint Commission focuses on everyday diagnoses such as the routine care of surgical cases, and people with pneumonia or myocardial infarction. It uses only wellattested process measures such a giving aspirin to people with chest pain and prophylactic antibiotics to patients undergoing surgery. Hospitals had to score 95% or better on all the 22 tested process measures.

The 405 hospitals included many small community hospitals and very few major urban and famous institutions. Some hospitals use their complex case mix as an excuse though it is hard to see how this would make a difference to drawing blood cultures before giving iv antibiotics or giving chemotherapy on time according to the prescribed schedule.

I do not think this is a purely American problem. In my role of inspecting pathology departments in most of teh big teaching hospitals in teh UK, I noticed remarkable carelessness in attention to detail. In looking at the glamorous aspects of a research institution they often took their eye off the ball. My son at teh CQC and my daughter as a junior doctor would concur, and most of the medicao-legal cases that I have been involved with involve large teaching hospitals.

I think at Bournemouth we had the best of both worlds. We were undoubtedly the District General Hospital with the best record for research and innovation, but we were also consistantly one of the best in teh country interms of achieving the highest standards in patient care and financial management.

John 7:17 Doing God's will

Anyone who chooses to do the will of God will find out whether my teaching comes from God or whether I speak on my own.

Being a Christian is an experiential thing. Apologetics are all very well, but you can't argue someone into the Kingdom. People talk about a leap of faith and there is something in that. When I was a convinced as I could be that there was no other way, I decided that I would live Chist's way and Lo and behold, it worked.

Biology of CD38

Although originally defined as a T-cell activation molecule, CD38 expression is found on other cell lineages. Within the B-cell compartment, CD38 is expressed by B lineage blasts in bone marrow and by B lymphocytes in germinal centers, activated tonsils, and by plasma cells. Mature virgin and memory B cells express only low levels of the molecule. CD38 also has been found in pancreatic acinar cells, smooth muscle cells, osteoclasts, and in different areas of the brain, although in most of these instances, CD38 is found in the cytosol and/or in the nucleus and not on the cell membrane.

The protein encoded by CD38 is a single chain type II transmembrane molecule displaying a molecular weight of ∼ 45 kDa. The functional CD38 molecule is a dimer, with the central part between the two monomers hosting the catalytic site. The monomer to dimer transition controls the functions of the molecule. Additional control is made by how the CD38 is arranged in lipid microdomains of the plasma membrane where the molecule has a tendency to associate with other proteins, forming large supramolecular complexes. CD38-associated molecules in human B cells include the CD19/CD81 complex, the chemokine receptor CXCR4, and adhesion molecules such as CD49d. CD38 is also found in exosomes, membrane vesicles secreted by B cells, and is probably part of an intercellular communication network.

An initial function attributed to CD38 was the regulation of activation/ proliferation of human T lymphocytes. Stimulating monoclonal antibodies (mAbs) specific for CD38 induce rapid Ca2+ fluxes and trigger the phosphorylation of a cascade of intracellular substrates, leading to activation of the NF-κB complex. Protracted effects include initiation of genetic programs causing cytokine secretion and proliferation of T lymphocytes. CD31 (also known as PECAM-1) is a non-substrate CD38 ligand that can start the signaling cascade and recapitulate the biologic events observed in vitro using surrogate agonistic mAbs.

The functional properties of CD38 on human B cells appear to be strictly linked to the stage of maturation. Blocking mAbs in cultures of CD19+ B-cell precursors on stromal layers markedly suppresses B-cell lymphopoiesis by inducing apoptosis. Opposite effects are observed in mature circulating B lymphocytes and tonsillar germinal center B cells, where CD38 ligation is followed by activation, apoptosis inhibition, proliferation, and cytokine secretion. In both instances, the mechanisms are attributed to the activation of an intracellular signaling pathway ruled by CD38 and requiring an association with CD19. The ensuing phosphorylation cascade includes lyn and phosphatidylinositol 3-kinase, among other kinases.

CD38 has a striking similarity to the enzyme adenosine diphosphate (ADP) ribosyl cyclase. This enzyme has the unique characteristic of cyclizing NAD+ to generate cyclic ADP ribose (cADPR), a second messenger that releases Ca2+ from internal stores, independently of the IP3 pathway. cADPR is a ubiquitous second messenger in eukaryotic cells. A further enzymatic activity recently attributed to CD38 is the pH-dependent conversion of NADP+ to NAADP+. These products bind different receptors and channels involved in the regulation of Ca2+ and activating critical signaling pathways.

How these varied functional activities can be conducted by a single molecule is yet to be defined.

More persecution of Christians

From Barnabas Trust

A young Pakistani Christian man was shot dead in a violent Muslim takeover of land allocated to a Christian village by the government.

Saqib (Sabir) Masih (22) was killed on the spot, and 37 people, including a one-year-old and seven other children, were seriously injured as a mob of around 60 Muslims descended on the village in Mian Channu, Punjab, on Wednesday (5 October). The wounded were taken to hospital; six of them were described as being in a critical condition.

The Muslim aggressors came to the Christian village to claim a plot of land that had been allocated by the government to house a resident workman. It had been illegally sold to two Muslims by the worker who was being accommodated there; he then fled with the proceeds of US$1,500.

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Women from a mainly Christian ethnic group are being raped and murdered by the Burmese military as government forces intensify their offensive in Kachin State.

Human rights activists are reporting an increased incidence of rape against Kachin women since the government broke a 17-year ceasefire with the Kachin Independence Organisation, which controls the territory, by attacking ethnic forces in June.

The Kachin Women’s Association Thailand (KWAT), which has been documenting incidents, reported 18 cases of gang rape over an eight day period in June shortly after fighting broke out between the Burmese military and the Kachin Independence Army. Four of the victims were killed after being raped. KWAT said that in one village, soldiers caught three families who had not managed to flee in time; six women and girls were gang-raped, and seven small children killed.

IRIN, the news service of the UN Office for the Coordination of Humanitarian Affairs, said on 26 September that the number of reported rapes to date that month was 37 in areas where government troops are active.

David Scott Mathieson, a researcher for Human Rights Watch, said: The use of sexual violence is one of the most serious within a whole litany of abuses that include forced labour, torture and ill-treatment and extra-judicial execution.

More than 25,000 people are now believed to have been displaced by the fighting as the Burmese army repeatedly attacks Kachin villages. Most internally displaced persons are living in temporary bamboo shelters with plastic sheet roofing at makeshift camps on the Chinese border. They are surviving on a small amount of rice a day as Kachin aid groups are running out of means to help them. Crowded living conditions, poor sanitation and lack of clean water have led to illness and the death of a number of children. At one site, 2,000 people are sharing ten toilets. Over 90 per cent of the 1.2 million Kachins are Christian. Most Christians in Burma are members of non-Burman ethnic minorities; they are frequently targeted by the military, partly for their ethnicity and partly for their faith.

