Wednesday, August 31, 2011

John 6:51: eating the bread of life.

I am the living bread that came down from heaven. Whoever eats this bread will live forever. This bread is my flesh, which I will give for the life of the world.

Here is the start of those cannibalism rumors. Jesus will surely give up his 'flesh' for the life of the world, but eating his flesh does not refer to the eucharist, but is hyperbole referring to accepting completely the gift that the Savior brings us.

Monday, August 29, 2011


Only primates have cones as well as rods in their retinas, so among mammals, only man and the great apes can see colors. 'Primate' also relates to Bishops in the Church of England, and only Bishops are allowed to wear purple shirts. My friend, Lee Rayfield, the Bishop of Swindon and an immunologist, tells me that there are two different shades of purple that are allowed, one bluish and one reddish.

Of course, things are not really colored at all; it is simply the way that light is reflected from their surfaces. Currently we have a vase of purple carnations in our sitting room. In daylight they appear bluish purple, but in artificial light they are definitely a reddish purple.

John 6::49-51a: Manna is not enough

Your forefathers ate manna in the desert and yet they died. But here is the bread that comes down from heaven which a man may eat and not die. I am the living bread that came down from heaven

Miraculous it might have been the manna of Sinai was just another temporary expedient. Just as the blood of bulls and goats could not take away sin, so manna could not give eternal life. Jesus is the bread of life and only his death on the cross would suffice.


How have I been spending my time while convalescing? I have been watching films, sleeping and reading.

I am still ploughing (plowing?) through the book on Bayesian statistics, but that has been a little heavy. I have also decided to attack 'A Game of Thrones' the first novel in George R. R. Martin's best-selling A Song of Ice and Fire series of fantasy novels. I believe it is being serialized on TV, but that is on one of the few TV channels I don't have. Still I have always preferred the book to the movie.

I did watch a spy thriller on BBC TV last night called 'Page 8'. For a thriller it was rather gentle but the cast was stellar. Perhaps it could have done with a real film director. David Hare's strong views about rendition failed to allow the equally valid view that fighting bad guys with one hand tied behind our back leads to the triumph of evil.

I finally got around to watching the movie "The time traveller's wife". I read the book some time ago and preferred it to the film. Brad Pitt owned the rights and his mate Eric Bana starred as the beefcake. It was less complicated than the book.

I have also watched The Apostle starring Robert Duvall and one to stand alongside Tender Mercies which I saw a long while ago.

Miss Pettigrew lives for a day is also a heartwarming RomCom starring Frances McDormand and Amy Adams and set in a London just before the second World War where night clubs and West End musicals are all that a young girl thinks about until she meets a couple of survivors from the first world war, who takes life a little more seriously.

Mrs Palfrey at The Claremont stars Joan Plowright as an elderly widow signed in as a long-term resident at a private hotel in London for the genteel poor. She expects her grandson to call but he never does. Instead after a fall she is adopted as a grandmother by a nice young busker on the London underground. As the friendship blossoms she finds she has more in common with him than with her own family.

Apart from the films, I have watched to football. Already after 3 games Manchester United are top of the league and Manchester City second. Both had big victories over London clubs at the weekend with United's drubbing or their closes competitors over the past 20 years, Arsenal, sensational. They won 8-2. I should h8-2 be an Arsenal supporter at present!


I have been pretty ill all week. The fall I had last week really knocked the stuffing out of me and left me with lots of bruises. I have spent the week mostly lying still and sleeping, but there are signs of improvement. The bruises are changing color and the swelling has been going down. Part of the problem is that I am fully anticoagulated and I have been bleeding from the LMW heparin injection sites.

I lost 7 pounds in weight, but I have regained 5 of them. The breathlessness is less but still a problem on climbing stairs.

I restart chemotherapy on Tuesday week.

Saturday, August 27, 2011

Losing a battle to win the war

Marilyn Monroe put it rather crudely, "When rape is inevitable, lie back and enjoy it." but I can see the point she was making.

Surprisingly, public policy decisions are not made on the merits of the cases being examined. There may be geographical points to make, but usually politics will win out.

At the moment Government is keen to close some of the pediatric cardiology units in the UK, in order to rationalize provision. It is universally agreed that size is important; if you don't do enough procedures your results won't be as good as those with more experience. The unit at Oxford has already gone on this basis.

It is also universally agreed that of the current units in the UK, the best unit is at Southampton and that the worst units are at Leicester and Leeds. Despite this under ant future configuration the Department of Health seems set on closing the Southampton unit. Unfair? Life's not fair.

They could delete the Bristol unit instead, but after the scandal at Bristol some years ago, much political power has gone into re-establishing and improving it and it would be a loss of face to lose it now. To ask patients from the north to travel to the south for their treatment would also be politically embarrassing.

Back in 1987 I was given the task of opening the new hospital in Bournemouth. There would be a lot of extra capacity as there was already a district general hospital at Poole, seven miles away. The plan (at least the plan of the managers) was that Bournemouth should become a hospital for geriatric patients while Poole should house the acute services like Accident and Emergency, Obstetrics, Pediatrics, Ear Nose and Throat, Orthopedics, Ophthalmology and Cancer Services.

That year was the hardest of my career. In a Committee loaded 5-2 against me I developed high blood pressure. I was twice offered a bribe to drop my opposition, once covertly and once blatantly. It would have raised my salary by 50%. I spoke to my old friend, John Trapnell, who told me to ignore the temptation; these things would come to me in time anyway. In the end I recognized that the political pressure would inevitably triumph. If the carrot didn't work, then the stick would be applied. It was certain that they would get their headline demands, but that did not mean they should have total victory.

I had to concede that there could only be one site for acute trauma involving broken bones and therefore acute orthopedics would have to be at Poole, but the great increase in work was in hip and knee replacements and the orthopods would actually prefer to keep that separate from the fractured hips and road traffic accidents for reasons of infection control. Given the age of our population we became the second largest joint replacement facility in Europe. When we examined it, we found that the majority of patients coming through the emergency department were medical patients. If Poole were going to concentrate on specialized departments the majority of medical beds would have to be in Bournemouth. That meant that Cardiology, Diabetology, Gastroenterology and Respiratory medicine would all be led from Bournemouth and similarly for surgery with large departments of colorectal, breast, and urological surgery. Because of the local personnel already employed, pancreatic and upper GI surgery were also secured. Because of the age range of our population it made no sense to have an artificial division at age 60 or even 80, though our previous geriatric hospital could now be converted to a rehabilitation service for the young chronic sick, the old and the post joint replacement patients. It could also house the palliative care services.

Talking of cancer service, there are some branches that make very use of radiotherapy and these didn't need to be centered at Poole. So we managed to get hematological cancer, urological cancers and gastroenterological cancers centered at Bournemouth. We had to concede that maternity and pediatrics went to Poole but we made a virtue of a midwife-led obstetrics service for uncomplicated deliveries should be at Bournemouth and we kept gynecological cancer. In the end by giving them their headline demands we ended up with a bigger, more complete and generally based hospital than Poole and one with a much better reputation.

So Southampton might have to give in over its pediatric cardiology, but by goodness they ought to play hard to get and take the Department of Health for every penny that's going.

I understand that my old department is under threat again from Poole. There is a proposal that in-patient hematology for the whole county should centralize at Poole. With David Oscier and myself retired this may well mean that the mice are going to pull political strings and again this might be an occasion when conceding headline demands may be the better option. Bournemouth could win though by getting control of all low-grade hematological diseases - CLL, SLVL, MDS and myeloproliferative syndromes and myeloma, to ensure that they are all done to a high academic standard rather than in the cheap as chips way they may be done elsewhere in the county.

Tuesday, August 23, 2011

Bournemouth in the news

We have had a week when Bournemouth has made the front page of all the UK national newspapers. First it was the floods. Running through the center of Bournemouth is Bourne stream, about 5 feet wide. On Thursday last we had 2 inches of rain in about 2 hours and the place was flooded. The stream overflowed its boundaries and became a lake. The promenade became a waterfall and Westover Road split, as gas pipes burst.

The next day everything was cleared after a remarkable work party and cleaned the streets. All was set for the Bournemouth Air show. Then the tragedy of the lost wing man of the Red Arrows. It seems that it was a bird strike that caused the loss of power. The pilot bravely flew his plane away from the village of Throop before crashing on the banks of the River Stour. He apparently ejected but at too low an altitude.

John 6:48: the everlasting bread of life.

I am the bread of life.

The is the Burning Bush, bread of life. The I am that I am, bread of life. The I, that has always been and am now and ever shall be, bread of life. This is the He that liveth, that liveth and was dead, behold he is alive for ever more, bread of life. This is the Creator God, bread of life. This is the self sacrificing son, bread of life. This is the Spirit that lives within me, bread of life. This is the bread of everlasting life.

Monday, August 22, 2011

How people with cancer die.

What do people with cancer actually die from? It think it is carelessness. I remember reading a book about leprosy. The main problem is that it causes a peripheral neuropathy which means that the leper has to carefully inspect his skin for cuts that might be come infected.

The complications of my cancer and its treatment that I am suffering from are decreased gut motility, a serious pulmonary embolus, proximal myopathy and a peripheral neuropathy. Yesterday afternoon I was trying to strengthen my legs by taking a walk in the garden. I spotted a large weed and stepped onto the flower bed to uproot it. On stepping back to the path, I overestimated my power to take a long stride and the amount of proprioception I had left in my feet. I tripped over the rockery and belly-flopped onto the shingle bath. My goodness, that hurt. I suppose my distended tummy acted like an air-bag, but I was left with superficial bruising on my abdominal wall and a large bruise/hematoma over my tibia (I am fully anticoagulated). After about 10 minutes screaming my wife picked mt up and put me in a chair.

This morning I am uncomfortable but conscious. I have not ruptured my spleen or sustained a cerebral bleed. No lasting damage seems to have been done. That's twice I could have died of carelessness. Perhaps men show too much bravado and this is the reason that women live longer? Perhaps this is why people who choose palliative care live longer than those who choose chemotherapy in some series?

