Monday, May 28, 2007

The demands of the dead.

As a result of the recent pay negotiations family practice has become immeasurably more popular than hospital practice in the UK. Very bright young doctors are choosing to be trained as general practitioners, where they can look forward to being their own bosses, having no night calls, a day off in the week and the opportunity to refer-on difficult cases, rather than suffer the uncertainty of difficult examinations, chasing training jobs all over the country, remaining a 'junior' doctor until their mid-thirties and having the buck stop with them when the going gets tough.

Perhaps that is what the government intended when they negotiated a contract so favorable to GPs.

There have always been very good GPs but there have also been some shockers. I remember one family practice from my younger days of whom it was said by the senior surgeon, "One of them doesn't read letters and the other one can't."

Perhaps you remember the scene in one of the Richard Gordon "Doctor" films. A perennial medical student finds that his great aunt's legacy (which supported him as long as he remained a medical student) had run out. It became necessary for him to pass the exams and earn a living. Passing exams was not something he was awfully good at, so he decided to take one of the back-door entries to medicine that used to be available in the 1940s and 1950s. He decided to become a Licentiate of the Apothecaries of Cork. He travelled over to Ireland to take the examination and was met by an old man in a pony and trap with a straw in his mouth (played I think by Cyril Cusak). As they drove along the old Irishman began to question him. "What can you tell me about urea?"

"Do you mean the chemical substance or my lug-hole?" asked the ignorant medical student.

"Oh well, as long as you know the difference." said the examiner, satisfied.

And that was the examination passed. It is a calumny against the Irish, of course, but these two doctors really were Irish.

Another practice made great use of the domiciliary consultation. In those days specialists from the hospital would do house calls on difficult cases rather than fit them into an already over-booked out-patient clinic. This particular practice used to request more domiciliary visits than any other and used the service indiscriminately. So much so that the senior surgeon and the senior physician used to meet for coffee at a local hostelry to swap referrals.

When I was very young I used to moonlight in GP evening surgeries. In those days the £5 fee was important to my financial survival. I remember one evening surgery when I deputised for a big-wig in the British Medical Association. I believe he was a member of the Ethical Committee. Perhaps I should have been warned by that. One member of the Ethical Committee has since been convicted of murdering his wife and another was involved peripherally in sale of donated blood to a pharmaceutical company. Anyway, this particular surgery was a doddle. Nobody came. At least until the last minute when a young woman came in. I asked her name and she told me it was Pauline Collins. (I have changed her name because I can't remember what it was.) I fished out her records from his filing cabinet. "That's strange," I said, "according to this you are 104 years old."

We checked the name and address, which were obviously correct, but when I gave the date of birth the penny dropped. "That must be my grandmother. She had the same name as me, but she died in 1949. Why have you still got her records?"

Why, indeed. GPs were paid a capitation fee by the NHS for every patient on their list. They were supposed to send back all medical records or patients who had died. But what a wonderful scam to hold on to them. One way of ensuring very little work and plenty of pay. And plenty of time to sit on BMA committees. Dead patients make very few demands.

Sunday, May 27, 2007


In the nineteenth century answers to prayer were obvious. George Muller prayed for money to fund his orphanages and God provided it. He only had to ask God, and a local baker would feel moved to get up early and make extra loaves for the children's breakfast or a milk cart would break down outside his door and need to dispose of the milk before taking the cart to the cart wright for repair. Similarly. Barnardo and Spurgeon could be provided with money for their orphanages, Booth got support for his Salvation Army, CT Studd for Africans and Hudson Taylor for the Chinese. They all had stories to tell of miraculous answers to prayer. Where now is the God of Elijah? And of George Muller, William Booth, CH Spurgeon, Dr Barnardo, Lord Shaftesbury, William Wiberforce, James Hudson Taylor, JG Patton, William Carey and Dr Livingstone, the God who answers prayer?

In Mark Ch 11 we read of a God who moves mountains in answer to prayer. Where is that God?

The first instruction that Jesus gives is to have faith in God (v 22). The Jews had faith in the Temple. Jesus had just revoked Temple worship as a means of doing God's will. He had put an end to the old covenant and brought in the new, a covenant that was a direct relationship between God and man. Now he says don't put your faith in the Temple, put your faith directly in God.

We never really do that do we? I've told the story before of the man who falls over a cliff, but saves himself by clutching to a branch of a bush by the cliff edge. He cries for help, "Is anybody there?" and there comes a response from the sky "I will save you. Let go of the branch and my arms will bear you up."

