Tuesday, November 27, 2007


The Peter Principle: in any organisation people are promoted to their point of incompetence.

They got rid of Sven Goran Erickson. He had taken the England soccer team to three tournaments in a row, but hadn't won anything. A large pay off was needed to terminate his contract early and he soon found another job coaching Manchester City, who are enjoying their best season for more than 20 years. They found it hard to find a replacement for Sven; nobody really wanted the job and eventually they gave it to his number 2, Steve McClaren. He started well, but when confronted by Macedonia, Croatia and Russia he couldn't cope. Now Steve has gone too; he wasn't up to the task, the Peter Principle applied.

They got rid of Tony Blair. He had taken the Labor Party to three election victories in a row, but the Iraq war was unpopular and he had to go. He quickly found another job and is now busily employed in the Middle East. They didn't find it hard to replace Tony; someone wanted the job and they gave it to Tony's number 2, Gordon Brown. He started well and opened up a big lead in the Opinion Polls, but when confronted by David Cameron at the Dispatch Box he couldn't cope. Successively he has presided over purloining Conservative policies on inheritance tax, a run on a British bank, the loss of the confidential financial details of half the population on a computer disc and now undeclared but disguised donations to Party Funds by a property developer who has mysteriously appears to have reversed unfavorable planning decisions. It looks as though the Peter Principle is applying again.

Sunday, November 25, 2007

Scandalous disciples

Listen to Mahalia Jackson singing ‘Just a closer walk with thee’.
I am weak, but Thou art strong;
Jesus, keep me from all wrong;
I’ll be satisfied as long
As I walk, let me walk close to Thee.

Just a closer walk with Thee,
Grant it, Jesus, is my plea,
Daily walking close to Thee,
Let it be, dear Lord, let it be.

Through this world of toil and snares,
If I falter, Lord, who cares?
Who with me my burden shares?
None but Thee, dear Lord, none but Thee.

When my feeble life is o’er,
Time for me will be no more;
Guide me gently, safely o’er
To Thy kingdom shore, to Thy shore.

“You will all fall away,” Jesus told them.

The word translated ‘fall away’ is from skandalon in the Greek, from which we have scandal in English. It originally described part of a trap. Imagine a bear trap, a cubical construction with one side propped open by a log. The bear enters and the log is pulled away, slamming shut the entry. The log that held the gate open would be a skandalon. Or supposing you were being chased by enemies in a forest; after you had passed them your friends raised a trip wire that bought your enemies down. The trip wire would be a skandalon.

In Hellenistic Greek the word was only used in a figurative sense. Something that brings someone down – but there is always a moralistic overtone. So here, there is not just a sense of the bubble being pricked for the self-important disciples, but also the sense that it is a scandal. They should be ashamed that they would be brought down. Not only are they deflated, they are shamed.

Jesus quotes from Zechariah 13:7, “Strike the shepherd and the sheep will be scattered.” Jesus tells us who will strike the shepherd; not the chief priests, not the crowd crying crucify, not Pilate, not the Roman soldiers; I will strike the shepherd and from the context in Zechariah it is God the Creator and Father who is doing the striking.

We forget sometimes that Jesus is Prophet as well as Priest and King. Here Jesus is prophesying exactly what will happen in a few hours.

Peter, poor puffed up Peter, denies it. “Even if all fall away, I will not.”
How many of us have such a high opinion of ourselves? When God created Man he saw that it was good. Adam was created perfect – but guess what? Adam fell. David was a man after God’s own heart. David fell. Abraham believed God and it was counted to him as righteousness. Abraham fell. So did Moses. So did Samuel. So did Elijah. And Peter, brave impetuous Peter; he fell too.

Does anyone think they could do better? Yet we have such high opinions of ourselves and our churches. The most famous pastors have fallen, the bravest missionaries, the most zealous evangelists. It is a scandal.

Peter was not alone among the disciples – verse 31 – “all the others said the same.” Peter, at least, was close enough to demonstrate his disloyalty; the others had fled.
“Before the cock crows twice, thou shalt deny me thrice.” The old English has ingrained it in our memories.

What led to the betrayal? Why, because the sheep were scattered. It is a warning to us. This is why I cited Mahalia Jackson’s ‘Just a close walk with thee’. If we stray from Him we become scattered; we become a scandal. We really are weak. It is only when we know that we are weak that we are strong. It is then that we lean on Him. When we stop holding His hand, like little children on a crowded beach we get lost and wander.

The most optimistic verse comes in the middle, “After I have risen, I will go ahead of you into Galilee.”

Here is the promise of forgiveness, the promise of redemption. If I falter, Lord, who cares? None but Thee, dear Lord, none but Thee.

Who struck the shepherd? None but God Himself. Why was the shepherd struck? To take the place of the sheep. There on the cross the price for Adam’s sin, for David’s sin, for Moses’ sin, for Abraham’s sin, for the sins of Elijah, Samuel, Samson, Gideon, and all the Old Testament heroes; for Peter’s sin; for my sin and yours was paid.

That’s why Mahalia could sing, “When my feeble life is o’er, guide me gently, safely o’er to Thy kingdom shore, to Thy shore.”

We, the redeemed, shall be free. He will go ahead of us to Galillee.

Saturday, November 24, 2007


Like many others we have been watching Cranford of BBC TV. Mrs Gaskell's story of life in a northern town with precise manners has been captivating millions as we all play spot the thespian. Dame Judy Dench and Dame Eileen Atkins will be joined tomorrow by Sir Michael Gambon, but we have already been entertained by several actors with plenty of experience of costume drama. Julia Sawalha was in Pride and Prejudice as well as Martin Chuzzlewit (and before that in Inspector Morse). Francesca Annis was in Wives and Daughters, a recent Jane Eyre and Madame Bovary and an early Great Expectations. Imelda Staunton was in David Copperfield and Canterbury Tales. Julia Mackenzie was in The Old Curiosity Shop. Lesley Manville was in North and South and a different David Copperfield to Imelda Staunton. She was also in Topsy Turvey, the Gilbert and Sullivan biopic and is a Mike Leigh regular.