A Kachin leader said: They want to wipe out our ethnic group and force us to become Buddhists like them, speak like them and become one of them.

The military has been pushing into other border areas including Shan and Karen. Many analysts believe that they want to access and control areas that are rich in energy resources to supply neighbouring China with electricity.

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An Iraqi convert from Islam to Christianity was violently attacked in America over a poem he wrote about the Jewish Holocaust.
Alaa Alsaegh was targeted in St Louis, Missouri, because of his Arabic poem, “Tears at the Heart of the Holocaust”, which expresses pain over the loss of six million Jews at the hands of the Nazis.

The attackers carved the Star of David on Alsaegh’s back with a knife while laughing as they recited his poem. They had trapped the Iraqi immigrant using two cars as he was driving along in St Louis. One cut across and struck his car, forcing him to stop, while the other blocked his vehicle from behind. Two attackers then got out of the cars, opened Alsaegh’s door and pointed a gun at him. They pushed his upper body down against the steering wheel, stabbed him and pulled off his shirt before carving the Jewish symbol on his back.

Alsaegh, who survived the ordeal, said that the assailants may have been Somali Muslims; they told him not to publish any more poems. The FBI has opened an investigation into the incident, but no arrests have yet been made.

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More than 50 churches have been shut down or demolished by the authorities in Indonesia since the start of 2010, often following pressure from Islamist groups.

The Jakarta Christian Communication Forum (FKKJ), which includes leaders of all denominations, reported that 47 were closed in 2010, plus a further nine in the first four months of 2011.

The official reasons given for the closures were that the buildings were being used as places of worship without a licence or without the minimum required number of 60 worshippers. But the FKKJ questioned: Why is this only applied to the Christian churches and not other places of worship?

In most cases, measures were taken following protests from radical Muslim groups, especially in areas where there is a strong presence of the Islamic Defenders Front.

The treatment of GKI Yasmin Church in Bogor, West Java, is a recent example of blatant discrimination by the authorities. The congregation has been holding services on the street in front of its half-constructed church since its building permit was revoked in 2008. Bogor city chiefs, spearheaded by the mayor, have refused to comply with a Supreme Court order issued in December 2010 that the church be reopened. The mayor has said that churches should not be built on a street with an Islamic name; GKI Yasmin is situated on a road named after an Islamic leader from West Java.

As well as discrimination by the authorities, churches in Indonesia are often attacked by extremists. On 25 September, a suicide bomber detonated an explosive at the Bethel Injil Sepuluh church in Keputon, Solo, Central Java, as people were leaving the service; 28 were injured in the blast.

The FKKJ recommended a number of responses for Indonesian churches that face problems with the authorities. These included knowing the rules and responding with legal action, establishing fruitful dialogue with local Muslim leaders, meeting the civil authorities, and initiating positive activities in the community. It said that Christians in Indonesia “want to be a blessing to society and the nation.”

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CD38 - a review

In the September issue of Blood is a useful review of CD38 by Fabio Malavasi from Turin. I will be taking it to pieces in the next few days and weeks to make it available to a lay audience.

Currently we view CLL as a disease with a balance between cells in the blood and cells in the lymphoid organs. The former are primarily mature-looking small lymphocytes resistant to apoptosis (programmed cell death), whereas the latter are composed of lymphocytes that undergo either proliferation or apoptosis according to the environment.

The varying clinical outcome of CLL patients is dictated, at least in part, by the nature of these microenvironmental signals and interactions that can promote or impair accumulation of genetic alterations. Detailed immunophenotypic and genetic analyses of different neoplastic clones have led to the identification of a number of molecular markers, some of which are gaining relevance in clinical practice to predict disease outcome. Cell surface CD38 is one of these markers. It is generally accepted that CD38+ patients will have a shorter progression-free interval, require earlier and more frequent treatments, and ultimately die sooner.

The most obvious explanation for the ill-effect of CD38 expression is that it reflects events occurring inside the cell. Indeed, the percentage of CD38+ cells within a leukemic clone was originally described as one of two independent indicators (along with IGHV gene mutations) of clinical outcome in CLL. Because both indicators marked somewhat overlapping populations, a link with IGHV mutation status, signals mediated by B-cell receptor (BCR), and CD38 was proposed but these two parameters are not obligatorily linked: and an alternative (and not mutually exclusive) hypothesis is that the presence of cell surface CD38 provides a bridge to the environment, shifting the balance between survival/proliferation and apoptosis in favor of the former. Evidence sustaining this idea has been collected over the past decade and has contributed to the formulation of the current concept of CLL as a chronic disease in which the patient physiologically provides essential elements and conditions leading to the acquisition and accumulation of genetic alterations by the leukemic cells.

These changes begin at a preneoplastic stage (ie, monoclonal B-cell lymphocytosis), or possibly even before, and continue to occur in a clone that progresses to a full-fledged CLL. This scheme accommodates the existence of structures that provide replicating and surviving signals to B cells on their way to neoplastic transformation. A key element in this view is that leukemic B cells can and do proliferate, with division taking place not in the blood, but primarily in specialized morphologically discrete structures of lymph nodes (LN) and bone marrow (BM) known as proliferation centers (PCs).

Different sets of molecules may have different roles and confer at times the ability to localize in privileged sites, to receive signals from the external environment, to undergo apoptosis, or to modify surrounding cells. In this context, evidence so far uncovered on the role of CD38 expression provides new depth and relevance about the regulation of the social life of the neoplastic B cell. In future articles the authors will explore the available evidence providing a mechanistic link between CD38 expression and CLL progression.

Scandinavian noir

The trouble with technicolor films from Sweden is that they are all back and white. It started with Wallender, but I am currently working my way though a series of foreign thrillers with English subtitles. As someone reared on Morse, Frost and Taggert, I find these continental thrillers much more brutal and callous, but also more convincing. The evil is more evil and the good guys, flawed, but more believable.

The Girl with the Dragon Tattoo is the first of the Millennium trilogy and I recommend it to those who won't be offended by scenes of rape and murder. Sadly these things take place in our society; they are painful to watch, but lest we should be soft about the perpetrators, it is as well to remember why we have the death penalty and why prison means punishment.

The French series, Spiral, is equally gritty and takes the evil into high places. From what we have recently heard about France corruption reaches into the very heart of government.

There is a Danish series entitled the Killing, which I have yet to watch, but I have it on my list.