"Who are you?"

"I am God. trust me and I will save you."

"Is there anybody else up there?"

The truth is that we would rather trust anyone but God. We trust in science, we trust in technology, we trust in ourselves.

It is only when we get to the end of our own resources that we begin to see miracles.

We should not have faith in prayer. It is not for our much praying or our eloquent prayers. Your heavenly father knows what you need before you ask. It is not how often or how long or how flowery are our prayers. It is the fact that we ask.

Why do we need to ask if God already knows are needs? Because he wants us to ask. As James says, "You receive not because you ask not".

We should not have faith in our faith. It is not those with the greatest faith that get answered. There should be no answer that goes, "You have not been answered because your faith is too weak".

But verse 25 tells us that we must also pray with a clean heart. We first need to forgive so that we may be forgiven. If we are harboring secret sins we won't be heard. Those secret sins may not be murder, theft or adultery. But resentment, bitterness, gossiping, unkind words, greed, covetousness, self-indulgence and back-biting.

I feel that some of us are past praying, or have gotten out of the habit, or have ritualised it, or have despaired of prayer. And some of us have been unwilling to give up something that we hold higher than God. And some of us are unwilling to accept God's answer.

Last week Liverpool played AC Milan for the Soccer Championship of Europe. There were Christians on both sides praying for victory. God's answer to one was yes and to the other no. It's the noes that we find hardest to accept; except when it's a yes to going to a Brazilian slum as a missionary. Those sorts of yeses are difficult too.

Saturday, May 26, 2007

Examining trainee doctors.

It's sad that the clinical part of the MRCPath (Haematology) exam has all but departed. It enabled examiner and examinee to engage in an enjoyable competition of exposing each other's ignorance. It was perhaps unfair of us to put up a case with cerebellar secondaries, but, in truth, the signs were so gross that even a haematologist could spot them. The intention tremor as she undid the buttons on her cardigan fair shook the building. I asked the candidate what tests he knew for demonstrating cerebellar dysfunction. He volunteered Romberg and dysdiadokokinesis. One tip for examiners is always to ask what the candidate does not suggest, so I requested a demonstration of the finger nose test. The idea here is to see if teh patient can move his finger back and forth between the doctors finger and his own nose. At first he did this very well, getting the patient to follow his moving finger with increasing inaccuracy and overshoot.

“Anything else?” I asked.

“Would you close your eyes, please?” The patient complied. “Now, touch your nose and then my finger.”

But instead of keeping his finger in the same place he proceeded to make it wander in a wide arc in front of the patient’s face. Of course with his eyes closed the patient had no idea wher the finger was.

“And what precisely are you testing now?” I enquired. “Extrasensory perception?”

In the same year my co-examiner introduced a patient as “one of our colleagues”. He was, in fact a local general practitioner with polycythaemia.

“Would you examine the abdomen?”

Now this candidate was behind on points, I had already asked her to exmine a patient's armpits. Shee had taken a very long time feeling for what she expected to be enlarged lymph nodes and found none, but she had forgotten to look before she felt and so had missed the black velvety rash of acanthosis nigricans. This time she was determined to leave nothing out. She drew back the sheet and stood staring at the man’s belly for fully sixty seconds. Then, with a sudden lunge, like an eagle swooping on its prey, she leaned forwards, grabbed the GP’s testicles and squeezed. Hard.

Thursday, May 24, 2007

Left behind

I have spent the afternoon hanging pictures in my daughter's new flat. I have always hated hanging pictures. However I do it, it seems impossible to get them straight, equally spaced and at the same level.

Part of the problem is that walls and ceilings and floors are never true. Also part of the problem is that however they are hung, the string or wire or picture hanger is behind the picture at a variable height so that you can't see where you are hanging it.

So all in all I am surprised that I deem the result a success despite the difficulties. It may not be perfect, but I could do no better.

Aiming for perfection is very laudable as long as you don't think you can attain it. I remember nearly 35 years ago treating a patient who had chronic myeloid leukemia that had transformed into acute myeloid leukemia. At the time I thought of myself as an expert in treating acute leukemia and I had just heard of a new regimen for blast crisis of CML. It was called TRAMPCOL, an eight drug regimen. I was gung ho for chemotherapy in those days and I felt sure that I could beat the disease.

Sure enough she went into complete remission. We had long conversations about how she would buy a caravan and go touring. She intended to see all those parts of England that she had never found the time for. She relapsed three weeks later.

I found the failure hard to take, but it was a lesson for me; I was not perfect nor was I a miracle worker. It's a lesson I need regularly to remind myself of.