Barbara Flynn was in Wives and Daughters and was Beatrix Potter's mother in Miss Potter, Mary Queen of Scots in Elizabeth 1; she was in Hornblower, the color version of the Forsyte Saga, Lorna Doone, the Barchester Chronicles and like many of the above, she was one of Morse's ladies. Deborah Findley was in Wives and Daughters and Anna Karenina. Jim Carter was in Wind in the Willows, Hornblower, the Madness of King George, Philip Glenister was in Hornblower, the Other Boleyn Girl, Vanity Fair, a Sharpe and, of course, the wonderful Life on Mars. Greg wise also did Hornblower, Madam Bovary, as well as Alice Through The Looking Glass, The Moonstone and Sense and Sensibility. Andrew Buchan did Jane Eyre.

Michael Gambon is of course famous for having done just about everything including Dumbledore, but as far as period pieces are concerned, he is in the new Brideshead to be released next year, and was in Gosford Park, Longitude, Wives and Daughters, the Wings of The Dove, Wind in the Willows (and since it's Thanksgiving I should mentions Squanto). Eileen Atkins was in Vanity Fair, Gosford Park, David Copperfield, Madame Bovary, Cold Comfort Farm, Oliver Twist, Sons and Lovers, The Duchess of Malfi and of course she was one of the creators of Upstairs Downstairs. Judy Dench was in a rather inferior Pride and Prejudice (the one with Keira Knightley), The Importance of Being Earnest, Middlemarch, and of course numerous interpretations of various British Queens.

Most of the actors have appeared in Miss Marples or Poirots or Midsummer Murders or Morse. It's almost as if there is one vast repertory theatre with actors swapping roles very week. Sometimes they are the lead, sometimes it's only a bit part.

Spurred on by Cranford, we have also watched the other Mrs Gaskell productions, North and South and Wives and Daughters. Excellent! And if you haven't seen them get the DVDs. Ladies, I guarantee that Richard Armitage as John Thornton will send teh same shivers of pleasure down your spine as Colin Firth did in Pride and Prejudice.

Monday, November 19, 2007

Vaccination against pneumonia

People keep asking about vaccination against pneumonia and although I have been able to give some advice, it hasn't been very encouraging advice. In general people with CLL don't respond well to vaccination and vaccination against polysaccharide antigens such as are present on the pneumococcus bacterium is particularly hopeless, especially in patients who have advanced, treated or longstanding disease. I have been advocating the use of the conjugated vaccine, Prevenar®, but only on theoretical grounds that it ought to be better, and with no documented evidence that proves that it is better. Now at last there is a paper that gives some facts and figures. Marjatta Sinisalo and colleagues from Finland have vaccinated 52 patients with CLL and 25 age- and sex-matched controls with Prevenar® pneumococcal conjugate vaccine (published today on-line in the journal, Vaccine. Serum samples were taken for antibody determinations before and four weeks after vaccination.

In the case of pneumococcal polysaccharide vaccine, in previous studies no antibody response has been detected (Hartkamp et al, Antibody responses to pneumococcal and haemophilus vaccinations in patients with B-cell chronic lymphocytic leukaemia, Vaccine 2001; 19:1671–1677; Sinisalo et al, Response to vaccination against different types of antigens in patients with chronic lymphocytic leukaemia, Br J Haematol 2001; 114:107–110.)

Here is a quote from an editorial in Clinical and Experimental Immunology about conjugate vaccines by David Goldblatt of the Institute of Child Health in London:

Polysaccharide antigens are large molecules consisting of repeating epitopes which are not processed by antigen-presenting cells (APC) but interact directly with B cells, inducing antibody synthesis in the absence of T cells (thus designated T-independent antigens). T cells can influence the antibody response to certain polysaccharides, such as the capsular polysaccharide of S. pneumoniae type 3, (S. pneumoniae is the microbiologists’ name for pneumococus) but an absolute requirement for T cells has not been demonstrated. T-independent responses are restricted in a number of ways. Most importantly, they fail to induce significant and sustained amounts of antibody in young children below the age of 18 months. While polysaccharides are immunogenic in older children and adults, the characteristics of the antibody responses are rather restricted. They are dominated by IgM and IgG2, are relatively short lived and a booster response cannot be elicited on repeated exposure. This failure to induce immunological memory is also reflected in the absence of demonstrable affinity maturation. In contrast to polysaccharides, antibody responses to protein antigens have an absolute requirement for T cells. The consequence of this T cell help are that antibody responses to protein antigens can be elicited in the very young and immunity is long lived due the generation of immunological memory. Antibody responses to protein antigens are dominated by the IgG1 and IgG3 subclasses and affinity maturation can be demonstrated over time.

As a result conjugate vaccines have been introduced for vacinating infants against both haemophilus influenzae and pneumococus. Studies have already shown that CLL patients do respond better to conjugate Hib vaccines but hitherto there are no data for Prevenar. Readers should note that haemophilus influenzae is nothing to do with influenza, and that it is not a significant pathogen in CLL. Pneumococcus is by far the most important pathogen in CLL pneumonia and one for which a decent vaccine is urgently needed.

So what did they find? As expected the immune response to Prevenar in CLL patients was significantly worse than for normal controls. However, if the vaccine had been administered at an early stage in the disease, before commencement of chemotherapy and the development of hypogammaglobulinemia, almost 40% of the patients developed a significant response to at least six antigens.

There is one further caveat, the serotype coverage of the 7-valent conjugate vaccine against invasive pneumococcal infections in patients ≥65 years was only 56% compared to that of 86% in 23-valent polysaccharide vaccine. So even in patients with early stage disease who have never had treatment and have not developed hypogammaglobulinemia, only about a quarter of patients will be protected against pneumonia by this vaccine, which is, I suppose better than nothing, but there is a lot more yet to do.

Sunday, November 18, 2007

The purpose of life.

What is the meaning of life? In the Hitch Hiker's Guide to the Galaxy the answer was famously 42, which is an oblique way of agreeing with the atheist's answer: there is no purpose to life, but as someone once said, "I do not have enough faith to be an atheist" (Write to me if you know who, but I am not ashamed at my ignorance, even St Paul was wont to write, "Somewhere it is written...").