Saturday, August 20, 2011

Health report

My father died of a very similar pulmonary embolus to mine 33 years ago. I had diagnosed the problem and got him admitted to the local hospital for appropriate treatment. Unfortunately, the local physician did not accept my instructions and my father died the next day. The physician was sorry afterwards but that horse had bolted.

My embolus was silent, but my own fault in that I didn't was to be on lifetime injections of clexane. I should never have stopped them. The embolus has left me breathless after walking 50 yards on the flat and won't resolve for some time. I am reducing the steroids again since I think that the proximal myopathy is only making things worse.

I had a consultation with the oncologists yesterday and while the clinical trial of cetuximab versus a TKI attacking the the EGRF receptor is on, it has to be entered within 6 weeks of failing chemotherapy, so I have to have another regimen before I am eligible. I therefore need to start capecitabine and mitomycin C. Here is the abstract recommending it.

Protracted venous infusion 5-fluorouracil (5FU) combined with mitomycin C (MMC) has demonstrated significant activity against metastatic colorectal cancer. Owing to potential synergy based upon upregulation of thymidine phosphorylase by MMC, the combination of capecitabine and MMC may improve outcomes in irinotecan-refractory disease. Eligible patients with progressive disease during or within 6 months of second-line chemotherapy were treated with capecitabine (1250 mg m-2 twice daily) days 1–14 every 3 weeks and MMC (7 mg m-2 IV bolus) once every 6 weeks. A total of 36 patients were recruited, with a median age of 64 years (range 40–77), and 23 patients (78%) were performance status 0–1. The objective response rate was 15.2%. In all, 48.5% of patients had stable disease. Median failure-free survival was 5.4 months (95% CI 4.6–6.2). Median overall survival was 9.3 months (95% CI: 6.9–11.7). Grade 3 toxicities were palmar-plantar erythema 16.7%, vomiting 8.3%, diarrhoea 2.8%, anaemia 8.3%, and neutropenia 2.8%. No patients developed haemolytic uraemic syndrome. Symptomatic improvement occurred for pain, bowel symptoms, and dyspnoea. Capecitabine in combination with MMC is an effective regimen for metastatic colorectal cancer resistant to 5FU and irinotecan with an acceptable toxicity profile and a convenient administration schedule.

I found the report on the pulmonary embolus shocking and depressing as if the Angel of death had passed over my lintel and seen the mark of safety there; yet I was extremely grateful to be spared. I am humbled by the fact that with all my knowledge and precautions, I made a wrong decision about prophylactic anticoagulants. I can really believe that someone is watching out for me. I am writing this at 5 am; being alert at that time for the first time in several days. Perhaps that is a sign of things (or my my mood improving).

Friday, August 19, 2011

John 6:47. The Spirit's vitality

I tell you the truth, he who believes has everlasting life.

Believes what? In the context it is he who believes Jesus's claims. This is later confirmed to the disciples when Thomas fails to believe unless he sees. Blessed are those who have not seen and yet have believed. This applies to us. This is Holy Spirit given faith.

Everlasting life begins with faith and continues forever - not as a reward but as a reality. Living with the Spirit is sharing in His accomplishments and vitality.

Thursday, August 18, 2011

John 6:46: Jesus is the way.

No one has seen the Father except the one who is from God; only he has seen the Father.

Jesus is unique. If you want to know God you must come through Jesus. There is no other way. Anyone who claims to know God another way is a liar or deceives himself. Our access to Jesus is through the Bible. That is why reading it is so important. That is why its veracity is so fundamental.

Wednesday, August 17, 2011

John 6:45: the difference the Spirit makes.

It is written in the prophets, "They will all be taught by God." Everyone who listens to the Father and learns from him comes to me.

This is a quote from Isaiah 54:13 but it is a typical promise of the later prophets and indeed of Jesus' time on earth. Thus Jeremiah looks forward to a new covenant written on men's hearts (31:31-4); a new heart and spirit is promised in Ezekiel (36:24-6); and Joel promises God's spirit poured out on all peoples (2:28ff). John announces the fulfilment of these prophesies in the language of being born again and in the farewell address of John 14 he emphasises the teaching role of the Holy Spirit and in his first epistle the anointing role.

The coming of the Holy Spirit is about to make devastating changes in the life of a Christian; it will never be the same again.

The best of times, the best of times

I must be more like my father than I realized. Not too much physically like him; he was taller than I with bigger facial features, but we were both underdogs with an ambition to better ourselves. 33 years ago he died of a saddle embolus in his pulmonary artery and a month ago I suffered a similar one. The difference was that I lived in the seconds half of the Twentieth Century whereas he lived partly in the first part.

The difference was that by the second half of the Twentieth Century, British scientists had discovered that cigarette smoking cause lung cancer, heart and lung disease. As a result he was a heavy smoker and I was a non-smoker. His blood was thicker than mine, with a hemoglobin of 22g/dl whereas mine was 16 g/dl; so he had a bigger clot to discharge from his leg. He also had narrower arteries than mine - another effect of cigarette smoking. SO what completely blocked his pulmonary arteries was only able to occlude 25% of mine.

I had a 'lucky' escape. Had I been a smoker, I could have died.

It got me thinking that my life has been greatly blessed by living in the UK for the past 68 years. When I was born there was a major war going on followed by a period of extreme austerity. Yet we became a prosperous nation that retained liberal democracy as a form of government. I had free health care and a free education, including university education, courtesy of the generous taxpayer. I have lived in a country that stood alone against tyrants, that according to the Japanese has been responsible for over half of useful inventions in the world, that has invented most of the sports and games we play, that has had during my lifetime world champions at running, jumping, swimming. cycling, football, rugby, cricket, boxing - even curling - sleighing and racket sports. It is a country that has won more Nobel prizes per head of population than any other.

It is a country that has been more generous to the poor around the world, that has been concerned with the wellbeing of other nations, that has contributed greatly to cultural standards in art, music and architecture; that has given the world the greatest poet and dramatist, the foreign language most used by non-natives, the best engineering on the planet and leadership whenever it has been necessary at no little cost. It has provided a basis of law and order throughout the world.

It is a country founded on the Christian religion and during my lifetime there has been a major revival under Billy Graham.

Life expectancy has increased by 15 years since I have been alive and many terrible scourges like smallpox and polio have been abolished.

It has been a great place and a great time to have been alive and I am extremely grateful to God.

Tuesday, August 16, 2011

John 6:43-44. Stop grumbling

"Stop grumbling among yourselves,” Jesus answered. “No one can come to me unless the Father who sent me draws them, and I will raise them up at the last day."

This is not something to be grumbling about; the facts cannot be changed by argument. John continues along his strong Calvinist line. Here is total depravity. You can't come to Christ unless the Father draws you because every part of your being is turned against him. Yet in 5:40 John has Jesus blaming them for refusing to come to Jesus and have life - human responsibility.

Divine sovereignty and human responsibility are firm friends, not enemies.

Grumbling is a horrible sin. It is a symptom of not accepting; of wanting to be right in ourselves. We should accept it when we are in the wrong and make it up with those who are in the right.

More on Bayesian statistics.

One of the problems about randomized controled trials is that they are about populations not individuals. One of the tyros about RCTs has said, "The individual case is entirely devoid of interest."

For the usual statistics that we talk about there is no doubt that this tyro is correct. Survival curves compare two median survivals. I remember when I first started treating colon cancer, I was impressed that the standard treatment, 5-FU, did not affect median survival, but there were 30% who survived longer than those who got no treatment beyond supportive care. Now I find that I am in that 30%.

In my own specialty of IGHV gene mutations, the observation was not at first about an RCT but about a retrospective look-back at factors that affected survival; had it not been for the fact that two groups made the same observation in December 1999, it is doubtful that it would have made much impact. The observation has since been confirmed in several RCTs, most notably in a trial of stem cell autografts, which showed that even in patients having an autograft the most important prognostic factor is the mutational status of the IGHV genes.

When it comes to the individual, he really does not want to know about the risk of the average population; he wants to know things like what are my chances of getting lung cancer; what are the chances of my road being flooded; what is the risk of a nuclear accident in my town; how many trucks should I buy for my business; how many workers should I take on; and so on with thousands of business or investment decisions.

RA Fisher invented statistical theory. When asked the risk of there being an accidental dropping of an armed nuclear bomb, his answer was zero, because it had never happened before. Other wiser heads prevailed. They discovered that by the time President Kennedy came to power there had been 60 occasions where an unarmed bomb had been dropped or involved in an aircraft crash. With all those prior risks there was bound, one day, to be a more severe explosion. This lead to many new precations to do with arming nuclear devices.

In 1950 Doll and Hill were investigating the cause of lung cancer. No-one could contemplate doing RCTs for chronic diseases; the observation period might be 50 years. Instead they did a look-back at risk factors. Lung cancer had appeared suddenly in the pre-war years. Explanations included finding cases that had been misdiagnosed prveiosly, the availability of chest X-rays, the rapid appearance of motor-cars and their exhausts, the London smog, industrial pollution, tarmacadamed roads and smoking. Looking at various factors it had to be something that was commoner in men and caused disease that got commoner with age. This probably ruled out a genetic factor, but not completely.

Among a large number of lung cancer sufferers, the stand-out statistic was that only two of them were non-smokers at a time when 80% of men smoked. It was so shocking that Doll and Hill and their wives immediately gave up smoking.

RA Fisher was a heavy smoker and received some of his grants from the Tobacco industry. To him, this search for prior indications of the cause smacked of the Bayesian heresy. He would have none of it. Correlation does not prove causation he hollered. It could just as well mean that lung cancer induces people to smoke or perhaps both have a completely different and unrelated cause. Both cigarette smoking and lung cancer are commoner in people who are married, for example. Perhaps we should ban marriage, he thundered.

But when the indirect evidence piled up Fisher was defeated. He would need an hypothesis that explained why more smoking produced greater rates of lung cancer, while stopping smoking reduced the rate, and that explained why pipe and cigar smoking was less dangerous than cigarette smoking and why cigarette tar placed on the skin of a mouse causes cancer.