Over the years I have accepted invitations to do things without recognizing that I would need time to prepare. I somehow thought I could get by on a wing and a prayer. It has resulted in my being over committed. I was afraid of saying no. I thought that if I refused I would never be asked again. The truth is just the opposite. Say yes too often and you are apt to get abused.

In the past couple of weeks I have had to say no. It brings a strange ennui upon one. It is compounded by the book I am reading at the moment, PD James' Children of Men.

I guess most people will know it by the movie, which I haven't seen. My daughter tells me it was terrible. The book, though, is rather good. It is very well written as one would expect with PD James, but the ideas, fantastic though they are, are those of an old woman nearing the end of her life.

You may know the plot. It is 25 years since a child has been born. For some unknown reason, the human race has become infertile. Consequently, there are no more schools, no more undergraduates, no more playgrounds, no more toys, no more perambulators, no more midwives or pediatricians. There are no more pedophiles; every silver lining comes wrapped in a dark cloud.

Without the hope of posterity things are running down. Soon there will be no-one but 80-year olds. No-one will keep the power stations going. There will be no-one to preserve the demented, to wash them, feed them, protect them. No-one will cut the grass.

It is a very depressing prospect, especially for someone contemplating retirement. I have been putting off finishing the book.

To build a house, to write a book, to father a son: a man will do these things to leave his mark on the world. Foolishness! Without a son no-one will read the books and the forest plants its own trees far more effectively than man. And sons leave their fathers behind. Only daughters remain in the end. They will inherit the house.

Trying, always trying; does it ever end? The only certain things are death and taxes, said Mark Twain (or was it Oscar Wilde?) Actually it was Benjamin Franklin. Franklin was given to bon mots. Time is money. Never a good war or a bad peace. What use is a new born child? For want of a nail a shoe was lost, etc. We must all hang together, or, most assuredly, we will certainly hang separately.

Sad to have your carefully thought out witticisms attributed to somebody else.

Sunday, May 20, 2007


Mark chapter 11 contains two stories that test the faith of believers and seem to be out of character for Jesus.

The first is the story of Jesus cursing the fig tree. It seems to be a fit of pique. The second is Jesus clearing the Temple of the moneychangers. This seems a strange act of violence from ‘gentle Jesus, meek and mild’.

How can we reconcile our vision of Jesus with these strange acts?

First we have to notice that they are linked. The story of the fig tree is wrapped around the story of the Temple clearing. The cursing comes first and the withering after.

Note that in Matthew’s gospel the cursing and withering both occur after the clearing and the withering occurs immediately. Luke doesn’t mention the fig tree at all, while John has the clearing much earlier in Jesus’ ministry – so perhaps this is a different occasion. Only Mark has the fig tree story wrapped around the Temple cleansing. This is a typical Marcan literary device; it tells us that the stories are related.

If they are related, what are they about?

The clue to this comes in the clearing story. Matthew, Mark and Luke all have the quotation, “a den of robbers”. I had always thought this to be a reference to the shady practices of the moneychangers and the sellers of sacrificial doves. In fact, in John’s Gospel, the Temple clearing has Jesus saying, “How dare you turn my Father’s house into a market?”

However, Mark has the “den of robbers” phrase, a direct quote from Jeremiah ch7 v 11. The context of the quote is Jeremiah preaching against false religion. He is complaining that the Israelites were trusting in deceptive words, “This is the Temple of the LORD, the Temple of the LORD, the Temple of the LORD.” He complains that they oppress the alien, the fatherless, the widow, and shed innocent blood, and follow other gods, that they steal, murder, commit adultery and perjury, burn incense to Baal and follow other gods and then come to the Temple and say, “We are safe – safe to do all these detestable things”. A den is not a market place, not a shop; it is a place of sanctuary, a hole to retreat into where you are completely safe. The Israelites were going to a place of safety that they weren’t entitled to. Like an ostrich who hides his head in the sand and thinks he can’t be seen because he can’t see anything.

In other words they are hypocrites; they pretend to be Holy and attend to the Temple rituals, but in their hearts they are evil and won’t change their ways. They are all show and no substance.

Just like the fig tree. Why should Jesus expect figs in April? Here we have to know some botany. Taqsh is an Arabic word that refers to an early crop of fig-like fruit on fig trees. Here’s a quotation from FF Bruce.