John 7:16. This is authority.

Jesus answered, "My teaching is not my own. It comes from him who sent me."

Not the careful unpicking of scribal works and historical documents. Not the wisdom of academics passed down through the ages by oral or written tradition. Not the brilliant insights of a genius. The teaching of Jesus comes directly from God.

How to reduce the cost of cancer drugs

What could make the cost of new cancer drugs cheaper? In the latest Lancer Oncology, NICE has some suggestions.

1. Recent proposals by an international group of academic clinical investigators suggest that clinical trial costs could be decreased by 40–60% without detriment to their quality. (EL Eisenstein, PW Lemons and BE Tardiff, et al. Reducing the costs of phase III cardiovascular trials. Am Heart J, 149 (2005), pp. 482–488. EL Eisenstein, R Collins and BS Cracknell, et al. Sensible approaches for reducing clinical trial costs. Clin Trials, 5 (2008), pp. 75–84.)

2 Simple measures to reduce costs include electronic data capture, reduction in the length of case-management forms, and modified site-management practices. The latter should include greater use of statistical techniques to detect fraud, rather than over-reliance on site visits by regulators and sponsors.

3 Greater use of Bayesian techniques in the design and analysis of randomised controlled trials holds real promise in reducing trial duration and numbers of patients needed.

4 Oncologists and patient advocacy organisations should start challenging the data requirements demanded by regulatory authorities.

5 Rather than criticise organisations such as NICE for declining reimbursement on grounds of cost-effectiveness, clinicians and patient advocates should start challenging pharmaceutical companies about the high prices they seek for products with modest benefits.

6 We should all be more concerned about the difficulties facing low and middle income countries in accessing affordable cancer care, rather than constantly focusing on the problems facing developed countries.

John 7:14-15. Jesus the author of our faith

Not until halfway through the festival did Jesus go up to the temple courts and begin to teach. The Jews there were amazed and asked, “How did this man get such learning without having been taught?”

They should not have been surprised. Even at the age of 12 Jesus had shown that his insight into the Scriptures exceeded theirs. How could he know more than them when he had never studied at their universities? Because he wrote the Scriptures and was the author of what they were about.

Two die from pancreatic cancer

By a strange coincidence two famous men died of pancreatic cancer last week. Steve Jobs, the co-founder of Apple succumbed and so did Ralph Steinman, who discovered the dendritic cell. Steinman was awarded the Nobel Prize for medicine, but when the telephone call came he had been dead for three days.

Ironically, Steinman was being treated for his pancreatic cancer with a dendritic cell approach.

So there you have it: pancreatic cancer is so terrible a disease that it cannot be defeated by all the money in the world or by the biggest brains on the planet.

John 7:1-12. Worldly advice

After this, Jesus went around in Galilee. He did not want to go about in Judea because the Jewish leaders there were looking for a way to kill him. But when the Jewish Festival of Tabernacles was near, Jesus’ brothers said to him, “Leave Galilee and go to Judea, so that your disciples there may see the works you do. No one who wants to become a public figure acts in secret. Since you are doing these things, show yourself to the world.” For even his own brothers did not believe in him.
Therefore Jesus told them, “My time is not yet here; for you any time will do. The world cannot hate you, but it hates me because I testify that its works are evil. You go to the festival. I am not going up to this festival, because my time has not yet fully come.” After he had said this, he stayed in Galilee. However, after his brothers had left for the festival, he went also, not publicly, but in secret. Now at the festival the Jewish leaders were watching for Jesus and asking, “Where is he?” Among the crowds there was widespread whispering about him. Some said, “He is a good man.” Others replied, “No, he deceives the people.”

Jesus practice seems to have been to live and preach in Galilee and to go up to Jerusalem for the feasts. However, he had to be circumspect about his visits to Jerusalem since he had already raise the antagonism of the Jewish leaders and he had not yer completed his preparation for the final Passover act. Therefore, when his brothers advise him to go to the capital, for what are worldly reasons, he easily resists them while intending to go up secretly afterwards.

Although his brother James later became leader of the church in Jerusalem, at this time his brothers were unbelievers.

We must all be circumspect about taking advice from the world even if it comes from people close to home.

Interlude

There is something delightful in watching a craftsman at work. Whether it is a bricklayer, a carpenter or a lady knitting, it is a delightful and satisfying experience.

In the old days of monochrome TV when the BBC had a monopoly, in the gaps betwen programs, instead of adverts and trailers we used to have 'interludes'. The most popular of these interludes was watching a pair of hands form a pot on a potter's wheel. I found out this week that the hands belonged to the grandfather of my brother-in-law. He used to work at Watt's gallery in Compton in Surrey.

Why I am quiet.

My time has mostly been spent drowsing. The combination of chemotherapy and pain-killers has kept me from blogging.

John 6:70-71. The ultimate betrayal

Then Jesus replied, “Have I not chosen you, the Twelve? Yet one of you is a devil!” (He meant Judas, the son of Simon Iscariot, who, though one of the Twelve, was later to betray him.)

From these verses we know that Jesus was omniscient; that the plan of salvation was there right from the beginning; that his betrayal was pre-planned and deliberate; that Judas was irredeemable; that the devil was sucked into the plan; that Jesus bravely faced a terrible outcome for him; that there could have been no other way; that God so loved the world that he gave his one and only son that everyone who believed on him should not perish but have everlasting life.

Aid to Palestine

The Palestinian leadership yesterday accused the US Congress of inflicting "collective punishment" upon its people by holding up almost $200m in aid earmarked for the West Bank and Gaza by the Obama administration. The freeze on funds earlier allocated for the financial year which ends today is the first concrete Congressional reprisal against Palestinian President Mahmoud Abbas to come to light since he angered US legislators by pursuing his application for full UN membership last week. The unpublicised block has been in force since August and was imposed in response to the then planned UN recognition bid and to earlier – so far fruitless – efforts to effect reconciliation between Mr Abbas's own Fatah faction and Hamas.

But no-one has a right to aid. The palestinians were warned that to elect a party like Hamas in Gaza would result in the US withdraing its goodwill. They thought the US was bluffing. It was not.

Laziness in the workplace

You would never think there was a recession going on. It has taken 4 days to get a technician out ro fix my cable connexion for my TV. Even when I threatened to go to their competitor, I couldn't budge them. They offered me £25 off my next bill for the lost connexion, but nothing would induce them to improve their service. I would pay an extra £25 to get the job done quickly. I wonder whether Richard Branson knows what is being done in his name.

You would think that the threat of competition would induce them to improve, but a great depression has set upon the country. No-one seems to have any initiative. Everyone is beset by the attitude that nothing can be done. I remember the same attitude beset the country in the 1970s before Mrs Thatcher came to power.