I still haven't understood Bayes' theorem, but it seems to be something to do with individual risk - which is why it is beloved by actuaries - and also to do with indirect risk factors when you can't get precise ones.

Monday, August 15, 2011

The Ministry of Dr John

Dr John started coming to Lansdowne at the same time as I and was baptized on the same occasion. He had been a GP in one of the most reliable practices in town and I was surprised to see him there. It turned out that he had been widowed some time before and was courting a widow in the church who was about ten years his junior.

We attended Pastor's Class together and became Deacons and Elders together, but he has had a ministry that I could never aspire to; that of visitation. I have been most grateful for it during my long illness. For me, in particular, it has been useful. Because we share a medical background there are many anecdotes and reminiscences that we can share, which keeps me entertained and distracted. He also understands my worries and cares, and difficulties in sometimes coming to terms with what I am suffering. He has had his share of the infirmities of old age and understands the frustrations.

But more than that he has a thorough understanding of Scripture and will bring a passage to our meetings that I am unaware of (such as from Zepheniah) which will uplift my heart. He has concentrated on the promises of God and passages that bring comfort and reassurance to the anxious. What a ministry!

John 6:41-42: Jesus is God; Jesus in Lord.

At this the Jews there began to grumble about him because he said, “I am the bread that came down from heaven.” They said, “Is this not Jesus, the son of Joseph, whose father and mother we know? How can he now say, ‘I came down from heaven’?”

The Jews referred to here are presumably members or leaders of the local synagogue. They knew that Joseph and Mary had come from Nazareth, but they did not know the Prologue of this Gospel nor the story of the Virginal Conception.

WE think we know Jesus, but our knowledge of him is often superficial. We had some JWs visit the other day, but when I challenged them over the nature of Jesus they retreated into platitudes and would not focus on the real issue that Jesus is God.

We also skip over that Jesus is Lord and find ourselves saying, "No, Lord," when it should be, "Yes, Lord."

ACD: suppression of hepcidin activity

Direct suppression/blockade of hepcidin activity

Anti-hepcidin antibodies.

Experiments in vitro and in vivo in a murine model of ACD suggest that suppression or inhibition of hepcidin expression may be a possible means of improving ACD: overexpression of human hepcidin in mice produces a picture of anemia similar to that seen in ACD, with resistance to exogenous EPO therapy, and mice rendered anemic by heat-killed Brucella abortus were effectively treated by hepcidin mRNA suppression. Treatment of mice overexpressing human hepcidin with anti-hepcidin antibodies did not by itself lead to resolution of treated animals, but did restore sensitivity to treatment with EPO.

Indirect suppression of hepcidin

Dorsomorphin is a small molecule inhibitor of BMP signalling that was identified during screening of compounds that dorsalize zebrafish embryos. In vitro experiments showed inhibition by dorsomorphin of BMP, IL-6 and haemojuvelin-stimulated expression of hepcidin, and in vivo inhibition of iron-stimulated expression of hepcidin mRNA in zebrafish, and induction of hyperferremia in iron-replete mice, suggesting a possible role in reducing elevated hepcidin levels in ACD.

Similarly, in a murine model of inflammatory bowel disease, inhibition of BMP by HJV.Fc, a recombinant protein that prevents binding of BMPs to their receptor, LDN-193189, a small molecule inhibitor of BMP signal transduction, and an anti-BMP-6 antibody, inhibited hepcidin expression and increased serum iron levels.

Finally, heparin is known to bind BMPs, and can variably modulate their signalling effects: exogenous heparin has recently been shown to downregulate hepcidin expression by the hepatoma cell line, HepG2 in a dose-dependent manner, and at pharmacological concentrations. Treatment of mice with heparin inhibited liver hepcidin mRNA expression and SMAD phosphorylation, reduced spleen iron concentration, and increased serum iron. Administration of heparin to five patients with deep venous thrombosis also produced reductions in hepcidin levels. The authors postulated that the effects of heparin in their study were mediated by sequestration of BMP proteins, with formation of complexes that are unable to stimulate SMAD signalling and hepcidin expression, and further studies of its potential in improving haemoglobin levels in patients with ACD seem warranted for this widely used agent.

Anti-IL-6 receptor antibodies.

Castleman disease is a rare lymphoproliferative disorder characterized by hyperplastic lymph nodes showing follicular hyperplasia and capillary proliferation associated with endothelial hyperplasia. Dysregulated production of IL-6 has been shown to be responsible for some of the systemic manifestations of the multicentric form of the disease. Five out of six patients receiving longterm treatment with an anti-IL-6 receptor antibody, tocilizumab, showed rapid reductions in serum hepcidin levels, and a more gradual, but progressive, improvement in hematological parameters, including anemia, was observed in nine patients. Anti-IL-6 receptor blockade may represent a future targeted therapy for ACD.

Vitamin D.

A recent study has shown an association between vitamin D deficiency and ACD in the elderly: the Third National Health and Nutrition Examination Study (NHANES III) examined health and nutritional status of non-institutionalized subjects over 60 years of age in the United States, and hemoglobin and vitamin D levels were obtained in 5100 and 4575 subjects respectively. A significant correlation between hemoglobin and vitamin D levels was found. Further analysis of a subset of 2610 patients, who had more detailed hematological data available, showed that this association was particularly strong for patients with ACD. Individuals with ACD were twice as likely to have vitamin D deficiency as non-anemic subjects. It remains to be seen if there is an etological link between vitamin D deficiency and ACD, and whether vitamin D replenishment will have any therapeutic role to play.


Pentoxifylline is a drug with anti-inflammatory properties, and can suppress production of TNF-alpha and IFN-gamma. Two studies have suggested a beneficial effect for this agent in chronic renal failure patients with anemia resistant to EPO: parallel reductions in pro-inflammatory cytokine levels suggested that the mechanism for this effect was via the anti-inflammatory effects of this agent, and future studies in ACD may be worthwhile.

Sunday, August 14, 2011

John 6:38:40. A foretaste of the banquet

For I have come down from heaven not to do my will but to do the will of him who sent me. And this is the will of him who sent me, that I shall lose none of all those he has given me, but raise them up at the last day. For my Father’s will is that everyone who looks to the Son and believes in him shall have eternal life, and I will raise them up at the last day.”

Here is the basis for irresistible grace and the final preservation of the saints. The Father's will and the Son's accomplishments. Nothing to do with the works of the elect.

These verses emphasize the divine sovereignty in salvation; it is God's will that is not forestalled by any failure in the accomplishment of Jesus. But John does not shy away from human responsibility; it is our duty to look to Jesus and believe in him.

Who are those who have been give to Jesus? In the first instance it is the disciples - though not even all of these; one was from the beginning the son of perdition. But there are other 'sheep who are not of this fold' (chapter 10). But there will be others everyone who looks to the Son and believes in him shall have eternal life.

This eternal life is more than just everlasting existence - it is a real resurrection life having been 'dead in trespasses and sins' we are no 'alive in him'; a transformed nature of being part of God's family; we do not have the fulfilment but we have the foretaste.

Malaria affecting British birds?

Also in today's Times are claims that the decline that has been seen in British Song Birds in recent years might be due to infection with avian malaria.

British birds, claims the article in the Times, including sparrows, chaffinches and nightingales are dying from malaria. At least 30 common types of bird are now infected. In some species the disease was unknown as recently as the mid-1990s but is now being regularly diagnosed by monitoring projects. Only 20 years ago less than 10% of house sparrows in Britain were infected. That figure has now reached 30% and is rising rapidly. The screening of birds such as blue tits, great tits and owls has shown even greater proportionate increases since the mid-1990s, when almost none were infected.

The bird form of malaria cannot be transmitted to humans but, just like human malaria, it kills by destroying oxygen-carrying red blood cells and is transmitted by mosquito bites. The study that identified this new epidemic was carried out by Laszlo Garamszegi, a world expert on avian malaria who is attached to the Spanish government’s Doñana biological station near Seville.

In the largest analysis carried out so far, Garamszegi compared malaria infection data from more than 3,000 species around the world, dating back to 1944. The findings follow disturbing studies from the Royal Society for the Protection of Birds that reveal a fall of up to 68% in the British house sparrow population since the mid-1990s. A survey of nightingales by the British Trust for Ornithology found a 90% decline in the past 40 years.

The role of iron in ACD

Iron therapy

The recognition of the role of functional iron deficiency in the pathogenesis of ACD, together with the development of new formulations of parenteral iron, have led to a re-evaluation of iron supplementation in the management of this anemia. As already discussed, IDA frequently co-exists with ACD, and it is clearly important that true deficiency of iron is corrected. However, even in patients with ‘pure’ ACD, iron supplementation may theoretically be beneficial. Iron deficiency may also develop during the treatment of ACD with EPOs and limit the hematological response to these agents.

Oral iron supplements are often poorly tolerated, and patients frequently show poor compliance: in addition, patients with ACD will usually have raised hepcidin levels, which would be expected to inhibit intestinal iron absorption. However, oral iron is cheap, widely available, and easy to give, and given the difficulties in ruling out concomitant IDA in many patients with ACD, a trial of oral iron will be undertaken by many clinicians treating ACD. It must however be recognized that failure to respond to oral iron rules out neither true, nor functional iron deficiency.

There is little literature on the use of intravenous iron supplementation alone in the treatment of ACD. Cazzola et al on the beneficial effects of intravenous iron in 20 consecutive patients with juvenile chronic arthritis, although it is likely that a significant proportion of these patients also had true iron deficiency. Studies in patients with gynaecological cancer also showed a benefit in terms of reduced transfusion requirements for those receiving intravenous iron supplementation. However baseline iron status was not reported in either of these papers, and clearly larger studies are needed.