A Christian should not be left in ignorance for in Paul's letter to the Ephesians we are told in chapter 1 and verses 9-10 << He made known to us the mystery of his will according to his good pleasure, which he purposed in Christ, to put into effect when the times will have reached their fulfillment - to bring all things in heaven and on earth together under one head, even Christ."

This is a difficult bit of Greek to translate and I can't do Greek letters on the blog (let me know if you know how). Transliterated it says anakephalaivsathai. The NIV translates it 'to head up' but it is used elsewhere in the Bible to mean 'sum' as in Acts 22:28 (For a large sum of money I acquired this citizenship) or summary, main point as in Hebrews 8:1 (Now the main point of what we are saying...) or to sum up as in Romans 13:9 (...commandment, is summed up in this word) so the ARV has "to sum up all things in Christ" (whatever that means). A popular rendering is the concept of unity, just as the a king brings unity to his subjects who have many diverse origins. Thus the KJV has "gather together in one all things in Christ", the RSV "to unite all things in him", the NEB "brought into a unity in Christ". the word has "cephalo" from which we get our English 'cephalic', a medical term referring to the head, so I suspect the meaning has something to do with the headship of Christ, but what do I know?

I think these language traps distract us from the message of the passage which tells us that the purpose of life is to bring everything together in Christ.

So if you have any other ambition or none you are missing the point.

Life may be tough and things might be going wrong and we may think life is futile, but don't despair. It all comes out right in the end. I know. I sneaked a look at the last page.

Saturday, November 17, 2007


An old man was walking down the street when a frog hopped up to him and said, "If you kiss me, I will turn into a beautiful princess."

The old man took no notice and walked on. Astonished the frog hopped after him. "I said, if you kiss me I will turn into a beautiful princess and I'm all yours."

The old man walked on and took no notice. In desperation the frog hopped after him and screamed at the top of its voice, "If you kiss me, I will turn into a beautiful princess, and I'm all yours and you can do what you like with me."

The old man reached down, picked up the frog and put it in his jacket pocket. Then he continued on his way.

Frustrated, there came a muffled cry from his pocket, "You've got to kiss me!"

The old man took the frog from his pocket and spoke to it, "Listen, at my age a talking frog is worth more."

Wednesday, November 14, 2007

The complexity of cancer

Today I went to a lecture by Nick Cross on tyrosine kinase inhibitors in chronic leukemias. The lecture was a tour-de-force, but I came away profoundly depressed. Nick runs an excellent genetics unit and is extremely erudite. He has managed to identify 43 chromosomal translocations in the chronic leukemias in which conjoined genes result in a constitutively activated tyrosine kinase that has the effect of causing the leukemic cell to continue to divide even when it is not receiving an appropriate signal from its environment.

This has nothing to do with CLL, by the way, the pardigmic disease is chronic myeloid leukemia in which the BCR/ABL tyrosine kinase is always in the switched on mode. Nick has looked at a variety of atypical chronic myeloid leukemias and has sorted out the molecular mechanisms.

Excellent though the science was there were several depressing features. First, in one case they had identified a Gleevec-like inhibitor which switched the tyrosine kinase off and would have had the effect of controling the leukemia, but so few patients suffered from this particular variant that no pharmaceutical company would spend the money to manufacture the product. Second, although he had identified 43 molecular mechanisms these represented less than 10% of all cases of atypical chronic myeloid leukemia. This is a rare variant of a rare disease; there are only 750 new cases of chronic myeloid leukemia in the UK every year.

The chronic myeloproliferative diseases are single gene disorders - there is usually only one molecular mistake. The common cancers, on the other hand, have 6, 7 or 8 molecular mistakes. If single gene diseases are so complex, how much more complex must the common cancers be?

When Gleevec was discovered I was very excited. The age of molecular therapies was dawning. That was 9 years ago. All we have done since then is produce one failed drug - Iressa - for common cancers. It is still the case that the most effective treatment for cancer is surgery, a treatment 150 years old.

The third depressing feature came from a meeting I went to the day before. WE were proposing a trial of mini-dose Revlimid for maintenance therapy in CLL. This was being opposed on the grounds that as the drug was so expensive, no matter how effective it might be, it would never pass NICE, and therefore there was no point in doing the trial. If Revlimid (a relatively easy to make molecule) is too expensive, what hope is there for new drugs in cancer.

The fourth thing that depressed me was seeing a doctor smoking. I have always refused to work on lung cancer on the grounds that the problem is already largely solved. Just stop tobacco smoking. As we unravel these molecular mechanisms at huge expense, society as a whole is unwilling to give up the thing that causes the commonest type of cancer. Why should we bother?

Monday, November 12, 2007

The cost of gene therapy

There is something of a controversy at the moment over the decision of the FDA not to recognise Oblimersen (BCL2 antisense) for the treatment of CLL. Spare a moment for Zheng Xiaoyu, once head of the Chinese FDA.

On July 10th this year Zheng was executed for taking bribes worth $840,000 from eight Chinese pharmaceutical companies in return for illegally approving their products. (There were 1010 recorded executions in China in 2002 according to Amnesty International).

Among the drugs approved by Zheng's regime were Gendicine, a recombinant human adenovirus type 5 which aims to introduce wild type p53 gene into cells with mutant p53. It was an immune reaction to adenovirus that killed Jesse Gelsinger the first person in the world to die from gene therapy.

This is not to say that the Chinese virus killed Jesse, but it suggests that the Chinese FDA might have been cavalier in licensing their product. Gendicine is analogous to the US drug Advexin, which is still in clinical trials and is not yet licensed. It may be that China, by applying less stringent criteria for licensing than the US, has leap-frogged America in the field of gene therapy. I suppose the lesson is if you are going to take risks with people's health don't take bribes for doing it.

Sunday, November 11, 2007

Cenotaph Sunday

We who have missed our wars, being either too young or too old to fight, are often perplexed by the heroism of those who died.

I was two when WW2 ended and still too young for Korea and Suez. In Britain, Harold Wilson kept us out of Viet Nam and by the time of the Falklands we had a professional army that did not require aging amateurs. The First Gulf War would have been my children's war, but my oldest were still at University and my youngest still at school. I have a nephew who was there and close to a friendly fire incident where American bombers demonstrated their effectiveness but not their efficiency.