We see it in hospitals. Despite the perception that things are going downhill, no-one seems to recognize that it is in their hands to change things. Recently I heard that bone marrow trephines were being booked at a famous hospital at one hourly intervals. The dostor doing the operations can do them in 15 minutes, but the times are dictated by the nurse who doesn't start work until 9-30 am and can therefor only accommodate 3 trephines in her working day. What does the nurse do? Does she lay up the trolley? No. Does she do the trephine biopsy? No. Does she collect the specimens for the lab? No. Does she consent the patient? No. What doe she do? Apparently she holds the patient's hand during the procedure and whispers encouraging words.

Do you remember when elevators in department stores had elevator operators who called out what departments were on each floor? Before they realized that customers could actually read. They used to call it overmanning.

If the nurse could actually do something then they might do 10 trephines in a morning, but instead patinets and doctors spend hours wasting their time.

One of the reasons that people enjoy being self employed is the ability to set their own pace for work. It is immensely frustrating to be at the behest of laziness in colleagues.

silence for a while

The long time spent away from my computer is not entirely down to ill health. The fan disintegrated on my lap top and the hard drive overheated and broke. I am now pretty well restored to function, though I haven't worked out why my wide screen monitor isn't working. I did have a period of poor health after restarting the chemotherapy, but that lasted a day or two and was largely due to an inadvertent overdose of the anti-emetic levo-promazine. I should have only taken a quarter of a tablet rather than a whole one.

To add to my woes, my TV went down so I have not had much to detract me; apart from arguing with the cable company on the telephone.

Anyway I am back up to speed again and should now be able to start blogging again.

John 6:67-69. The Holy One of God

"You do not want leave too, do you?" Jesus asked the Twelve. Simon Peter answered him, "Lord, to whom shall we ho? You have the words of eternal life. We believe and know that you are the Holy One of God."

This is Holy Spirit-given faith. Is it ours too? Brother, have you found what you were looking for? Sister, have you stopped your search? Jesus is all in all. Eternally, he has the words of life. That is not going to change. He is God

The image of scientists

If you ask anyone, they will tell you that science has transformed their world with amazing discoveries. But then if you invite them to draw a scientist, what they depict is precisely what people would have described 50 years ago: they draw someone with a hangdog look, frizzy hair and test tube in hand, all in a scene where things are going wrong. There are national variations. In Italy, scientists tend to be scarred and have bolts in their necks, like Frankenstein's monster. In general, though, they are mostly white, male, bald and wearing a white coat.

Perhaps it comes from the image of the old Einstein with tongue out - the one everyone knows – the one taken on his 72nd birthday. But he was a dapper 26-year-old when he had his “annus mirabilis” and wrote the four papers that changed physics.

In fact scientists look like anyone else; many of them are women, most of them are young and some even look like Brian Cox who presents science of TV and looks like a rock star.

Global warming

From this week's New Scientist:

Last week the Times Atlas announced that "For the first time, the new edition… has had to erase 15 per cent of Greenland's once permanent ice cover. This is concrete evidence of how climate change is altering the face of the planet forever.”

Glaciologists cried foul, saying the ice is definitely receding, but the 15 per cent figure is wildly inaccurate.

If what The Times Atlas has said were true, something like a metre of sea level rise would have occurred in the past decade. In fact, Greenland has contributed roughly 3 millimetres to sea level in that time.

So what went wrong? The Times Atlas team say they mapped the ice sheet from ice thickness data on the National Snow and Ice Data Center (NSIDC) in Boulder, Colorado website. But NSIDC says its scientists were not consulted. The data are complex and thickness maps are not intended to show the edge of the ice sheet, so it is possible the cartographers misinterpreted the data.

It is interesting how various media sources handled this piece of information. The Daily Mail assured us that the whole publication would have to be pulped, whereas the BBC passed it off as a trivial error with only the statement having to be withdrawn. The truth is somewhere in between. Publisher Harper Collins apologised for not consulting scientists and retracted the 15 per cent figure, but stood by its map, for now. A spokesperson said it may be modified in annual reprints.

Objections to Christianity

Why does God hate gays and prostitutes?

Does he? When Jesus was walking on planet Earth he used to spend his time talking to prostitutes and other social outcasts. he had more time for them than for religious people.

Why are Christians such hypocrites?

Yes, why? Did you know that that Jesus got so upset with religious hypocrites that he started throwing the furniture about in their religious buildings?

John 6:66. The soul-searching verse.

From this time many of his disciples turned back and no longer followed him.

This is one of the saddest verses in the whole of the Bible. Having come this far, they desserted him. For them he was just a passing fashion like Moon Boots or mini-skirts. I wonder whether at the Great Excise it will be the same for you? There is much that is superficially attractive about Christianity: the miracles, the ordered life, the rules, the community spirit, the 'niceness' of other Christians, the excitement, the hymns, the wonderful music, the beautiful buildings, the stained glass, the liturgy, the lives of Christian heroes, the wonderful stories - but are you willing to bet your life on it? Do you hold it above all? Do you love God with all your heart, mind and strength? And do you show it by how you treat your neighbor?

John 6:64-65. Willful disobedience

Yet there are some of you who do not believe. For Jesus had known from the beginning which of then did not believe and who would betray him. He went on to say, "This is why I told you that no-one can come to me unless the Father has enabled him."

This alone should put a stop to the idea of universalism - that all will be saved. Sadly, it is exactly the other way round - all are doomed - unless they become special cases. Salvation is all of grace. No-one comes to God unless the Father draws him. Our nature is to be rebellious; God's nature is to be forgiving, but he will not impose his nature on ours. For some of us, we will not believe and we will betray him.

John 6:61-63 Life in the Spirit

Aware that his disciples were grumbling about this, Jesus said to them, “Does this offend you? Then what if you see the Son of Man ascend to where he was before! The Spirit gives life; the flesh counts for nothing. The words I have spoken to you—they are full of the Spirit and life.

How different are the spiritual life and the physical life! I suppose that for the majority of people in Britain, 'spiritual' has connotations of crystals and lay-lines. So much has the Devil taken over and corrupted Biblical language! The true spiritual life is about communication with God through God, the Holy Spirit. This is the only true life; the rest is just animal existence. For the Christian this (eternal) life has already begun and will continue after physical death.

When we are caught up with hustle and bustle of physical life - families, career, entertainment - it is hard to focus on the spiritual dimension. That is why we need our quiet times. For an eternity to come it will be nothing but a spiritual life. Hallelujah! No distractions. No wickedness. No tears. No disputes. All will be clear.