Much of the literature concerning intravenous iron supplementation has come from the field of renal medicine, where the superiority of parenteral over oral iron supplementation is now well established, and not only improves the responses to EPOs but can also lead to reduced doses of EPOs being used. The DRIVE (Dialysis Patients’ Response to IV iron and with Elevated Ferritin) trial randomized selected hemodialysis patients with elevated ferritin and reduced transferrin saturation to receive or not receive intravenous ferric gluconate together with EPO. The patients who received IV iron showed more rapid and better responses in Hb level than the controls, and similar responses were seen in patients with transferrin saturations above and below 19%, leading the authors to conclude that functional iron deficiency was a significant contributor to anemia in this setting, and that this could be overcome by intravenous iron supplementation.

There is now evidence that intravenous iron can enhance the effects of EPOs in patients with other forms of ACD, particularly cancer-related anemia. Auerbach et al randomized 155 patients being treated with EPOs for chemotherapy-related anaemia to no iron, oral iron or intravenous iron: there were significant improvements in hematological responses in patients receiving intravenous iron compared with those receiving either no iron or oral iron. These observations have been confirmed in several subsequent studies. Criteria for exclusion of co-existent IDA varied between these trials, and it is possible that significant numbers of patients included were in fact iron deficient, but the study by Hedenus et al is of particular interest as it enrolled only patients with lymphoproliferative malignancies not receiving chemotherapy, and all patients had detectable bone marrow iron stores.

In contrast, a recent study by Steensma et al randomized patients with chemotherapy-associated anemia to no iron, oral iron or intravenous iron plus darbepoietin: all had serum ferritin >20 μg/l and transferrin saturations <60%. There was no difference in erythropoietic response between the three groups. The mean pre-treatment ferritin levels in this study were higher than in the other studies, suggesting this population was less likely to have co-existent IDA, and the doses and scheduling of iron infusions were lower. Both these observations may partly explain the different results observed, but it is clear that further prospective studies, with better characterization of baseline iron stores are needed to define the role of intravenous iron supplementation in this setting. The ASH/ASCO guidelines recommend periodic monitoring of iron status in patients receiving treatment with EPOs but fall short of recommending intravenous supplementation to augment responses.

It is not yet known how intravenous iron might overcome the reticuloendothelial blockade on iron utilization thought to be fundamental to the pathogenesis of ACD, but it is possible that the infused iron may become bound directly to transferrin rather than being taken up by macrophages, and is thus available to the erythron. There are however no in vitro data to support this hypothesis.

Safety issues also need to be considered when using intravenous iron, particularly as older preparations were associated with significant adverse events, including anaphylaxis. Recent pharmacological developments have led to the release of several new iron formulations including low molecular weight iron dextran (Cosmofer), iron sucrose (Venofer), ferric carboxymaltose (Ferinject) and sodium ferric gluconate (Ferrlecit). In the trials above, no excess of adverse effects was observed with these newer intravenous iron preparations. One hypothesis for the hypoferremia seen in ACD is that low iron levels might inhibit bacterial growth, as iron is essential for the growth and survival of intracellular bacteria, but there is no evidence to date that supplemental iron increases the risk of infections. However, the long-term effects of intravenous iron administration on other parameters, for example tumor growth and cardiovascular disease, have not been studied.

Background to the riots

I re-publish this article from today's Times, which seems to me to reflect a mature attitude to whet happened last week in London. Well done Tim Rayment!

Soon after Leni White settled herself into a seat on her London Underground train, she knew something was wrong. First her fiancé rang to say there was trouble on the streets. Then she realised that two girls sitting opposite were heading for where she lived, intent on mayhem.

The girls, one black and one white, were no older than 15. They were dressed as if for a night out, anxious not to be late for the rendezvous sent to their diamanté-covered BlackBerrys.

“We’ve got to be in Ealing by nine,” they were saying, “because that’s when it’s kicking off.”

White, a classical music singer and composer, wondered if she could deter them. As the train rattled west from Bond Street she rehearsed lines in her head.

“I wanted to say: do you understand the gravity of what you’re about to do?” she recalled. “You won’t realise the consequences until it’s too late. You’re going to ruin your lives.”

In the event, it was her life that suffered. Looters later set fire to the shop below her flat. As White, 31, prepared to flee, she bundled her heavy Apple computer into the kitchen in desperation, thinking that if she could get her life’s work into the oven it might survive the flames. It did not.

Her flat was destroyed and she lost everything, including an unreleased album.

White was just one of many victims as riots, looting and arson spread across London. Pictures of the capital, host of next year’s Olympics, were broadcast around the world showing fires and mayhem on the streets. As disorder spread to other cities, the toll rose to five dead, scores of displaced families, more than 1,600 people under arrest, £200m in stolen and damaged property and a country in shock.

Many of those responsible were gang criminals who could not care less. Others were baffled by their own conduct. One young woman turned herself in after three sleepless nights, unable to explain the theft of a television that she did not need. “I don’t get it,” Natasha Reid sobbed, fearing that her hard-won university degree was now worthless. “Why did I do it?”

Why indeed? Some blamed deprivation, others the consumer society. Many pointed the finger at feckless, failed parents. Perhaps all those factors played their part: what is clear is that last week’s events shattered any illusion that the sort of disorder more often associated with other countries could not happen here.

Few have tried to dignify the lawlessness with a cause. But in one place, and one place only, it started with a grievance. The trigger was a police shooting in north London.

Mark Duggan, 29, was the target of a pre-planned arrest by Operation Trident, Scotland Yard’s gun crime unit.

Described by police sources as “an important player” in the criminal underworld of the Broadwater Farm estate in Tottenham, he was also a father of four whose dual reputation is shown by his entries on Facebook.

As a family man he posted pictures of his children and a poem for his stillborn daughter: another photograph shows him in a T-shirt bearing the words Star Gang, one of the criminal groups whose turf wars in north London have caused at least three deaths. During the bid to arrest him, police, who suspected that Duggan was armed, shot him dead in the back of a minicab. In a misunderstanding, no family liaison officer was sent to tell his parents that they had lost their son.

The intelligence was correct: Duggan did have a firearm, an Olympic BBM 380 starting pistol converted for live rounds. Popular with gangs, these guns were banned two years ago because they can be adapted in under an hour to fire short 9mm ammunition. Before the ban they were available to anyone aged 17 with identification and £85. At one time they were being used in four in 10 shootings in the capital. At first it was claimed that Duggan opened fire on the police. Then it emerged that his weapon had not been discharged. Seventy people gathered for a peaceful protest at Tottenham police station on Saturday, August 6.

The demonstrators included families with children who wanted answers to the confusion over Duggan’s death. The police station was the obvious place to seek them.

Although local officers have worked hard to improve community relations since the hacking to death of PC Keith Blakelock at Broadwater Farm in 1985, the police were in a difficult position. First, the shooting was a Scotland Yard operation and had nothing to do with them. And second, like all fatal police shootings, it was being investigated by the Independent Police Complaints Commission. A constable kept promising the small crowd that someone would address them. Nobody did.

As the afternoon wore on, passers-by joined the group. Many of the newcomers were not close to Duggan and had their own reasons for resentment. The crowd swelled to 300 when fans streaming from the Tottenham Hotspur football ground joined in.

“A local black constable kept telling us the commissioner was going to come down and give us a statement,” said a female resident who is close to the Duggan family and who asked not to be named.

“First he told us it would be just an hour, then 10 minutes, then two hours. He was treating us like idiots, hoping we would just go home, and people were getting more and more frustrated. You could hear the crowd getting angrier and angrier but the police were just standing there saying nothing. At about 8.30pm one guy threw a bottle at the police and that set everyone off. We decided to get out of there because we just knew it was going to get nasty.”

The mob broke windows and set fire to cars and a double-decker bus. At 2am, more than five hours after the first thrown bottle, the mob turned on a 1930s landmark, the Carpetright showroom. Windows were smashed and the store was set alight, with tyres thrown through the broken glass to intensify the blaze. Residents in 26 flats above the showroom pleaded to be spared the fire, pointing out they had children. They were ignored.

Omar Malik, 47, who lived with his wife and young son in one of the flats, called the police twice and the fire brigade three times. Nobody came. In a measured voice, he said: “We felt completely abandoned in our hour of need.”

Their son Oskar, 5, was traumatised. As therapy, his father later asked him to draw a picture of the fire. The child drew his burning home with firefighters pointing their hoses in the wrong direction, while police stood by doing nothing.

The response to the riots was run from the Metropolitan police Gold Command centre in Lambeth, south London. The commander in charge of the response that night was Simon Pountain, the force’s highly respected deputy head of intelligence.

As it became clear that a crisis was unfolding, Gold Command began to fill with dozens of uniformed officers. They sat at banks of computers studying email and radio reports from officers on the ground.

Shortly after midnight on Saturday, Tim Godwin, the Met’s acting commissioner, arrived to be briefed. He stayed into the early hours of Sunday, watching the increasingly alarming situation unfold on huge television screens in Gold Command’s suite of open-plan offices. Yet Godwin and his team failed to grasp the nature and scale of the disorder. Their limited response seems to have encouraged others to chance their luck.

On Sunday a text message sped from phone to phone, inviting “all the brehs in north” to rally at Enfield station, north London, at 4pm. “Whatever ends your from put your ballys on link up and cause havoc, just rob everything”, read the street-slang message.

Soon after 6pm there were reports that shop windows on Enfield’s high street were being broken. Other gangs had targeted Brixton, south London, where three police officers were injured after intervening in an altercation. By 12.45am on Monday, a Foot Locker store on Brixton Road had been set alight. Fanned by social network sites, riots were rippling through the capital Next up was Hackney, in east London, where, according to one former gang member, local youths were bent on revenge against the police. The borough is home to the Pembury Boys, one of London’s most notorious gangs, who had been raided the week before.

On August 3, a “Wire-style” operation by the Met had hit 32 addresses around the Pembury estate, arresting 23 alleged gang members, including the leaders, and confiscating drugs and firearms. The dawn raids had been 18 months in the planning and were presented as a decisive blow against the gang culture dominating Hackney’s estates.

Darrell James, a reformed gang member who works with youths in the area, said the rioting in Tottenham and Enfield had given the Hackney gangs their chance to strike back. As many as four gangs co-operated.