The problem is most satisfactorily cleared up in a discussion called "The Barren Fig Tree" published many years ago by W. M. Christie, a Church of Scotland minister in Palestine under the British mandatory regime. He pointed out first the time of year at which the incident is said to have occurred (if, as is probable, Jesus was crucified on April 6th, A.D. 30, the incident occurred during the first days of April). "Now," wrote Christie, "the facts connected with the fig tree are these. Toward the end of March the leaves begin to appear, and in about a week the foliage coating is complete. Coincident with this, and sometimes even before, there appears quite a crop of small knobs, not the real figs, but a kind of early forerunner. They grow to the size of green almonds, in which condition they are eaten by peasants and others when hungry. When they come to their own indefinite maturity they drop off." These precursors of the true fig are called taqsh in Palestinian Arabic. Their appearance is a harbinger of the fully formed appearance of the true fig some six weeks later. So, as Mark says, the time for figs had not yet come. But if the leaves appear without any taqsh, that is a sign that there will be no figs. Since Jesus found "nothing but leaves" - leaves without any taqsh- he knew that "it was an absolutely hopeless, fruitless fig tree" and said as much.

Just as the maple leaf is the symbol of Canada, the thistle of Scotland and the leak of Wales, so the fig tree is the symbol of Israel. Jesus was saying very plainly that Israel had not borne fruit. Just as judgment had come upon the fig tree so it had come on Israel.

How does this relate to the Temple? The Temple was the place of sacrifice. By overturning the tables of the moneychangers and the benches of those selling doves Jesus was stopping the sacrifices. There is a phrase in Mark that is not in the other Gospels. In verse 16 we have “and would not allow anyone to carry merchandise through the Temple courts.” Even those who had already bought their doves or had managed to find an unblemished lamb outside were prevented from sacrificing them.

There is another quotation from the Old Testament in this passage. “My house will be called a house of prayer for all nations.” It comes from Isaiah ch 56 v 7, but the principle enshrined there goes all the way back to Solomon’s prayer of dedication of the Temple in I Kings ch 8 v 41: Solomon is praying to the LORD “As for the foreigner who does not belong to your people Israel but has come from a distant land because of your name…when he comes and prays towards this Temple, then hear from heaven and do whatever the foreigner asks of you so that all the peoples of the earth may know your name and fear you as do your own people Israel.”

In Isaiah Ch 56 the prophet speaking on behalf of the LORD says, “Let no foreigner who has bound himself to the LORD say ‘the LORD will surely exclude me from his people’. Instead he says, “These I will bring to my holy mountain and give them joy in my house of prayer… for my house will be called a house of prayer for all nations.” And the Jews had set up a market place in the Court of the Gentiles.

The Jews were fruitless because they lived hypocritical, godless lives, but also because, instead of trying to lead the Gentiles to God, they had made the very ritual of the Temple a barrier to their coming to Him.

The response of Jesus was to curse Israel (= the fig tree) and to block the daily sacrifice. Symbolically he was putting an end to the old covenant and proclaiming a new one.

Day after day every priest stands and performs his religious duties; again and again he offers the same sacrifices, which can never take away sins. But when this priest – a priest for ever in the order of Melchizedek – has offered for all time one sacrifice for sins, he sat down at the right hand of God.

The time is coming declares the LORD when I will make a new covenant … it will not be like the old covenant… because they did not remain faithful to my covenant and I turned away from them.

This is the covenant I will make… I will put my laws in their mind and write them on their hearts, I will be their God and they will be my people … they will all know me … for I will forgive their wickedness and remember their sins no more..

By calling the covenant ‘new’ he made the first one obsolete; and whatever is obsolete and ageing will soon disappear.

The message was plain to his hearers. When the chief priests and the teachers of the law heard him speaking they began looking for a way to kill him for they feared him.

Little did they know that this was the very way that the new covenant would be brought in and all the paraphernalia of the law and sacrifice finished with.

Thursday, May 17, 2007


I have been relatively silent for the past week. Partly it I because I have been suffering and partly it is because I have been working. The work part has been rewriting the article that Professor Dighiero and I have been doing for the Lancet Oncology. It has ended up about 50% longer than it started in order to put in all teh detail that the referees wanted.

The suffering has been to do with my teeth. I thought I was going for a filling, but it turned out to be an extraction. The dentist dug away for an hour but left two roots behind that he couldn't remove. As a result I had to have emergency oral surgery at the weekend to have the roots removed. the whole thing has left me with a painful, swollen face.

Consequently, I have had to cancel my trip to Florence to attend the International MDS meeting this week.

To treat or not to treat: that is the question.