My youngest toyed with a career in the air force, but eventually ended up designing racing cars instead. Had he joined he would now be in Iraq or Afghanistan.

My father was deferred military service because of TB, but my grandfather was in the trenches in world war one, surviving, no doubt, by the luck of having charge of the horses. My wife had an uncle who was a fighter pilot in the Battle of Britain, but he too survived.

As a family, therefore, we have escaped the warmongering of the twentieth century.

I heard on a news item this morning that a large proportion of British soldiers killed in Iraq and Afghanistan were victims of friendly fire, road accidents or logistic errors, like the soldier killed by a roadside bomb when the defence against it, radio-jamming equipment, had been delivered to his base but not fitted to the vehicle because someone had forgotten to sign the requisite chitty.

Watching an old movie on TV last night, 'D-Day, 6th of June', it was galling to see the Richard Todd character, having survived the battle with only the sort of scratch that war heroes dismiss with heaps of aplomb and modesty, carelessly step on a landmine so as to leave the beautiful Dana Wynter for Robert Taylor.

I suppose things like happen in the fog of war, but were I the parent of a soldier who had put his life on the line to preserve our land, our liberty, our lives, and then found that he had died because someone left the handbrake off, or left early for lunch, of hadn't memorized the call sign or for some other trivial error I should be dismayed. Our soldiers deserve more.

This morning watching the great and the good leaving their wreathes around the Cenotaph in London, I was moved to write this poem.

Poppies on every coat,
Wreathes of regret;
Was it for this they wrote,
"Lest we forget"?

Ploughshares and pruning hooks,
Wolves with the lamb;
Splendid the pageant looks;
All just a sham?

Reverent with pomp and show,
The dead they adore,
Then as they bend quite low,
Plan the next war.

Friday, November 09, 2007

Zebras, Pandas, Pelicans and Puffins

In the UK we have strange ways of crossing the road. We once had zebra crossings, so called because of the back and white stripes painted on the road. They were marked by black and white poles on which sat orange globes - Belisha Beacons - which were named after Leslie Hore-Belisha, the Minister of Transport who introduced them in 1934.

In 1962, concerned that pedestrians were disrupting the traffic flow by jumping on to 'their territory' the zebra crossing and occupying it (one retired colonel in Highcliff smashed the windscreen of an encroaching Rover with his walking stick), Ernest Marples the great innovator (he introduced Premium Bonds and Motorways) introduced Panda crossings which were controlled by pedestrian-operated light buttons and had black and white triangles rather than stripes on the road.

By 1967 the Panda experiment was deemed a failure. The flashing and pulsating lights were too confusing and the triangles were unpopular, so in 1969 the simpler Pelicon crossing was introduced. Note that strictly speaking they are Pelicon crossings (not Pelican) which stands for Pedestrian Light Con trolled crossings. You can watch this amusing government information film about them on You Tube

The pedestrian lights are situated on the far side of the road to the pedestrian. A Puffin crossing has the lights on the same side as the pedestrian; a toucan (Two can)crossing is a crossing for pedestrians and bicycles and a Pegasus crossing allows horse-riders to cross as well.

Someone at the Ministry of Transport spends their time thinking up these silly names.

Tuesday, November 06, 2007

Stem cell transplant - a lifelong committment

Some people think I am against transplants. Not at all, I regularly attend a ward round at the biggest transplant center in Britain. There are certainly situations where I recommend it unequivocally. I just want people to be realistic about the likely outcomes.

Everyone is aware that there is a certain mortality to stem cell transplants (SCT), especially in CLL, where at one time we were talking about a 40% risk of death in the first 100 days. Since the introduction or reduced intensity conditioning (RIC) that has been reduced so that in the best centers more than 80% are alive at a year post transplant. It is what happens afterwards that I want to write about today. In next week's Blood an article by Bhatia et al deals with the late consequences of SCT. Th is a report from very reputable centers including City of Hope, University of Minnesota, Ann Arbor, Michican and St Jude's, Memphis.

The paper deals with the long term consequences of transplants in leukemia and lymphoma excluding CLL and these were full intensity transplants not RICs.

By June 30, 2003, 21.6% (n = 320) of the patients who had undergone SCT between 1974 and 1998, and survived at least 2 years, had died. Median age at death was 33.4 years. Most of the deaths (69%) occurred in the 2- to 5-year period after allogeneic SCT, although 43 deaths (13%) did occur after 10 years from SCT.

The graph shows a survival curve comparing patients who had survived for 2 years after SCT with the normal US population of the same age.

For CLL patients it is important to realise that this is a young population. For most of the time covered by the study, the upper age for transplants was 40. CLL patients are generally older, and mostly would have RIC SCT. CLL patients have a more damaged immune system than other leukemic patients and would be more susceptible to infection.

Overall, premature death occurred 10 times more often than expected both in males (8-fold) and females (13-fold). Relative mortality was elevated across all age groups, but was highest in subjects undergoing SCT when younger than 18 years (17-fold). Relative mortality was highest in the 2- to 5-year period after allogeneic SCT (78-fold), and declined dramatically in the 6- to 10-year period (8-fold). Relative mortality remained elevated (2-fold above that of the general population) in patients followed for more than 15 years after SCT.

Two hundred forty-one deaths were observed in patients who had survived disease free for 2 years after SCT. Relapse of primary disease was the leading cause of death(29% of all deaths) mostly between the second and fifth year of follow-up. Chronic graft-versus host disease (cGVHD) was the second most common cause of late mortality accounting for 22% of deaths, while late infection in the absence of cGVHD was the cause of 11% of deaths. Late mortality was attributed to treatment-related causes in (25%), including 7% due to subsequent malignancy, 5% due to pulmonary complications, 3% due to cardiac toxicity, and 8.4% due to miscellaneous treatment-related complications.