“These guys have each others’ numbers: they talk all the time,” said James, who has served three years in prison for gun dealing. “They clash when some of the younger guys fail to show respect but for those in charge it’s about making money. Their phones were going crazy all morning.”

The Pembury Boys came in from the north and the London Fields crew hit the side streets to the south. “This was a chance to smash up a few coppers and make money,” said James. “They didn’t care about Duggan.”

Mare Street runs through Hackney. By 8pm on Monday the whole road was on fire, cars and rubbish bins ablaze, glass and rubble crunching underfoot, shops with their fronts torn down and the contents looted. Hundreds of people were cheering, yelling obscenities at police and throwing bricks, stones and bottles.

A girl drinking cheap white wine from a looted bottle staggered past and cried at an onlooker: “Welcome to Hackney! This is the best time ever.”

There were children, girls, blacks, some whites, young men, middle-aged men. John Cantlie, a photographer for The Sunday Times who was present, said: “You were immediately struck by the complete lack of coherence or sense of point. It was like a street party but with Molotov cocktails.” Some rioters concealed their faces: others did not bother.

Richard Kenworthy, a film director who lives in the area, noted the body language of the rioters. It was all swagger and male display, he said. One young rioter threw a Molotov that did not ignite — and was visibly embarrassed in front of his friends.

“They do it to show off to their mates,” Kenworthy said.

In his view, the police did an “amazing job” but elsewhere there was no sign of help and precious little protection.

Saturday, August 13, 2011

Behind the riots

I reprint today an article by Peter Oborne from today's Telegraph as a background to the riots in London.

The rioters who have rampaged through the streets of Britain over the past seven days were the children of Tony Blair. Many of them were born under Tony Blair. They went to school under Tony Blair. They learnt their system of savage values and greed under Tony Blair. They are the product of the policies of Tony Blair.

So what happened? What explains the savage irony that New Labour, a movement that was supposed to do so much good, created instead so much evil and despair? This is the urgent question that David Cameron, Nick Clegg and Ed Miliband must each try to answer as they get to grips with the horror of last week.

At the heart of this problem lies New Labour’s approach to the welfare state. Gordon Brown developed a social security system that entrenched dependency and trapped the unemployed in poverty. Certainly he gave them more money – the benefits to which a single mother is entitled rose by 85 per cent under New Labour. But he made one crucial mistake as he set out to create a Labour client state. He did not give people hope or self-respect. Indeed, as Iain Duncan Smith, the Secretary of State for Work and Pensions, is starting to discover, Brown made it economically irrational for many people to seek work, thus turning unemployment into a way of life. I would guess that many of the young men and women drawn into last week’s frenzy come from families where there have been no jobs for generations.

Shamefully, New Labour knew that form of dependency was a by-product of its policies. It did not care. I once sat on a panel with Lord Giddens, a social theorist and one of the architects of the “Third Way”. I drew attention to the phenomenon of intra-generational unemployment and he replied that, statistically, it was fairly insignificant. Well, we are experiencing the consequences today.

How I should have liked to have been at this encounter. "Statistically, it is fairly insignificant" is a meaningless statement. I can only imagine that Lord Giddens was in his cups when he made it. Did he mean to say that intergenerational unemployment was not statistically significant? Whatever does that mean? How can statistics be 'fairly insignificant'? Or does he mean that it was socially or politically insignificant? I should like to have asked him for his evidence. But of course this was all bluster. We know that one unemployed generations children are the unemployed of the next generation. The statistics are very clear about that.

The second New Labour failure concerns education. Blair promised the earth, and his government poured billions of pounds into the creation of gleaming new school buildings. But New Labour did not challenge the culture of failure in British schools. It did not improve discipline in the classroom.

Instead it created the illusion of change. Year after year exam results would show a marked improvement, and ministers would claim that this reflected an underlying improvement in what they called “standards”. Of course nothing of the sort was taking place, as employers and universities knew all too well.

Fundamentally New Labour lacked the will to take on the teaching unions, partly because the education profession provides such a high proportion of their party activists. This meant that they never took the brutal and necessary step of sacking useless or idle teachers. Only at the very end, with academy schools – a reinvention of John Major’s city technology colleges which New Labour had abolished when it first came into office – did New Labour take a step in the right direction. But this move came too late to save the generation of rioters and looters.

What we have been seeing is the feminization of primary schools. There are hardly any male primary school teachers. Young boys are routinely excluded from lessons in the afternoon because female teachers are unable to provide for their needs - competition, aggressive games, exercise, noise, male role models. Add to that the fact of absent fathers, and it is easy to see why they join gangs, but the pot-smoking petty criminal is the worst of all role models.

Most disturbing of all was New Labour’s teaching on the family. Behind much of the outrage of the past few days lies the absent father, and the collapse of traditional marriage. Young children, boys in particular, need male role models. If they cannot find such figures at home, they will look elsewhere. Horrifically, this means joining the gangs that caused such mayhem and destruction.

New Labour simply refused to acknowledge this basic truth of human nature. It is true that Tony Blair loved to parade himself as a family man to send out a reassuring image to the voters of middle England, but behind the scenes party policy was captured by feminists such as Patricia Hewitt (who became health secretary) and Harriet Harman (eventually elected deputy leader) who viewed the traditional two-parent family as an instrument of male, patriarchal oppression. Any attempt to bolster marriage or the traditional family was repulsed on the grounds that it would stigmatise single mothers.

So New Labour in office ended the married couples allowance. This happened in one of Gordon Brown’s early budgets, cynically entitled “a budget for the family”. By the end, marriage itself ceased to be a category recognised in Whitehall, meaning that when data were analysed for policy purposes it was impossible for civil servants to make any judgment about whether marriage had better outcomes for children

What New Labour was doing was encouraging a remarkable social experiment. Traditional marriage has been at the heart of British society since time immemorial, providing stability, security, a bulwark against an overmighty state, and the ideal framework for rearing children. The riots of last week show the devastating consequence of that leap into the dark.

Fourthly, New Labour promoted a divisive and unequal society. Within months of entering office, Peter Mandelson, then trade secretary, made his infamous pronouncement that Labour felt “intensely relaxed” about people becoming “filthy rich”. Meanwhile, Gordon Brown pioneered a series of tax breaks that have enabled a tiny group of men and women to make personal fortunes of a kind not seen since the plutocrats of Edwardian Britain. A significant proportion of these hugely rich men feel the identical sense of impunity and entitlement as the unemployed youths who plundered shopping centres last week. Every bit as surely as so-called feral youth – and with far less excuse – they have played a malign role in generating the moral disequilibrium of modern Britain.

New Labour could not see this. It believed – and this is perhaps understandable in a party that lost four elections in a row from 1979 – that the only thing that mattered was election victory. So Labour strategists only concentrated on those sections of society who voted. Unemployed black youths in Tottenham, or the white working class in Manchester and Liverpool, were simply taken for granted. Crucially, they tended to congregate in constituencies with large Labour majorities, not the vital marginals where elections are won and lost.

So for 13 years they were the invisible and the forgotten – until last week’s eruption. Successive British governments, through wilful neglect, have created a monster, and now we have to live with the consequences or, better still, to find a solution.

Paradoxically, I believe that the Conservatives are best placed to do this. To their enormous credit they used their long years in opposition to ponder the problem of an emergent urban underclass. Iain Duncan Smith, during the wilderness years that followed his humiliating assassination as Tory leader, led this work – with the full backing of David Cameron. In a series of reports from the think tank Centre for Social Justice, Duncan Smith identified the factors that lead to social despair – drugs, alcohol, debt, unemployment, family breakdown. He argued that the answer to social collapse does not just depend on the injection of large sums of money, which was Labour’s answer to any predicament. Far more important is the restoration of people’s independence, pride and self-respect. This is hard, for there are now many parts of Britain where the tradition of work has vanished, and entire communities that have become dependent on the state.

Changing the welfare system so that there is a genuine economic incentive for the unemployed to go out to work is one part of the answer. Restoring hope and aspiration is another. Rebuilding the family, and the values of independence and steadfastness it brings, is perhaps most important of all.

Iain Duncan Smith’s programme of change and renewal means redefining what it is to be a human being and a British citizen. It means widespread moral regeneration – and not just for the poor. All of us have to acknowledge that we are part of society, with the obligations and duties that involves. It also means recognising the power of virtues that have been unfashionable for much too long: decency, courage, discipline, duty and self-sacrifice. Only if we rebuild those age-old values can we come close to confronting the disaster in Britain’s inner cities.

John 6:37; the basis of Calvinism.

All that the Father gives to me will come to me, and whoever comes to me I will never drive away.

Here is the basis of one of the strongest Calvinist statements of faith. Irrisistable grace - Those that the Father gives to Jesus, the Elect, will surely come to him, and those who come will be preserved - the final preservation of the elect of God.

Health again

Yesterday I had an attack of subacute obstruction - probably cause by a bowl of tomato soup and two slices of bread. I increased my steroids and used a hot water bottle and by the morning it had settled. Today I have been on clear liquids. It does seem as though I shall have to have some more treatment soon.

Record breakers

We broke all sorts of records yesterday with 1508 page views of the blog - that was the first time over 1000.

England did with the cricket too. 710-7 finally beating India by an innings and 200+; the second worst defeat that India have suffered.

This ensures that England are now the No 1 Test playing nation: the first time for a very long time.

It was sad to see Sachin Tendulkar getting out. We all hoped that he might score his 100th Test century, but he was out for 40 in a freak dismissal. His partner drove the ball back towards the bowler who dived to try and stop it but merely succeeded in deflecting it on to the stumps. Tendulkar was unable to reclaim his ground and was run out.

Anemia of chronic disorders: the use of EPO

Erythropoiesis-stimulating agents

The reason for the use of erythropoiesis-stimulating agents like EPO in the anemia of chronic disorders (ACD) is the blunted response to EPO, with lower serum levels of EPO detected than would be expected for the observed degree of anemia, together with the reduced sensitivity of red cell progenitors to endogenous EPO seen in ACD. In addition, there are some data to suggest that the use of EPO may reverse the cytokine-mediated inhibition of red cell production.