Chlorambucil - still not bad: a reappraisal

In the current issue of Clinical Lymphoma and Myeloma are articles by Daniel Catovsky and Kanti Rai about the relative merits of chlorambucil and fludarabine. I won't go into Kanti's article except to quote this "We do not by any means suggest that chlorambucil as a therapeutic agent should be abandoned."

Daniel's article goes much further. He suggests that clinical trials using chlorambucil have been unfairly biased against it. (Why would that be, I wonder? Could it be that there is no money to be made from chlorambucil?)

He presents evidence to show that the dose of chlorambucil needs to be at least 70 mg/sq meter/month and that the duration of treatment needs to exceed 6 months, preferably up to 12 months. I have already written about this until I am blue in the face, but here is additional evidence that I have not previously mentioned.

I had often puzzled over the fact that the French version of CHOP did so much better than other versions. The answer is now clear: they used double the dose of alkylating agent (cyclophosphamide) and half the dose of anthracycline (doxorubicin) as other people. The Jaksic trial of 1997 had impressive overall response rates of 89.5%. He pushed chlorambucil to toxicity at a dose of between 150-180 mg/sq m/month.

Catovsky comments that the chlorambucil arm of the bendamustine trial was a real outlier, with a response rate of only 31% and a PFS of only 7 months. This compares with the CLL4 trial which had a response rate of 72% and a PFS of nearly 2 years. What he doesn't realise is that the dose of chlorambucil in this trial was calculated according to 'ideal weight'. How many of us (especially we older ones) are at our ideal weight. And if you delve into the small print you find that 'ideal weight' is a function of height. So the dose of chlorambucil in that trial was calculated according to the patient's height! Who ever heard of such a thing? I cannot believe that anything other than obfuscation was intended. And to show Bendamustine in a more favorable light.

Chlorambucil is considerably less toxic than fludarabine, even when given in full doses. My spies tell me that Bendamustine is a lot more toxic than it is claimed to be. There is still life in the old dog, yet.

Away from my desk

I'm sorry not to have communicated recently. but I have been very ill. I had to reduce my dose of Capcitabine because of toxicity and initially this improved the side effects, but only for a day and then fatigue and abdominal pain returned with a vengence; so much so that I could not take the full 14 day course. Even after stopping the toxicity continued and I had to stop eating. On water alone by mouth plus Buscupan and Co-codomol the symptoms gradually settled and I woke at 4 am today feeling better. I am due to start the same regime next Monday.

Thanks for all the good wishes.

Dose reduction

No blogging for the past few days because I have been so unwell. Yesterday, I was aslep for 20/24 hours. It was only pain or diarreah that woke me up. I phoned my oncologist theis morming and he suggested a dose reduction. My chemo-brain was so bad that I could not work out the dose of capecitabine I was taking. 500 mg x 10 was beyond me.

I have reduced the dose by 20% and today I have felt much better. I have actually sat for an hour in the garden under a clear blue sky; the first time I have been outside for many days.

CLL and leukemic stem cells

I have been think about cancer stem cells as they might affect CLL. The concept if that there is a damaged hemopoietic stem cell that feeds in to the tumor that does not carry the same markers as the tumor and would therefore not be susceptible to the type of treatment that would be effective for the bulk of the tumor cells. There is strong evidence that leukemic stem cells exist for acute myeloid leukemia, but the B cell malignancies would seem not to be involved with such because clonal commitment is a late event occurring after rearrangement of the immunoglobulin genes..

However, there is some indirect evidence that a leukemic stem cell might exist. First, there are the familial cases; For these to exist there must be a defect in the germ line - and in at least one family case we know there is a mutation in DAPK. We also know that in families with a high incidence of CLL the CLLs are not clonally related, that there is a 3 times higher incidence of monoclonal B cell lymphocytosis than in normals and that other B cell malignancies also have a higher incidence. Moreover some people finds that MBL is frequently oligoclonal and some people have claimed to find a second B cell clone in up to 10% of patients with CLL. WE, ourselves found that about half of MGUS cases are oligoclonal.

Many years ago (1986) we reported 20 patients with B cell malignancies that had MDS without receiving any form of cytotoxic treatment - evidence that a precursor cell to both myeloid and B-cells was injured. One occasionally sees CLL and CML in the same patient.

Freda Stevenson wrote an important paper in 2010 in Blood which showed that the V1-69 stereotype that is common in CLL was also commonly used in the normal immune response.

So this is how a CLL stem cell would work: a] One would expect that there might be an excess of other hematological malignancies. b] one would expect that there would be an excess of other B cell tumors. c] One would expect that there would be some biclonal or even triclonal CLLs. d] One would expect there to be a precursor condition that was oligoclonal. e] One would expect the same maturation pattern as in the normal immune response.

There is one other fact to add: while MBLs with easily detectable lymphocytoses use the same repertoire of V genes as CLL while those with minimally detectable disease use a random repertoire, the very late relapse of some B cells malignancies.

Having been a sceptic on leukemic stem cells in CLL, my views are changing; all this is only possible if we postulate a very slow progression and a very long natural history.

Healthcheck - sleepiness

In me the chief side effect of this new chemotherapy seems to be tiredness. I spent much of the weekend asleep, so no blogging. I am still slogging through the book on Bayesian statistics, so perhaps that is part of the reason, but it is a particularly relaxed form of sleep so I can't complain.

Almost for the first time in my life, I feel no compulsion to do anything. It seems that all my life I felt guilty if I wasn't active, making things happen in a typically alpha-male sort of way. These days it doesn't seem to matter. I drop of to sleep, dream away and then wake up for a bit. Then I fall asleep again. I am quite happy about it.

John 6:59-60: no Jesus plus ...

He said this while teaching in the synagogue in Capernaum. On hearing it, many of his disciples said, “This is a hard teaching. Who can accept it?”

FF Bruce wrote a book entitled "The Hard Sayings of Jesus". It was not that what he said was hard to understand, but they were hard to accept and go along with. These are among the hardest. They are of course metaphorical, but even so they demand a level of committment that most people are inwilling to accept. Shortly we will see 'disciples' beginning to desert Jesus. It is easy to follow a miracle worker of a good speaker, but someone who demands that we change our lives is another matter.

You can't have Jesus and your old ways; he is much more demanding than that.

John 6:57-58. Keep the main thing the main thing

Just as the living Father sent me and I live because of the Father, so the one who feeds on me will live because of me. "This is the bread that came down from heaven. Your ancestors ate manna and died, but whoever feeds on this bread will live forever.”