The risk of late mortality due to any cause was 2.6-fold increased among individuals older than 45 years at the time of SCT, compared with those who were younger than 18 years; 2.3-fold increased among patients with cGVHD compared with those without cGVHD; and 1.7-fold increased among patients at high risk of relapse at the time of SCT, compared with those at standard risk. Patients undergoing SCT after 1980 were less likely to suffer from relapse-related mortality, compared with those who underwent transplantation before 1980.

In order to look at morbidity the investigators produced a questionnaire which looked at whether the patient had married or stayed married, was employment or not, could obtain health insurance and life insurance, and compared them with their siblings who had mot had a transplant.

Marital rate (proportion currently married) for the survivors was significantly lower compared with siblings (55% vs 69%, P < .001).

SCT survivors were 14-fold more likely to report a health problem preventing them from holding a job compared with siblings (19% vs 2%). Presence of cGVHD (OR = 3.2; 95% CI, 1.9-5.4), and female sex (OR-1.7; 95% CI, 1.1-2.7) were associated with difficulty in holding a job.

SCT survivors were 7-fold more likely to report difficulty in obtaining or retaining health insurance (26% vs 5%, P < .001), and low annual household income (< $20 000) was associated with difficulty in obtaining health insurance (OR = 2.7; 95% CI, 1.4-5.0). However, 90% of the survivors did report health insurance coverage at the time of study participation, although the rate in siblings was 95% (p = 0.01).

A significantly greater proportion of SCT survivors reported difficulty in obtaining or retaining life insurance compared with siblings (30% vs 5%, P < .001) and the survivors were 10-fold more likely to report difficulty in obtaining or retaining life health insurance. Only 56% of the survivors had life insurance at study participation, compared with 76% of the siblings (P < .001).

Tough though it is to have a transplant, it is better than being dead. When it is appropriate a transplant is the right course to take, but it should not be entered into unadvisedly.

Monday, November 05, 2007

Hope for p53 mutants

The worst cases of CLL are those with reduced or absent p53 function. There are two reasons for this. p53 is known as ‘the guardian of the genome’. I like to think of it as a sort of bumble bee buzzing up and down the DNA seeking out mistakes. When it finds them, it puts the cell into stasis and instructs the DNA repair enzymes to put the matter right. If they cannot do so, it instructs the cell to commit suicide – apoptosis, or programmed cell death. If this doesn’t happen and the cell continues to multiply the mistake is perpetuated and more accumulate. Characteristically, cells with a defunct p53 molecule develop a complex karyotype with many mistakes. Without p53 the cell gets progressively more malignant.

In addition p53 is needed by most cytotoxic drugs to kill the cells. They don’t work by committing murder, but by inducing p53 to tell the cell to commit suicide. Thus cells with aberrant p53 tend to be drug resistant.

CLL cells can be defective in p53 either by losing the part of chromosome 17 on which it is located, or by a molecular mistake so that the DNA sequence that codes for p53 has an error in it (ie a mutation). There is a third way that diminishes the effectiveness of p53. The ATM gene of chromosome 11q23 codes for an enzyme that adds a phosphate group to p53 which makes it much more active, so no ATM and your p53 is a bit effete, weak and watery. That’s not as bad as having no p53, but it will do for you in the end.

A poster at the IWCLL from the Royal Marsden confirmed what most of us had suspected. 85% of those with deleted p53 on one chromosome had a mutated p53 on the other one. Since they did not look at the complete length of the gene it is likely that the true figure is 100%. Interestingly, this was only true for those with >20% cells with the del 17p, lesion. In those with <20% the mutation rate was only 7%. This confirms the finding of the LRF CLL4 trial that only those with >20% del 17p had a very poor prognosis.

I have already written about Nutlin-3, a molecule that antagonises MDM-2, a natural inhibitor of p53 and about PARP-1 inhibitors, chemicals that enhance the effect of ATM, but here I want to introduce you to two other ways of putting right defective p53.

RITA (2.5-bis (5-hydroxymethyl-2-thienyl) furan) binds to the p53 N-terminal domain and preventing the p53-HDM2 interaction which leads to the accumulation of p53 in tumour cells lines, increasing its half-life. Of course there must be some normal p53 present for it to work, but it may have a use in del 11q CLLs where the p53 is there but not very strong.

PRIMA-1 (2,2-bis(hydroxymethyl)-1-azabicyclo[2,2,2]octan-3-one)is a low-molecular-weight compound that can restore wild-type conformation of mutant p53 and specific DNA binding, consequently triggering apoptosis in tumor cells carrying mutant p53.

Look forward to seeing papers reporting the use of these two molecules in early clinical trials.

Sunday, November 04, 2007

Autumn at Exbury

After a really terrible summer we have had a splendid autumn. The rain kept everything green and in many places the leaves remain on the trees, but now they are falling. Beech, oak, sycamore and horse chestnut each has its particular shade of gold. From dull brown to marmalade, amber to cadmium yellow, through ochres, tans, beiges and buffs, bays, roans and sorrels to foxy reds, coppers and bronze. With the fevered reds, russets and carmines of acer and maple contrasting with the lemon yellows of silver birch.

Last week we went again to Exbury and this time took a camera.

Mark 14; 12-26

Jesus knew that he was going to be betrayed, but he wanted some quality time with his disciples. He knew that one of the Twelve would do the betraying, so he made secret arrangements for the Passover meal. It reads like a spy story: follow the man with the water jar (normally women carried water jars, men carried wine skins). There was a coded message to give and then Peter and John (for Luke gives their names) could prepare the meal.

Mark gives us only 9 verses, but it lasted much longer than that. John gives five chapters to the Lord's Supper.

Eating together, especially in the Middle East, is a sign of fellowship and friendship. Imagine how it must be to be betrayed by your guest. We don't have to imagine. Glencoe reminds us. The Macdonalds welcomed the Campbells to their home, roasted an ox and broke out the whisky, then in the night when all were asleep, the Campbells rose and slaughtered every Macdonald, man woman and child, that they could find. Was there ever an act of greater betrayal? Just one, when Judas betrayed Jesus.

This was Jesus' last meal with his disciples, indeed his last meal. The Passover was the most important of all Jewish occasions. It was the most important family occasion. It was a symbolic meal to remind them of the time in Egypt when God had sent the Angel of Death to slay the first-born. Only those who were covered by blood on the lintel and doorpost were saved. The Angel passed over their houses. Every part of the meal had a meaning - the lamb, the bitter herbs, the unleavened bread, the hurry.