Recombinant human EPO and its derivatives are widely used in patients with chronic renal failure, patients with cancer undergoing chemotherapy and patients infected with HIV on myelosuppressive anti-retroviral medication. Several different EPOs are currently available or in development: epoetin-alpha (Procrit, Epogen, Eprex), epoetin-β (NeoRecormon) epoetin-δ, biosimilar epoetins (Retacrit, Binocrit, Eporatio), darbepoietin-alpha (Aranesp), and continuous erythropoietin receptor activator (Mircera). In addition, a PEGylated synthetic dimeric peptide capable of binding to and stimulating the EPO receptor, Hematide, is undergoing clinical trials.

Much of the literature relating to the use of EPOs in ACD comes from renal medicine, but there is also evidence that these agents have useful activity in other forms of ACD, for example that seen in rheumatoid arthritis, HIV infection and cancer. Only relatively small studies of EPO usage have been performed in patients with ACD secondary to inflammatory conditions, for example a study by Pincus et al in which four of 13 patients treated with EPO at doses ranging from 50–150 iu/kg thrice weekly showed hematological responses, whereas none of four patients in the placebo arm responded. In another study, 34 patients with inflammatory bowel disease (IBD) refractory to iron therapy were randomly assigned to receive oral iron plus EPO or oral iron and placebo: after 12 weeks, Hb levels had increased by more than 10 g/l in 82% of the patients in the EPO group, as compared with 24% of those in the placebo group. However, the improvement in treatment of inflammatory conditions, such as rheumatoid arthritis or IBD, with anti-inflammatory and disease modifying agents, such as TNF-alpha inhibitors, with associated improvements in Hb levels, means that there is only a limited place for EPOs in their treatment.

There are many more studies of the use of EPO in patients with both solid tumour and hematological malignancies with response rates of 40–80% being seen. Many of these studies describe patients receiving anti-cancer treatment, so the anemia observed may be partly due to the myelosuppressive effects of chemotherapy or radiotherapy, rather than to the inflammatory effects of malignancy alone. However, early studies indicate that, although relative EPO deficiency contributes to the anemia of cancer in patients who are untreated, this effect is increased by the effects of chemotherapy.

Smith et al performed a dose- and schedule determining study in 188 patients with cancer not currently receiving chemotherapy, showing responses in the majority of patients. A recent large systematic review of 46 randomized controlled trials of ESA therapy in patients with cancer concluded that patients receiving EPO had a mean 16.3 g/l higher Hb level than controls, were 18% less likely to require blood transfusions, and had improved health-related quality of life, but survival benefits could not be established.

Responses may be reduced in ACD patients with more marked inflammation or where there is associated iron deficiency, especially in patients with IBD, highlighting both the importance of aiming treatment at the underlying condition and of ensuring replenishment of iron stores in patients who are iron deficient. As discussed previously, it may not always be easy to determine whether patients have ACD alone or ACD with iron deficiency, and evidence is accumulating that iron supplementation may be desirable in many patients treated with EPOs to ensure optimal response.

Predicting which patients with ACD will respond to exogenous EPO would be useful, but although various algorithms incorporating baseline endogenous EPO level, early response indicators and other factors, none of these will reliably predict response, at least in the setting of cancer-related anemia.

Warnings about the Dangers of EPOs

There has recently been mounting concern at possible detrimental effects of EPO administration in ACD, both in terms of cardiovascular risk and thrombosis, and relating to possible risks of tumour recurrence in patients with ACD related to malignancy. The CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) study showed that trying to achieve a target Hb level of 135 g/l (compared with 113 g/l) increased the risk of cardiovascular events and did not improve quality of life and the TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy), demonstrated that patients with diabetes and chronic kidney disease were at greater risk of stroke following ESA administration and no clear benefit was observed. A randomized study of EPO in patients with non-small cell lung cancer (NSCLC) who were not receiving chemotherapy was terminated prematurely when a higher mortality rate was observed in the group receiving EPO.

These, and other, studies, together with suggestions that some tumour cells might express EPO receptors, raising the possibility that EPO might modulate tumour growth via cytoprotective effects, led the FDA in the United States to recommend that (i) prescribers should use the lowest dose of EPOs that would gradually increase Hb concentration to a level that would avoid the need for transfusion and (ii) treatment with EPOs might increase the risk of serious cardiovascular events and death when administered to produce Hb levels >120 g/l. In addition, the FDA recommends that (iii) EPOs should not be used in specific tumour types (breast, head and neck, NSCLC), nor be administered to patients with active malignancy not receiving chemo- or radiotherapy. Similar conclusions are reached in the updated guidelines published recently by ASH and ASCO.

However, a recent large meta-analysis of over 15,000 patients in 60 studies of EPOs in patients with cancer has shown no evidence that EPOs reduce survival or increase tumor progression in patients with cancer, although some increase in venous thrombembolism was observed. In addition, two recent studies have cast doubt on the idea that EPO receptors may be expressed at significant and clinically relevant levels on non-hematopoietic cells, including tumor cell lines, and it is clear that further, well-designed, clinical trials are necessary to define the role of EPOs in the anemia of malignancy. In the meantime, blood transfusion remains an option for treatment of anemia in patients with contraindicated cancers or those at high risk of venous thromboembolism.

Friday, August 12, 2011

Behind the riots

More information has come out about the young man whose shooting triggered the riots in London. Mark Duggan was the nephew of a renowned gangland criminal with a history of violence. Duggan's late uncle has been revealed as Desmond “Dessie” Noonan, whose feared crime family ran Manchester's underworld for 20 years. In 2005, Noonan featured on Donal MacIntyre's TV documentary Gangster and claimed his family were “untouchables”. He boasted “I've got a bigger army than the police. We have more guns than the police.”

Noonan's second wife Julie, 50, is the sister of Duggan's mum Pamela. Duggan is understood to have regularly visited his uncle and Julie to babysit their children.
When the couple divorced following Noonan's 1993 acquittal for the murder of gangster Anthony Johnson, Duggan continued to visit him for family parties.

A source told the Sun newspaper: “They took Mark under their wing, they liked him, not just as a nephew, but as a mate. When he came to Manchester he'd see them, and if they went to London they'd have a night with him.”

In 1995 Noonan was described as a "psycho" in court for a violent attack on twin brothers. He was jailed for 33 months.

In MacIntyre’s Gangster documentary he joked that key witnesses at his court hearings failed to turn up because “some are deranged... because they are in the back of a boot tied up and they don't know what day it is”.

Later that year the 45-year-old was stabbed to death by drug dealer Derek “Yardie” McDuffus.

The link emerged yesterday as police sources said the officer who opened fire on Duggan had “an honest-held belief that he was in imminent danger of him and his colleagues being shot”. A gun belonging to Duggan was found at the scene in Tottenham, North London, but is not thought to have been fired during the incident.

The backlash against the riots and looting has been substantial. Attempts to blame the rioting on austerity measures have been dismissed. One suggestion has been that young people have been involved since the government has withdrawn a subsidy offered by the last government to pay youngsters to stay at college between the ages of 16 and 18. But that subsidy has not yet been withdrawn and anyway it is the school holidays at the moment. 1100 people have been charged with offences of violence and theft in London alone. There is much remorse. One student has a 6 month prison sentence for stealing a bottle of water. Children as young as 11 have been in court. David Cameron has spoken of Draconian measures to keep the streets safe and the Test Match has taken place without incident. I think things are largely back to normal - thanks to the rain, more than anything.

More gene therapy

The CLL "cure" is not the only gene therapy paper published this week. In today's Lancet is another 'miracle'. It is a study that I gave authority to proceed when I was on the Gene Therapy Advisory Committee.

Duchenne muscular dystrophy is a progressive, severely disabling neuromuscular disease that affects one in 3500 newborn boys and causes premature death in late teens of twenties. In Duchenne muscular dystrophy, the open reading frame of the X-linked dystrophin gene (DMD) is disrupted by deletions (roughly 65%), duplications (10%), point mutations (10%), or other smaller rearrangements.

That means that this is a very severe genetic disease of young boys that is universally fatal at an early age. We know the genetic lesions that cause it, though only two thirds have the commonest mechanism, the other mechanisms have the same effect in producing (or failing to produce) an abnormal muscle protein. These boys get weaker and weaker until they are completely paralyzed.

Dystrophin is located underneath the sarcolemma and assembles with sarcolemmal proteins such as dystroglycan, α-sarcoglycan, and neuronal nitric oxide synthase
(NOS) to form the dystrophin-associated glyco protein complex. The essential function of dystrophin in muscle is to connect the subsarcolemmal cytoskeleton to the
sarcolemma by binding N-terminally to F-actin and C-terminally to β-dystroglycan. Loss of dystrophin results in inflammation, muscle degeneration, and replacement
of muscle with fibroadipose tissue.

That bit is really for those with a technical background.

In the milder allelic Becker muscular dystrophy, dystrophin mutations do not disrupt the open reading frame; a shortened but functional dystrophin protein is produced, and most patients (male and female) are able to walk into late adulthood and have a normal lifespan. Therefore, induction of exon skipping to restore the open reading frame is an attractive therapeutic strategy in Duchenne muscular dystrophy that can be achieved with splice switching oligomers.

This means that they are going to try by genetic engineering to replace the faulty gene with one that at least gets read by the cells even though it does not produce the proper protein. It will mean substituting a fatal disease by a less severe one, though one which will mean being unable to walk by the time they are 60.

These oligomers are typically 20–30 nucleotides in length and are complementary in
sequence to regions of the pre-mRNA transcript relevant for targeted DMD exon skipping. Splice switching oligomers targeting dystrophin exons have been successfully used to restore dystrophin expression in vitro and in various animal models of Duchenne muscular dystrophy. In the mdx mouse, administration of 2´O-methyl-ribooligonucleosidephosphorothioate (2´OMe) and phosphorodiamidate morpholino oligomers (PMOs) identified PMOs as more effective for induction of exon skipping and restoration of long-lasting dystrophin production after intramuscular or intravenous administration. In the X-linked muscular dystrophy dog, PMO administration was followed by dystrophin restoration and clinical benefit without adverse reactions.