We are totally dependent on the Lord Jesus. This is why the story of the cross is so central to our faith. There are churches where the cross is barely mentioned, indeed it is a bloody embarrassment. The 'other bread' they are fed includes social work, feeding the hungry, healing the sick, aiding the poor, helping the political underdog. All these are good things but they are not fundamental to the faith. I often ponder that in the new heaven and the new earth they will not need doctors. Or missionaries.

The main thing is the cross. Keep it the main thing.

How you make a writer

I have been asked how I came to be a writer. Can I call myself a writer? Counting this blog I have written about 2500 articles, books, scripts, chapters, abstracts and scientific reports including over 700 that other people have published; so yes I can call myself a writer.

I began by writing poetry. I had a good grounding at school in Latin and English grammar, but I never studied English literature until I was 17 and had free time in the sixth form. I had always been a good reader, though, and as a child had rapidly read through the schoolday adventures of Frank Richards, the military adventures of Captain W E Johns, the detective and horror stories of Peter Cheyney and Dennis Wheatley and the lawyer and doctor stories of Henry Cecil and Richard Gordon. I remember being asked by my headmaster at the age of 13 which authors I read. When I volunteered H E Bates (of the Larkin stories) he had never heard of them. He claimed to be one of 6 Englishmen who had read the whole of Cervantes in Spanish.

At seventeen I was heavily into the science fiction of Isaac Asimov, Ray Bradbury, James Blish, Theodore Sturgeon, Alfred Bester and Frederick Pohl. Later in my life I discovered Tolkien and his lineage: Robert Jordan and Stephen Donaldson. Meanwhile Graham Greene, John LeCarre and Raymond Chandler had captivated me.

When I started writing poetry, my biggest influences were John Donne, Wilfred Owen and Gerrard Manley Hopkins.

After I was married I virtually stopped writing poetry until after I retired. Medicine is a demanding mistress. Someone told me that if I wanted to become an expert on something I should write a book about it. So I did. I wrote the first book about Plasmapheresis. I also wrote a funny article for the Christmas BMJ called Mononucleosis and the Miniskirt about a girl with glandular fever, cold hemaglutinnins and a miniskirt who got a rash on the outside of her thighs on a cold night. This gave me an appetite for writing for a Freebie doctors' journal called World Medicine. I wrote about medical politics and about funny things that happened to me on the lecture circuit. To be honest it was an easy way to make money. I could dash off 500 words in about half an hour and make £100. When World Medicine closed (Jewish businesses refused to advertise in it after someone wrote a pro-Palestinian article) I started selling my wares to other journals, but my research fellow Ghulam Mufti (now Professor at Kings) persuaded me that no-one would ever take me seriously unless I stopped the frippery. Thereafter my writing apprenticeship served me well for writing serious articles.

However buried in one of my CLL articles in B J Haem. is a joke that I as editor would have put the blue pencil through. It would probably be excluded for bad taste in these PC days.

It goes like this. In Bournemouth there is no male excess of CLL patients. Why? Like elephants seeking their burial ground, the old ladies come to die, but whereas elephants have prodigious memories, the old ladies become senile and forget what they have come for.

Going to war

Both the first and second world wars were started by the UK because we went to the aid of a country with which we had treaty obligations. Germany invaded Belgium and then Poland. When Iraq invaded Kuwait the same principle applied. After that things got complicated.

With the break up of Yugoslavia after Tito died the Serbs committed atrocities against the Bosnians despite a UN peacekeeping force. Tony Blair persuaded Bill Clinton to help him defend the Bosnians, even though their action was very late and subsequently the Kosovans were also protected from the Serbs. Blair had been encouraged in all this by the success of the invasion of Sierra Leone to protect the government against Charles Taylor in a rebellion funded by blood diamonds.

I see today that Tony Blair is advocating regime change in Iran and Syria. On television yesterday there was a worry that Iraq is now an Iranian vassal state. Yer no-one has advocated invading Zimbabwe or Byelorussia where there are really nasty dictatorships.

Interference in the internal affairs of another country is forbidden by the Treaty of Westphalia. Taking sides in a civil war is dangerous if you are found to have supported the loser (as Tony Blair did in Libya).

What do you do when pitted against a private army. In Sierra Leone it worked out well, but it took 10 years for the might of the US to kill Osama bin Laden. The private army is unlikely to obey the Geneva conventions. Should you? War has become much more difficult.

Harry Potter

The London Institute for Contemporary Christianity is situated in a an old church just round the corner from the Royal Society for Medicine in Wimpole Street. It was established by the late John Stott and its current Executive Director is Mark Greene was converted out of the advertising industry. We have had him to preach at Lansdowne on being a Christian in the workplace. He was extremely good.

He has written a review of the latest Harry Potter film in the September issue of Evangelicals Now

Many evangelicals in America have criticized the Harry Potter series as dabbling in sorcery. I have always thought this was Baloney. You might as well criticize CS Lewis or Tolkien on the same grounds. The Harry Potter series is a fantasy based on the spiritual battle between good and evil and the 'magic' is just a matter of pointing a 'wand' and shouting a command in cod Latin. Let me tell you, it doesn't work.

The theme of Harry Potter is self sacrificing love and it picks up on many Biblical themes. At the start of the story we have Harry's mother, Lily, sacrificing herself to save her baby - literally covering him with her blood.. In the first book we have Ron putting himself at risk to save Harry and Flammel giving up his own immortality by allowing the destruction of the Philospher's stone. Throughout the series there are several instances of people sacrificing them selves to save Harry's life. In the last film we had Dobby the House-elf and Mad-eye. Snape has been working with Dumbledore at great danger to himself for the sake of the son of a man he despised for the unrequited love for Harry's mother and Dumpledore, Harry's surrogate father has known all along that in order to defeat Voldemort, Harry must subject himself to his power and die. Imagine a father who knew that in order to defeat evil his son must die.

Still it falls short of what Jesus did. The love that Jesus showed was love for his enemies. He didn't just die for his side. While we were yet sinners Christ died for us.

John 6:55-56. What is the value of the Lord's Supper?

For my flesh is real food and my blood is real drink. Whoever eats my flesh and drinks my blood remains in me, and I in them.

Does this refer to the Eucharist? In a sense, as it points forward to the feast of the Last Supper, but it does not mean that the regular consumption of the bread and wine is a pre-requisite for eternal life. Would you exclude all Salvationists and Quakers? Not to mention the Thief on the Cross. Don Carson gives several arcane references as to why this is not so and Ignatius back in the Second Century had already worked it out. So don't worry on this score if you have sometimes missed communion. The value of the Lord's Supper is to keep the cross always before us - so that we remain in him and he in us - but also as we share in the communion of saints. We eat and drink together as part of the Koinonia. We are all, however wealthy of important in this world's view, united in our abjectness before the Holy God. Penitent sinners before a pure and Holy God; we come for grace; undeserved mercy that is our only remedy.