Jesus transformed the symbols. It is still a symbolic meal, but now Jesus makes the bread symbolise his body and the wine the new covenant in his blood.

Christians have misinterpreted the communion and tried to turn it into something magic, as if simply by eating and drinking some magic blessing is conveyed. But just as the Passover meal was explained by the asking of questions and the giving of answers, so the Lord's Supper needs explanation and understanding. The wine does not turn into blood or the bread to flesh - Jesus vowed not to drink again of the fruit of the vine, not of his blood.

Gone are the Jewish symbols of lamb and herbs etc. We are left with only two symbols, bread and wine. Jesus is our Paschal Lamb. His body was broken, his blood was shed. We now have a new Covenant in his blood. No longer are we imperfect people failing to keep perfect rules, we recognise ourselves as such because one perfect person has kept those rules. We no longer rely upon the blood of bulls and goats which cannot take away sin, but in His sacrifice he has once and for all taken away our sin. This is his last will and testament. It is our inheritance.

Paul's description in I Corinthians 11 has the intriguing verse "Anyone who eats and drinks without recognising the body of the Lord eats and drinks judgement on himself." Here 'the body of the Lord' refers to the church. The context of chapter 10 makes that abundantly clear.

The meal remains a family affair. On the Persecuted Church Sunday we should remember not just the local family, but our brothers and sisters in Christ worldwide.

The Persecuted Church

The persecution of the Christian Church in Moslem countries is only too well known.

A Pakistani official in a northern district warned female teachers and students to don Islamic garb this week, citing threats from Taliban Islamic supremacists (Islamists) active in the area. The Pakistani Executive District Officer (EDO) issued a notice requiring female students in Swat district to wear burqas, an outer garment cloaking nearly the entire body, according to an article on 25 September in a regional newspaper, the Daily Mashriq. Christians in the Afghan-border region 120 miles north of Peshawar say Islamists from the Taliban movement, which ruled most of Afghanistan from 1995 to 2001, have targeted them in recent months.

It is no better in Hindu countries.

In a case typical of false accusations that Hindu ultranationalists file against Christian workers, a pastor and his sister have been cleared of charges of rape and forced abortion in Chhattisgarh state. The Evangelical Fellowship of India announced that pastor Simon Tandi, aka Rohit Ranjan, a convert from Hinduism, and his sister Sanjeela Begum were acquitted by a court in Chhattisgarh's Kanker district on 12 September. Pastor Tandi was facing charges of raping and forcing a girl to terminate the resultant pregnancy after she filed a complaint – prompted by a Hindu nationalist group – against him in June 2005. Pastor Tandi had spent six months in jail, and his sister four months, before they were released on bail prior to the acquittal. The court reportedly found discrepancies in the statement of the complainant and a lack of evidence against the accused. Christian rights activists say facing false police complaints is common for Christian workers in several parts of the country.

And in communist countries it is just as bad.

Beijing house-church leader Cai Zhuohua, jailed since 2004 for conducting "illegal business practices" by distributing Christian literature, has been released with stern warnings to stop practising his faith outside the government-sanctioned church. Rev Bob Fu of China Aid Association (CAA) told reporters that on 13 September, three days after Pastor Cai's release on 10 September, officials of China's Public Security Bureau (PSB) took the well-known Beijing house-church pastor to their offices and tried to intimidate him with threats. "They warned him to be careful – not to be interviewed by the media, to obey the law and not to attend religious activities," Rev Fu said.

Officials from the National Security Bureau – China's equivalent of America's Central Intelligence Agency – on two occasions gave Pastor Cai similar warnings before he was released, Rev Fu said. As an ex-convict whom the government is especially interested to control, Rev Fu said, Pastor Cai must report to the PSB once a month. Pastor Cai is now at home in Beijing with his wife and mother, who leads a church that meets in their house. Deprived of his Bible whilst in prison, Pastor Cai was forced to make soccer balls for the 2008 Beijing Olympics for 10 to 12 hours a day, according to the CAA. Pastor Cai's mother, Rev Fu said, reported that the pastor was well and in good spirits.

Pastor Cai was sentenced to three years in prison on 8 November 2005 for "illegal business practices" and fined 150,000 yuan (then about £9,275). His wife, Xiao Yunfei, was sentenced to two years and fined 120,000 yuan, and her brother Xiao Gaowen was given an 18-month sentence and a fine of 100,000 yuan. Both were released after serving out their sentences. Having been arrested by state security officers on 11 September 2004 at a bus stop, Pastor Cai had been incarcerated for three years by last 10 September even though he was not convicted until November 2005. At the time of his arrest, authorities found more than 237,000 pieces of printed Christian literature, including Bibles, in a storage room he managed. By law, only the government-sanctioned Three-Self Patriotic Movement (TSPM) church is allowed to print and distribute Bibles in China.

The US State Department's 2007 International Religious Freedom Report, released last week, noted that many unregistered evangelical Protestant groups in China refuse to register with the TSPM due to theological differences, fear of adverse consequences if they reveal names and addresses of church leaders or members, or fear that it will control sermon content. "Many evangelical house-church groups also disagreed with the TSPM's admonitions against proselytising, which they consider a central teaching of Christianity," the report states. Recently Chinese authorities have been trying house-church leaders under Article 225 of China's Criminal Law against "illegal acts in business operation," according to Rev Fu of the Texas-based CAA.

Last week the Saudi King was welcomed to London with great pomp and ceremony (even though the band played the Darth Vader march from 'Star Wars' as he arrived. Pakistan is a key ally in the fight against the Taliban. India has been welcomed into the family of nations as thE world's largest democracy, and Western countries are cosying up to her as a future mega-consumer. China is due to host the Olympics shortly and wishes to be seen in a good light.

In the old days Palmerston would have sent a gunboat if a missionary were threatened. Today, Western nations care more for money than for their Christian brothers and sisters. Individual Christians should write to their MP, congressman, MEP or Senator to let them know how we feel about this persecution.

If you want to know more this website is useful.