I know it sounds terribly complicated, but this is what scientists do all day. In a former life I made a film for television about these boys and made a plea that animal experiments should be allowed to continue in order to find a cure.

In this paper, the authors show for the first time that repeated systemic
administration of a PMO splice switching oligomer (AVI-4658) induces targeted exon skipping in skeletal muscle in patients with Duchenne muscular dystrophy, restoring correctly localised dystrophin at the sarcolemma. The administration of AVI-4658 was very well tolerated, without clear drug-induced adverse events with single doses of up to 900 mg and cumulative exposure exceeding 10,000 mg. The absence of drug-related adverse events after 12 weeks is encouraging, but caution is still needed because any splice switching oligomer would need to be given lifelong.

A clear and significant dose response was recorded in terms of dystrophin protein expression, leading to seven patients who responded to treatment at the higher doses.
This finding was accompanied by a significant reduction of inflammatory infiltrates in patients in the two highest dose cohorts. Patients with the highest levels of
dystrophin also had increased sarcolemmal expression of proteins of the dystrophin-associated glycoprotein complex.

The safety profile that they have noted with AVI-4658 at doses of 20 mg/kg, supported by animal testing at up to human equivalent doses of 100 mg/kg, is encouraging and bodes well for longer administration periods and higher clinical dose. Preclinical data suggest that repeated administration of even small doses over an extended time achieves more homogeneous restoration of dystrophin than does the
same cumulative dose administered as a bolus injection of PMO. This finding suggests that a long period of administration will be necessary to achieve homogeneous
dystrophin expression.

John 6:35-36. I am the bread of life

Then Jesus declared, “I am the bread of life. Whoever comes to me will never go hungry, and whoever believes in me will never be thirsty. But as I told you, you have seen me and still you do not believe.

Jesus at last speaks plainly. This is the first of the great "I am" statements in John's gospel. He is still speaking in metaphor but the metaphor is being unpacked. Note it is not those who eat and drink that will have their hunger and thirst satisfied, but 'those who come to him' and 'those who believe'.

He had previously admonished those at Jerusalem for their unbelief; now he admonishes his fellow Galileans. They had seen the miracles, they had fed their bellies, but this had not brought forth faith, only a political vigor to crown Jesus as King.

Treatment of the anemia of chronic disorder

The anemia observed in ACD is frequently mild, and correction may not always be necessary. There are, however, several reasons for attempting to correct the anemia present. First, anemia may be deleterious in itself, with effects on the cardiovascular system needed to maintain tissue oxygen supply. Second, anemia may be associated with a poorer prognosis in many chronic disease states, although whether anemia plays a causative role in determining prognosis is open to debate. Third, treatment may improve the quality of life for patients living with chronic conditions.

Treatment of the underlying inflammatory or malignant process associated with ACD will often result in improvement in the degree of anemia, examples being the use of corticosteroids in polymyalgia rheumatica, the use of TNF-alpha inhibitors in rheumatoid arthritis or inflammatory bowel disease, and the use of antiretroviral drugs in HIV infection. Indeed the severity of the anaemia will frequently mirror the activity of the chronic condition causing it, for example in rheumatoid arthritis. However, treatment of the underlying condition may not always be possible, for example in patients with incurable cancers or cardiac failure and alternative strategies may be necessary. Correction of as many contributory factors as possible is also desirable, for example correction of nutritional deficiencies.

Blood transfusion

Blood transfusion is widely available in the developed world and is a simple means of treating patients with moderate to severe anaemia, but blood remains a precious and expensive resource, and transfusion therapy carries long-term risks of viral transmission, iron overload and alloimmunization. Transfusion should therefore be reserved for patients with severe or life-threatening anaemia in the context of ACD, and is not an appropriate treatment for patients with this form of chronic anaemia.

Thursday, August 11, 2011

A cure for CLL - what do I think?

To summarize: The authors have reported the delayed development of the tumor lysis syndrome and a complete response 3 weeks after the treatment of a case of TP53 deleted, multiply treated, CLL with his own genetically modified T-cells. They were modified to target CD19 by infecting them with a lentivirus vector expressing anti-CD19 linked to CD3-zeta and CD137 (4-1BB) signaling domains.

Genetically modified cells were present at high levels in bone marrow for at least 6 months after infusion. There was a CD19-specific immune response in bone marrow as shown by the release of cytokines and the disappearance of leukemia cells that coincided with the peak infiltration with genetically modified T-cells.

This is the first time that the tumor lysis syndrome has been caused by cellular immunotherapy. The fact that such cells can be so potent means that future clinical trials will need to be very carefully designed.

Although in B-cell lymphomas the targets for immunotherapy like this are readily available, possible targets present themselves for non-hemic cancers and this approach may have a wider application. An important feature of this approach is that no tissue matching is needed and there is no risk of GVHD, so that “off-the-shelf” lentiviral vectors might be constructed for tumors of a wide variety of histologic types.

In previous trials of redirected T-cells, objective tumor responses have been modest, and the expansion of the modified T-cells in the body has not been sustained. This limitation seems to have been overcome by incorporation of the CD137 (4-1BB) signaling domain. In this respect it seems superior to CART-19 cells incorporating a CD28 signaling domain.

The authors were surprised that the very low dose modified T-cells would result in a clinically evident antitumor response. It is possible that the chemotherapy used might have potentiated their effects, possibly by increasing engraftment and migration of the T-cells to tumor cells as well as synergizing with the T-cells to kill stressed tumor cells that would otherwise survive the chemotherapy.

Although the prolonged persistence of the modified T-cells in the blood and bone marrow of our patient might have resulted from inclusion of the 4-1BB signaling domain, another serendipitous mechanism suggests itself. There was no anti-mouse or anti-idiotype response generated, possibly from the choice of CD19 as a target. By eliminating all the CD19 positive cells it rendered impossible the chance of making specific antibodies.

Although CD19 is an attractive tumor target because it is expressed only on normal and malignant B-cells, there is concern that persistence of the modified T-cells will cause long-term B-cell deficiency. In fact, in this patient, B cells were absent from the blood and bone marrow for at least 6 months after infusion. This patient did not have recurrent infections. Targeting B-cells through CD20 with rituximab is an effective and relatively safe strategy for patients with B-cell neoplasms, and long-term B-cell lymphopenia is manageable. But CD19 is more extensively expressed than CD20. Patients treated with rituximab have been reported to have a return of B cells within months after discontinuation of therapy; this is unlikely to occur in this patient and management might be much more difficult.

Is this an important paper? Yes, because it shows the possible potency of redirected T-cell treatment.

Can it be rolled out tomorrow? No. Two other patients with advanced CLL have also received CART19 infusions according to this protocol, and although all three have had tumor responses, everybody puts their best case forward first (remember Mr Carr, the first patient treated with anti-idiotype monoclonal antibodies back in the 1980s - that treatment is no longer with us).

Can we expect clinical trials of this treatment shortly? Perhaps, or something like this. I get the impression that the final form of this treatment has not yet been optimized. There may be several more pilot studies before we see a definitive trial.

What is my verdict on it? I am excited by it but mainly because it is close to the field that I am working in, rather than as a treatment for today or even tomorrow. Remember, this is only a single case report and the remission has only lasted for about a year. We shall know more later, but it is an elegant approach to the problem. It is not a cure - yet.

I will still continue to advocate FCR for many patients and chlorambucil for some. Others will be more suited to Revlimid or to trials containg CAL-101 or PCI32765 for some time to come.

Finally, celluar therapy is extremely expensive. There will be few for whom it can be afforded, especially at present.

John 6:34. Give me the bread of life.

"Sir," they said, "from now on give us this bread."

After today's news, I echo that thought. Break thou the bread to me as thou didst break the bread beside the sea. When all seems dire and dreadful, what could we want but Jesus? I am too numb to think about doctrine. All I need are the loving arms of Jesus, who laid down his life for me because he loved me; not for anything that I had done or would do; just because he loved me.

More technical stuff. Omit if it isn't your thing

Toxicity of CART19 Cells

The cell infusions had no acute toxic effects. The only serious adverse event noted was the grade 3 tumor lysis syndrome described previously. The patient had the expected disappearance of blood B-lymphocytes beginning on day 1 and continuing through the most recent follow-up visit, 10 months after treatment. The patient had transiently low platelets from day 19 through day 26 and neutropenia from day 17 through day 33. Other signs and symptoms that were probably related to the study treatment included mild elevations in aminotransferase and alkaline phosphatase levels, which developed 17 days after the first infusion and resolved by day 33. Mild constitutional symptoms consisted of fevers, chills, feeling 'shocky', muscle pains, headache, and fatigue. Mild hypogammaglobulinemia was corrected with infusions of ivIg.

Analysis of Serum and Bone Marrow Cytokines

The patient's clinical response was accompanied by an increase in levels of inflammatory cytokines with levels of interferon-γ, the interferon-γ–responsive chemokines CXCL9 and CXCL10, and interleukin-6 that were 160 times as high as baseline levels. The temporal rise in cytokine levels paralleled the clinical symptoms, peaking 17 to 23 days after the first CART19-cell infusion.

The supernatants from serial bone marrow aspirates were measured for cytokines and showed evidence of immune activation. Significant increases in interferon-γ, CXCL9, interleukin-6, and soluble interleukin-2 receptor were noted, as compared with the baseline levels on the day before the T-cell infusion; the values peaked on day 23 after the first CART19-cell infusion. The increase in bone marrow cytokines coincided with the elimination of leukemia cells from the marrow. Serum and marrow tumor necrosis factor α remained unchanged.