Riots in Northern Ireland

Belfast Child raised the question of the riots in Northern Ireland and to be sure they were more severe and more severely dealt with. They were different, however, in that there was, at least for many, a political motivation.

Most independent observers took an instant 'gut-reaction' side on what was going on in Northern Ireland and tended to be blind to its own side's foibles. My instant reaction was to side with the Unionists, but I know that those on the left politically and most Americans sided with the Republicans. Mrs Thatcher also favored the Unionists and who can blame her? She lost Ian Gow and Airey Neave from her Cabinet and was herself blown up in Brighton by the IRA. (Airey Neave was the first British escaper from Colditz and ran the Escape operation from Germany for MI9 for the rest of the war.)

When the Irish Troubles began there was undoubtedly an abuse of human rights by the Protestant hierarchy in Northern Ireland. The troops were originally sent in by Harold Wilson to protect the Roman Catholics. In some institutions Catholics were denied jobs and the devolved government favored protestants unfairly. The police force (especially the B specials) was biased and unfit for purpose.

On the other hand what was going on in the Republic, and what the North wanted no part in, was far worse. We now know that priestly celibacy was a running joke, that pedophilia was rampant, the abuse of women was legendary and that a conspiracy between the Roman Catholic church and a corrupt government engineered a cover-up of gigantic proportions. So many Irish men had emigrated to New England that similar wickedness existed there. What we now know about the Kennedy clan disgusts right thinking people. People in Northern Ireland regard Eamon Devalera as the devil incarnate.

The troubles in Northern Ireland have a long history and I know people will point back to the potato blight, absentee landlords and even Cromwell. The point is that whatever the justification nothing can excuse the terrible things that were going on on both sides, nor the breakdown in Law and Order that resulted in the deaths of thousands. Since the Good Friday resolution people who were regarded by the other side as monsters have sat down together and formed a government, putting the past behind them. In some respects they have found a common enemy - secularism. Northern Ireland is the most religious part of the UK; both Protestant and Catholic are anti-abortion and in favor of Holy living. That they have different concepts of quite what that means is not surprising in a modern state, but it surely includes the rule of law. The fundemental differences between each side are not that great; what separates them are the acretions on to each side's religious basis. Segregation of schools is the greatest barrier remaining and for this I hold the Roman Catholic Church to blame.

The British Government has done as much as it could to favor peace and has continued to subsidize the cost of Northern Ireland even more than it subsidizes Scotland. So it should, England is still one of the rishest countries in the world. From John Major's onwards British governments cannot really be faulted in their benevolence.

The rule of Law

How do you stop people doing what is wrong?

One answer might be, you don't. What you call 'wrong' is only wrong in your opinion and it's their business not yours.

If you live in a society which is supposed to function as a whole, it all eventually depends on the use of force. We employ a police force to restrain and even, if necessary, kill those who are breaking the law. The law that they break has many origins but comes down, in a democracy, to the will of the majority demonstrated in a ballot. There are fine checks and balances in a mature society. There is also separation of powers so that the executive, the parliament and the judiciary are able to disagree. The fourth estate is empowered to investigate. The balance between these four powers must be preserved so that no-one predominates. Who judges that? The Demos; the people.

In the recent riots in London and elsewhere in England, 75% of those arrested were known criminals and I dare say the rest were mostly criminals who had hitherto escaped arrest. One 11 year old was on police bail for setting fire to a bus the previous week. They seemed to have thought that the Law had been suspended or switched off for a day. Result: anarchy.

Not for nothing does the magistrate bear a sword, says St Paul.

Liberal opinion seems to think that rioters and looters should be treated lightly. Police tactics are expected to be those with a 'light touch'. But the public (in opinion polls) favor a more robust approach. In many European countries they go beyond the riot shields and police batons used in the UK. Water canon, tear gas, plastic bullets and even live rounds may be used.

The problem with such escalation is that people must be allowed to demonstrate freely against perceived ills. Drawing the line between a peaceful demonstration and a riot may be difficult. Regimes like Syria have clearly got it wrong, but often the decision lands on one man's lap and a quick answer is needed. In the UK the police tend to act with caution. In the recent riots, rather than escalate the violence the police chose to photograph it and use the images to prosecute the perpetrators afterwards. If the justice now seems harsh - 4 months in prison for stealing a pullover - it should be remembered that it was not for the theft that the punishment was exacted, but for the riot and looting, which was a threat to the structure of society.

The Director of Public Prosecution has protested about the harshness of the sentencing. This man was a Tony Blair appointment who was named after the founder of the Labour party and has been a lifelong Marxist. Th American idea that functionaries such as he are reappointed by an incoming administration is a good one. The man should be dismissed.

Samuel Rutherford during the Glorious Revolution of 1688 summed it up in a Latin phrase: Lex rex; the Law rules. The Riot Act, which was repealed by the last Labour government, allowed the police to fire live rounds at a mob that refused to disperse after it had been read to them. Undoubtedly, it has been misused (though not for a century) but we need it back on the statute book, not least to demonstrate that law and order is ultimately guaranteed by the use of force. We may be 'slow to chide and swift to bless' but the eventual sanction is the use of force.

In international affairs the problem is even more complex. If we are attacked we have the right to defend ourselves, but how far does that extend to the defence of a third party; especially if that third party is a citizen of the country doing the attacking. And suppose the attacker is not a state but an armed gang beyond the control of that state? Tomorrow I shall try and explore that question.

Health report

I have completed day 1 of my chemotherapy - 13 more to come. I acually feel better than before I started; probably because my bowel was acting in slow motion (boom!boom!) and now is more free flowing.

This treatment consists of a 5 minute injection then 5 tablets twice a day for 2 weeks. The side effects are mainly associated with the gastrointestinal tract, which I won't mention further apart from saying that a computer friend has described it as the rapid downloading some software.

My bruises from the fall in the garden (I mean my garden, not the Garden of Eden) are gradually healing; they are at the less painful but more colorful stage. Still, I have to take regular painkillers.

John 6:54b: Raised by him.

I will raise them up at the last day.

But doesn't St Paul tell us that "all will be raised"? This phrase has been used earlier in verse 40 in the context of believing in him.

I think that the emphasis here is that we don't believe in the way that we believe in the sky being blue - if it were red I would believe that too - in a way that nothing really depends on it. It means believing with an intesity that trusts absolutely.

As for being raised by Jesus this means being raised as one of his own. Sure, all will be raise but some for glory and some for destruction.