Friday, November 02, 2007

Up to date on CD38

Readers may have noticed that I have not yet delivered my promised summary of the IWCLL meeting. This is because I have been working on one of the topics that featured at the meeting, and it has taken some time to get my appreciation of this topic clear enough to write about it. The topic is CD38.

CD38 is an interesting molecule for CLL doctors and patients alike. It is found on many types of cells, but we are really interested in its role on B-lymphocytes. It is there from time to time as the B cell differentiates. It appears on bone marrow precursor cells, but is lost on mature lymphocytes; on germinal center cells it protects against apoptosis, but on leaving the germinal center, memory cells lack the antigen; on terminally differentiated plasma cells it is one of the few surface antigens present. In chronic lymphocytic leukemia (CLL) expression of CD38 signifies a poor prognosis although it does not correlate precisely with the presence of unmutated immunoglobulin variable region (IgVH) genes and it may vary during the course of the disease.

It is a molecule that lives on and in the cell membrane and it is an enzyme; that is, it catalyzes chemical reactions. It is involved in signaling through the B-cell receptor (BCR) and such signaling causes cell division. We also know that some cytokines like IL-2 and interferon gamma can increase the level of CD38 present.

The molecule that binds to CD38 (its ligand) is platelet endothelial cell adhesion molecule-1 (PECAM-1) which is also known as CD31, and it is present on CLL cells and the cells lining blood vessel walls (endothelial cells).

The microenvironment is critical for the growth of CLL cells. The cells that are in the peripheral blood deceive us; the tissue is where the action is. In lymph nodes, spleen and bone marrow are proliferation centers and in these centers the CLL cells come into contact with activated T lymphocytes and various stromal cells. The bulk of CLL lymphocytes are in the solid lymphoid organs rather than the blood. Studies using heavy water labeling of CLL cells demonstrate that they have definable and substantial birth rates varying from one cell in a hundred to one cell in a thousand of the clone per day. It is established that CLL cells circulate from blood to lymphoid organs and back, and that the solid organs provide a favorable environment for dell division, and that this is in part mediated by CD38.

A number of recent studies have examined precisely what goes on in those proliferation centers, and how CD38 is involved.

It is well established that T and B lymphocytes talk to each other and the chief means by which they do this is through the CD40-CD40 ligand system. CD40 is present on all B cells and CD40 ligand (or CD154) is present on activated T cells.

A well known culture system for B cells is to lay them on a human fibroblast cell line which expresses CD154 and feed them the cytokine IL-4. A recent paper from Willimott et al demonstrates that when CLL cells are treated in a similar way it causes them to increase the amount of CD38 and in many cases also ZAP-70. This occurred in cases with both mutated and unmutated IgVH cells. The authors speculate that CLL cells visit the lymph nodes, spleen or bone marrow and there are stimulated by CD154 which increases the amount of CD38 and ZAP-70. Some lose these molecules after leaving the proliferation center but others retain them and those that lose them are the abnormal ones that don’t divide very well and snooze most of the time. These are the ones to have, and it occurs most commonly in those with mutated IgVH genes.

Another paper from Damle et al looks at a similar question. They separated CLL cells from individual patients into CD38+ and CD38- cohorts and examined them for markers associated with cell division: CD27, CD62L, CD69; or with entry into the cell cycle: Ki-67; or with signaling: ZAP-70; or with protection from apoptosis: telomerase and Bcl-2. In general these molecules marked the CD38+ cohort of cells, no matter whether it was large or small. But both positive and negative cells had telomeres of equal length, suggesting that they belong to the same population and have undergone a similar number of divisions.

Some years ago, Tom Kipps’ lab described what he called ‘nurse-like cells’. A subset of blood cells from patients with CLL spontaneously differentiates in vitro into large, round, or fibroblast-like adherent cells that display stromal cell markers, namely vimentin and STRO-1. These cells also express stromal cell-derived factor-1 (SDF-1), a CXC chemokine that ordinarily is secreted by marrow stromal cells (it is also known as CXCL12). Leukemia B cells attach to these blood-derived adherent cells, down-modulate their receptors for SDF-1 (CXCR4), and are protected from undergoing spontaneous apoptosis in vitro.

CLL cells certainly express CXCR4, but there is no difference in expression between those with mutated or unmutated IgVH genes. However, Deaglio et al have found that the attraction to SDF-1 is greater for CD38+/ZAP-70+ cells than for CD38-/ZAP-70- cells. This paper also demonstrates that when CD38 is stimulated it results in the phosphorylation of ZAP-70 (the effect is very transient, occurring for just 5 minutes, starting 5 minutes after the stimulation). Phosphorylation is just a means of measuring that a molecule has been activated, and it so happens that by noting which tyrosines (one of the amino acids in the protein chains) has accepted the phosphate group they can determine whether the phosphorylation leads to activation (as in this case) or inhibition. Patients that are ZAP-70 negative are unable to signal via CD38.

This is not the whole story about CLL cells homing to bone marrow and lymph nodes. Nurse-like cells also express B-cell activating faction of the TNF family (BAFF), a proliferation-inducing ligand (APRIL), plexin-B1 and the chemokine CXCL13 (also known as B-cell attracting chemokine 1 – BCA-1). Its receptor, CXCR5, is expressed by CLL cells

There has been controversy over the stability of CD38 ever since we reported cases where CD38 increased during the course of the disease. It is known that exposing CLL cells to IL-2 increases the amount of CD38 they express; this paper demonstrates that similar culture conditions increase the expression of ZAP-70, and other workers have reported that in about 10% of patients ZAP-70 expression rises during the course of the disease.

This is a very busy paper, because it also looks at the gene expression profile of CLL cells that express both CD38 and ZAP-70 and are attracted to SDF-1. Remember it was gene expression profiling that first identified ZAP-70 as the gene that most comprehensively differed in IgVH mutated and unmutated CLLs. This approach identified 24 genes separating the bad prognosis cases from the good prognosis cases. Four of these, ZAP-70, LPL, ADAM29 and SEPT10 were already known. Of the others two are involved in cell-cell contacts (CD86 and CD11a – as are ZAP-70 and ADAM29), two control cytoskeletal organization (BAMBI and SEPT10), five are involved in the control of lipid metabolism (LPL, ABCA9, BCAT1, LTF and PXDNL), two are involved in transcription regulation (L3MBTL4 and HIST2H2AB) and one is thought to be a tumor suppressor gene (PTCH1). The function of the remaining eight is unknown.