Expansion and Persistence of Chimeric Antigen Receptor T Cells

DNA encoding anti-CD19 chimeric antigen receptor (CAR19) could be detected beginning on day 1 after the first infusion. More than a 1000 fold expansion of the cells in the patient was noted by day 21 after the infusion. At peak levels, CART19 cells in blood accounted for more than 20% of circulating lymphocytes; these peak levels coincided with the occurrence of constitutional symptoms, the tumor lysis syndrome and elevations in serum cytokine levels. CART19 cells remained detectable at high levels 6 months after the infusions, though the values decreased by a factor of 10 from peak levels. The doubling time of CART19 cells in blood was approximately 1.2 days, with an elimination half-life of 31 days.

Chimeric Antigen Receptor T Cells in Bone Marrow

CART19 cells were identified in bone marrow specimens beginning 23 days after the first infusion and persisted for at least 6 months, with a decay half-life of 34 days. The highest levels of CART19 cells in the bone marrow were identified at the first assessment 23 days after the first infusion and coincided with induction of an immune response, as indicated by cytokine-secretion profiles. Flow-cytometric analysis of bone marrow aspirates indicated a clonal expansion of CD5+CD19+ cells at baseline that was absent 1 month after infusion and in a sample obtained 3 months after infusion. Normal B cells were not detected after treatment

Health Report following CT scan

I had my CT scan this morning and this afternoon had a phone call to attend the hospital. The most serious finding was that I have had a large volume pulmonary embolus straddling the two pulmonary arteries. Although there is still blood flow around the embolus, it does explain why I have been breathless for the past few days and my general fatigue. Looking at it shows that there has been a genuine emergency and justifies my going back on full dose Clexane, which I have already started this evening.

The rest of the scan shows no liver metastases and no change in the size of the mass where the stricture is, but there is a significant thickening of the omentum, which will account for the bloating and discomfort that I am feeling. I think it is probably time that I restarted my treatment and it looks as though the most likely option id a clinical trial comparing cetuximab and an EGRF TKI.

Cure (?) for CLL; What they actually did.

The way they did this study can be scrutinized at the NEJM website, but I am not going into it in any detail. Although the 'methods' part of the paper is vital for scientists who want to evaluate the work, a lay audience has to take them on trust.

The trial ( number, NCT01029366) was not looking at whether the treatment worked; that will have to come later. It was designed to assess the safety of the procedure and whether it was really feasible. It was approved by the institutional review board at the University of Pennsylvania. No commercial sponsor was involved in the study.

They designed a self-inactivating lentiviral vector (GeMCRIS 0607-793), which was subjected to preclinical safety testing. Lentiviruses are types of retroviruses that are now commonly used in Gene Therapy experiments and have lots of advantages. They can deliver a significant amount of genetic information into the DNA of the host cell and have the unique ability among retroviruses of being able to replicate in non-dividing cells, so they are one of the most efficient methods of a gene delivery vector. HIV is an example of a lentivirus.


Cell Infusions
T-cells from the patient were thawed and infected with lentivirus to express the CD19-specific chimeric antigen receptor. Four days before the cell infusion, the patient received chemotherapy designed for depletion of lymphocytes (pentostatin and cyclophosphamide without rituximab). Three days after chemotherapy but before cell infusion, the bone marrow was hypercellular with approximately 40% involvement by CLL. Cytogenetic analysis showed two separate clones, both resulting in loss of chromosome 17p and the TP53 locus. Four days after chemotherapy, the patient received a total of 3×10e8 T-cells, of which 5% were infected with the lentivirus, for a total of 1.42×10e7 infected cells (1.46×10e5 cells per kilogram) split into three consecutive daily intravenous infusions (10% on day 1, 30% on day 2, and 60% on day 3). No postinfusion cytokines such as IL-2 were given and there were no toxic effects of the infusions.

Clinical Response and Evaluations
Fourteen days after the first infusion, the patient began having chills and low-grade fevers associated with fatigue. Over the next 5 days, the chills got worse, and his temperature rose to 102.5°F, with more shivering attacks, feeling 'shocky', loss of apetite, nausea, and diarrhea. He had no lung or heart symptoms. Because of the fevers, CXR and blood, urine, and stool cultures were performed, but all were negative or normal. Tumor lysis syndrome was diagnosed on day 22 after the infusion with raised uric acid, phosphate and LDH levels. There was evidence of acute kidney damage, with a raised creatinine level. The patient was hospitalized and treated with fluid and rasburicase. The uric acid level returned to the normal range within 24 hours, and the creatinine level within 3 days and he was discharged on hospital day 4.

By day 28 after the CART19-cell infusion, the lymph nodes could no longer be felt, while on day 23, there was no evidence of CLL in the bone marrow. The karyotype was now normal, and FISH testing was negative for deletion TP53. Flow-cytometric analysis showed no residual CLL, and B cells were not detectable. CT scanning performed on day 31 after infusion showed no lymph node enlargement.

Three and 6 months after the CART19-cell infusion, physical examination remained unremarkable, with no lymph nodes to feel and CT scanning performed 3 months after the CART19-cell infusion showed sustained remission. Bone marrow studies at 3 and 6 months also showed no evidence of CLL, with a continued lack of normal B cells as well. Remission had been sustained for 10 months so far.

Cure for CLL. The Case Report

Although three patients have been treated in the pilot study of this new gene therapy treatment of CLL, the authors of the NEJM article give a single case report on one patients who would have been expected to do badly with further treatment because of a TP53 problem. I have attempted to simplify the case report for a lay-audience.

Case Report

The patient was diagnosed as Rai stage I CLL in 1996 but did not need treatment until6 years of watch and wait had passed. The reason for treatment was a progressive increase in white cell count and in lymph node size. In 2002, he was treated with two cycles of rituximab plus fludarabine (FR) which normalized his blood count and shrunk his lymph nodes, though they could still be felt. This would have been a partial remission. In 2006, he received a further four cycles of FR for disease progression, again with normalization of blood counts and partial regression of his lymph nodes. This response was followed by a 20-month progression-free interval and a 2-year treatment-free interval.

In February 2009, he had a rapidly progressive rise in white cell count and recurrent enlargement of his lymph nodes. At this stage his bone marrow was extensively infiltrated with CLL. Cytogenetic analysis showed 20% of his cells contained a deletion of chromosome 17p, but much more sensitive FISH testing showed an 85% deletion involving TP53 on chromosome 17p. He received rituximab with bendamustine (BR) for one cycle and three additional cycles of bendamustine without rituximab (because of a severe allergic reaction). This treatment resulted in only transient improvement in lymphocytosis and a CT scan showed that the enlarged lymph nodes were getting bigger.

In December 2009, his own T-cells were collected by leukapheresis and preserved in liquid nitrogen. The patient then received alemtuzumab (which actually works in TP53 disordered CLL) for 11 weeks, with improved blood cell production and a partial resolution of his enlarged lymph nodes. Over the next 6 months, he had stable disease but with persistent, extensive marrow involvement and diffuse lymph node enlargement (with multiple 1- to 3-cm lymph nodes). In July 2010, the patient was enrolled in a phase 1 clinical trial of chimeric antigen receptor–modified T-cells.

A new and successful treatment (cure?) for CLL

The only cures of CLL have been with stem cell allografts. Whereas in the past we thought that this was another way of directing massive doses of chemotherapy or radiotherapy at the bone marrow and being able to rescue the normal cells with a transplant from someone else, we now know that the benefit comes from the transplanted cells not the chemotherapy. Chemotherapy (or radiotherapy) is only needed to allow the transplant to take place and its main characteristic is to be immunosuppressive rather than myeloablative. So immunosuppressive drugs like fludarabine and alemtuzumab are more important than myeloablative drugs like melphalan or busulphan, and the dose of Total Body Irradiation needed is more like 2 Gray than 12 Gray.

The transplant works by what is called Graft-Versus-Leukemia (GVL). The problem with this approach to cure is that it is mixed up with a Graft-Versus-Host (GVH) effect which is capable in the worst circumstances of killing the recipient and if not, of conveying a very unpleasant and hard-to-treat disease.

The GVL effect works through the graft's T-cells which are directed at minor differences between the histocompatability antigens of the graft and host. We often don't know what they are or even if there are any.

For some time several scientists (including my own daughter) have been working at re-educating T cells so that they will attack specific tumor targets. Today's breakthrough presents a successful way of doing this. I first came across this particular approach when I received the papers for a Gene Therapy Meeting in January this year, and I was very enthusiastic about it, although I could not do more than hint at its promise then. Gene therapy has reached a greater maturity in the 10 years that I have been attending GTAC meetings and for the most part now it is very safe. Although it makes use of retroviruses like HIV to transfer genes into different cells, the HIV has been thoroughly gutted of all the harmful ingredients and as I demonstrated earlier in the year, there have been sone remarkable successes.

With the use of gene-transfer techniques, T cells can be genetically modified to stably express immunoglobulin molecules (antibodies) on their surface, conferring new antigen specificity. Chimeras were mythological animals that consisted of part one animal, part another. An example would be a Centaur with a man's head and chest and horse's body or a mermaid with a woman's top and a fish's tail. We now use the term to describe a mixed molecule from different cells.

Chimeric antigen receptors combine an antigen-recognition domain of a specific antibody with an intracellular domain of the CD3-zeta chain or FcγRI protein into a single chimeric protein. Although chimeric antigen receptors can trigger T-cell activation in a manner similar to that of normal T-cell receptors, a major barrier to the clinical application of this technique to date has been not having enough cells to attack the tumor. It has not been possible to expand the numbers of these cells inside the patient resulting in disappointing clinical activity.

The activity of chimeric antigen receptor–mediated T-cell responses can be further enhanced with the addition of a costimulatory domain. In preclinical models, these scientists found that inclusion of the CD137 (4-1BB) signaling domain significantly increased antitumor activity and the persistence of chimeric antigen receptors in the patient compared with inclusion of the CD3-zeta chain alone.

In most cancers, tumor-specific antigens for targeting are not well defined, but in B-cell neoplasms, CD19 is an attractive target. Expression of CD19 is restricted to normal and malignant B cells and B-cell precursors. The authors of the report in the New England Journal of Medicine have begun a pilot clinical trial of treatment with autologous T-cells expressing an anti-CD19 chimeric antigen receptor (CART19); three patients have been treated. In my next blog I will give details of what they have done.