John 6:53-54. Vampires and cannibals

Jesus said to them, “Very truly I tell you, unless you eat the flesh of the Son of Man and drink his blood, you have no life in you. Whoever eats my flesh and drinks my blood has eternal life, and I will raise them up at the last day.

This is about as gruesome as it gets. Vampires and cannibals. The Jews drained the blood from their meat so this saying is doubly offensive. Blood does not have the connotation of life, but of death. The implication is that we must participate fully in the death and resurrection of Jesus. We are not simply giving assent or going along with the whole thing. This is a message that rams home. Do we truly believe? Are we completely trusting in Jesus? Has all other hope been dismissed?

Why experts do better.

What has got the CLL world talking at the moment is a paper in Cancer from the Mayo Clinic which suggests that patients treated by the CLL team live almost 2 years longer than those treated by teams at the Mayo that are expert in other hematological conditions like myeloma, lymphoma or MDS. Why should this be?

This was not a randomized prospective trial so the obvious explanation would be that the groups were not well matched. However a multivariate analysis of known prognostic factors such as age, stage, sex, and total white count still leaves the expertise of the doctor as a significant factor.

The most striking difference between the two groups was that the experts kept the patients on watch and wait longer. Once treatment starts then hazards are introduced. The patient is more likely to develop infections, autoimmunity, extra chromosomal abnormalities, pancytopenia, Richter's transformation and MDS. The commonest mistake I see made by general oncologists is to treat just because of a high white count - not an indication in the international guidelines.

Non-experts are much less likely to request biological prognostic markers; so much so that it was not possible to separate the two groups of patients according to these parameters. Even the cheap Beta-2M test was not done sufficiently frequently, so it was more likely ignorance rather than expense that was the deterrent.

Non-experts were much less likely to enter patients into clinical trials even though it is well known that patients entered into trials fare better tan those treated according to physicians' choice.

Non-experts were more likely to choose chlorambucil or rituximab alone than a purine analog combination. Now I think there is a place for chlorambucil alone in the right patient, especially at the right dose, but this should be chosen from a position of expertise rather than ignorance.

So I find the paper believable. It is not necessary to be treated by an expert - their fellows do even better than they do, but make use of an experts expertise.

The FAB Group

I had a visit yesterday from Jerry Marti from Washington. Jerry is writing a history of CLL and he interviewed me for 3 hours in my office. By interviewing senior figures he is able to get a seecond-hand look at the truly greats like Davic Galton who are no longer with us.

David was one of the FAB group (French-American-British) who defined many of the malignant hematology diseases that we treat today. My link to David was via Ghulam Mufti, who was my research fellow for 6 years in the 1980s. Ghulam, who is now a Professor of Haematology at Kings Collge London, was a young fellow at the time and we had received a research grant from the the LRF for me to supervise him in research into MDS. One of the specifications of the grant was that we should both learn from David Galton and so we had regular trips to the Hammersmith hospital where David would serve us Darjeeling tea and teach us from his vast experience. Any case we mentioned would trigger a memory and he would pull down a blue notebook in which he had kept a record of a similar case.

Of the other members of the FAB group, I, of course, know John Bennett very well since we jointly edit Leukemia Research, but I also met Claude Sultan fron the Henri Mondor hospital in Paris. I was attending the World Apheresis Association meeting in Dijon, when I was president of the European Haemapheresis Society. Claude picked me up at Gare de Nord off the Eurostar, took me to lunch (oysters), showed me over his hospital and then put me on the train at Gare de Lyons.

Last chance Harvey

Last chance Harvey is about a middle aged divorced man who goes to his daughter's wedding and has his life changed around by a middle aged spinster. Dustin Hoffman and Emma Thompson play the principals and it has a feel-good factor, but you can't quite see where it comes from.

Early days

Mr Grosch was my Latin master. He played a game with his first year boys. They sat in rows and lines and he would ask them questions in turn if you answered a question that the others had got wrong you moved up closer to the front, supplanting those in error. This competitive game suited 11-year old boys and would be useful, even today, in instilling a sense of competition where it is needed.

Mr Morgan was my Maths teacher. He hated untidiness. I was and always have been untidy. He thought I was useless at Maths. His particular punishment for untidiness was to percuss the perpetrator's skull with his middle finger as a doctor percusses an abdomen or a chest. It hurt. He was very surprised when I came top of the class in Maths.

Mr Sweet was my French teacher. His particular punishment was to lift the boy from sitting to standing position by the short hair in front of the ear. That is even more painful even though it doesn't leave a mark. It did not improve my French, though this was the first time I heard someone use the 'F' word at school.

As methods of carrot and stick, the carrot was more successful than the stick. Although I was good at Maths, my handwriting never improved. I trace my proficiency at Maths (and indeed all maths-based sciences, to my rote learning my tables from the age of 4 onwards.

Mr Wetton was my primary school teacher. He was keen that we should do sport and keen on mental arithmetic. I was the only child in his care who had achieved 100% for three successive mental arithmetic tests. He gave me his silver pocket watch as a reward.

Is a pattern emerging here?

John 6:52. The word became flesh

Then the Jews began to argue sharply among themselves, “How can this man give us his flesh to eat?”

Don Carson writes, "Any dullard can see that Jesus was not speaking literally!"

Jesus is so explicit about this metaphor that these days we would call him a 'wind-up' merchant. Yet for those who have read the whole gospel, we remember that "The word became flesh." and the Greek word used there 'sarx' is the same word for flesh as is used in John 6 and not 'soma' as is used for the Eucharist "this is my body".

My first memories

The other day we had a visit from my youngest granddaughter. She is 18 months old and not quite used to us. She wants to be holding on to her mother's hand. I think it is a case of
'Always keep a hold of nurse
For fear of finding something worse.'

I was trying to imagine what it might be like for her by recalling my own memories of being that age.

My earliest memory is of visiting my rich Jewish great grandmother. I am told that she died when I was 18 months old and I know that as a family we visited Worcester at Christmas and in the summer, so I must have been either 9 or 15 months old at the time. I remember that I was still in napkins (diapers) and not walking. Although I understood many words I didn't know the difference between a wireless and a piano. I could speak but I was too shy to do so. I was sitting on my father's knee. I therefore suspect that this was Christmas 1943.

Even then, although I could not and cannot remember what they were, I already had memories. What I remember of the day was that everybody was talking about things I didn't understand, but at one stage of the afternoon I became the center of attention. I was asked if I wanted to play the piano which left me confused because perched on the piano was a Bakelite radio which I knew I had been forbidden to touch. I clearly didn't know the difference.

So I suspect that my granddaughter still finds life very confusing.