The way that CD38 results are expressed – as a percentage of cells staining positively is very dependent on where the zero is set and some workers have preferred to give results as mean fluorescence intensity. But neither method truly expresses what is seen in the laboratory. In most cases there is a mixture of positive and negative cells; sometimes there is a single population of cells that looks to have a gradation of staining intensity, but in others it looks like there are two distinct populations of cells, one being CD38+ and one CD38-. Paulo Ghia has called these cases bimodal. Chris Pepper in Cardiff has been looking at these populations for some time. At first he used to talk about these cells as ‘biclonal’ but in a recent paper he has separated the positive and negative cells with a cell sorter and shown that they are part of the same clone – their IgVH gene signature is the same. However, although part of the same clone, the CD38 positive and negative populations express different levels of certain gene products. In particular, levels of vascular endothelial growth factor (VEGF) and its receptor (VEGFR-2) were higher in CD38+ cells than in their negative counterparts in the same patient. These raised levels correlated with resistance to spontaneous apoptosis in the test tube, which could be reversed by a VEGF inhibitor, SU1498, but not by anti-VEGF antibodies, implying the use of an internal autocrine VEGF survival loop. However, CD38- cells did survive better when bathed in exogenous VEGF.

One possible mechanism for this was identified. Mcl-1 (a member of the Bcl-2 family) is known to be upregulated in CLL and is thought to be responsible in part for the anti-apoptotic effect. Mcl-1 was expressed in higher levels in CD38+ cells.

Pepper’s group gave us some more information at the IWCLL meeting. The CD38+ population had higher Ki67 expression (meaning that more cells were close to division) than the CD38- population. Was the positive population dividing more rapidly than the negative population? No, when they looked at telomere length (telomeres are the ends of the chromosomes that get bitten off with every cell division) they were similarly short in CD38 positive and negative cells and moreover the levels of telomerase were the same (which ensure that this wasn’t an artifact). This means that both positive and negative cells had been through the same number of cell divisions and to me implies that the cells are cycling; that they acquire CD38 in the proliferation center, but as they leave it they lose it. The longer it is since the cell left the proliferation center, the lower will be the CD38 level.

Further elucidation of this story came form Chiorazzi’s group at the IWCLL. They have extended their heavy water experiments to study the CD38+ and CD38- populations. They demonstrated that cells that were CD38+ and that expressed brighter CD5 were more likely to have recently proliferated than those with negative CD38 and rather dimmer CD5.

Finally, some beautiful pictures of the whole process were generated by Piers Patten from Kings and presented at IWCLL. Using confocal microscopy, he demonstrated higher levels of CD38 in bone marrow than blood and in white pulp of spleen rather than red pulp – these are places where proliferation centers are likely to occur. All cells tat were Ki67+ also expressed CD38 and CD23, and all proliferating CLL cells were in contact with CD4+CD25+FOXP3- T-cells. Proliferating CD38+ CLL cells surrounded CD31+ microvessels in close proximity to areas of T-cell infiltration. In an in vitro model, contact with a CD31+ endothelial cell line and activated autologous T-cells caused an upregulation of CD38 on the CLL cells and increased viability.

From thse recent studies on CD38 we begin to understand what is happening in CLL. What we see in the blood is a reflection of what is happening in the tissue. Cell proliferation takes place in proliferation centers in lymph nodes, spleen and bone marrow. In these centers stimulation by CD31 on endothelial cells and CD154 on T-cells activates the CLL cells, upregulating CD38 and perhaps ZAP-70. This has the effect of protecting the cell against apoptosis. From the proliferation center it is sent out into the circulation where activation markers begin to decline. There is probably something intrinsically different about some CLLs compared to others (probably related to the mutational status of the IgVH genes) because some cells seem to be better at retaining some activation markers than others. At any rate the CLL cells are drawn back into the tissues by chemokines and once there repeat the whole cycle. CD38 can be seen as an index of how recently the CLL cell has visited a proliferation center.

Getting rid of the poppy

When we committed troops to Afghanistan, one of the stated aims was the reduction of the poppy crop. It doesn't seem to have happened, indeed more opium is being produced than under the Taliban. Hidden in a written answer to a parliamentary question may be some of the reasons.

Kim Howells replied "Poppy eradication in Helmand Province is performed by Afghans in the Poppy Eradication Force (PEF) and in the Governor Led Eradication (GLE) forces. There are approximately 615 personnel in the PEF. Governor Wafa has not confirmed how many personnel he will commit to the GLE force this year."

"UK personnel do not conduct eradication, but do provide support to the planning and targeting work. Implementation of eradication is the responsibility of the Afghan Government. No eradication targets have been set for Helmand for 2008."

"The Government's main involvement in livelihoods diversification in Helmand is through the Department for International Development (DFID)—funded Helmand Agriculture and Rural Development Programme (HARDP). This is a three-year programme designed to increase the economic opportunities for rural poor people in Helmand, including those that make a living from growing poppy. Activities include construction of rural roads, wells and latrines; provision of legal credit; support for small-scale community development projects; and agricultural support. The overall target for the programme is to deliver improved livelihood opportunities for 590,000 people by the end of the third year."

"HARDP is managed by the four-person DFID Livelihoods team based in Kabul. Additional programme support is provided by the three-person DFID Helmand team which is split between Kabul and Lashkar Gah. However, actual implementation is carried out by the Ministry for Rural Rehabilitation and Development (MRRD), and by a number of non-governmental organisations working under the auspices of MRRD and the Ministry for Agriculture, Irrigation and Livestock."

Forgive my cynicism, but this sounds to me to be a means of subsidising the poppy crop rather than eradicating it. Easier credit for poppy growers and better roads to move their crop out, latrines for their workers and agricultural support. No wonder the crop is increasing. The HARDUP poppy growers have never had it so good.