This is a point that confuses a lot of people so I need to spell it out clearly. It has become an accepted fact that the new treatments for CLL do not extend life. This is not what the trials show.

The first thing that they show is that delaying treatment until symptoms appear (or the other features indicated by the NCI guidelines) does not put a patient at risk compared to starting treatment at diagnosis. The caveat for this is that when the trial was done we had no way of distinguishing the patients who would never need treatment from those who would need it eventually and the best available treatment was chlorambucil. The trial that demands to be done now is to compare outcomes in patients with poor-risk prognostic markers looking at a treatment better able to produce complete remissions than chlorambucil compared with watch and wait. These trials are either under way or in late stages of planning, using FCR, FR or Campath as the more effective treatment.

The second thing that they show is that overall survival is not affected whether the first treatment is chlorambucil, fludarabine or FC. Certainly FC is more effective in terms of response rate, CR rate, molecular remission rate, and length of remission, but despite there having been three trials comparing F v FC and 7 trials comparing fludarabine and alkylating agents and 1 trial comparing chlorambucil and FC, none has shown any advantage for starting treatment with anything other than chlorambucil. This is because those who fail chlorambucil or relapse after chlorambucil can have a second bite of the cherry with fludarabine or FC.

Unfortunately, there are no randomized trials comparing FCR or FR with chlorambucil, though there is a trial comparing FC with FCR, but it is not yet mature enough to be analysed; we will have to wait until 2008 or 2009. It may be, as MDACC think, that everybody should be given FCR as first line, but honestly there are no data to justify this.

What the trials do not show is that patients who are left untreated do as well as those who are treated. Quite the contrary. They show that patients who achieve a remission, especially a CR, live longer than those who do not. Of course getting drugs and not responding probably shortens your life, so this is not a fair comparison. But we do know that most patients who receive chemotherapy get a response. Patients who meet the NCI guidelines and are not treated mostly run into severe problems that are frequently fatal.

There are suggestions that patients with CLL are living longer than they used to, but this observation is unreliable because we are diagnosing CLL at an earlier stage than we used to.

There are suggestions that some treatments make the serious complications of CLL like transformation, immunodeficiency and MDS more likely. This may be true, but a properly designed clinical trial will show this, and the bottom line is, "Do the patients live longer?"

At the moment I am sure that, overall and when necessary, treatment is better than no treatment, but how and when the treatment is given is still a matter for individual decision. The NCI guidelines are just that: guidelines, not regulations.

Thursday, May 10, 2007

Watching and waiting too long

There is no evidence that early treatment improves survival in CLL compared to watching and waiting until symptoms arrive. Because the potential side effects of the treatment are so worrying many patients are quite pleased when their doctor tells them that there is not treatment necessary at the present time. However, because treatment is so scary there is a great temptation to prolong the watching and waiting beyond the time when NCI guidelines suggest that treatment should begin. This can be dangerous.

The NCI guidelines should be interpreted sensibly. Fatigue, for example must be the sort of fatigue that disables; that prevents a patient from carrying out normal activities like going to work or managing the house work. It shouldn't be just the 'tired all the time' symptom that is the commonest reason for doing a blood test. Similarly night sweats should be out of the ordinary, not just what most of us get on a hot summer night. Similarly, one platelet count of 95 should not trigger a rush to treatment. Patients with enlarged spleens often have a slightly low platelet count and it doesn't necessarily mean treatment needs to start there and then. The platelet count needs to be falling progressively.

On the other hand patients are apt to let their spleens enlarge and their lymph nodes grow bigger and still put off treatment. The reason that this is dangerous is that it is much more difficult to treat bulky disease than less bulky disease. It is all a question of bone marrow reserve. The drugs used in CLL tend to cause pancytopenia. If they are given late in the disease they cause worse pancytopenia because more of the marrow has been replaced by CLL cells.

As with all things the right course in the treatment of CLL is a moderate one - between the two extremes.

Wednesday, May 09, 2007

One, ten, a hundred.

Sunderland greengrocer, Steve Thoburn died suddenly of a heart attack in 2004 aged 39. No, this is not a post about the dangers of vegetables. Steve was a metric martyr.

He was the victim of repeated prosecution by trading standards officers who objected to his selling bananas by the pound rather than the kilo. They even confiscated his scales, and several times brought him before the beak. I believe he even served time.

Today is a great day for those who love Imperial measurements. The European Commission announced yesterday that it had abandoned plans to force Britain to abolish Imperial measurements by 2009. EU trade and industry commissioner Gunter Verheugen declared that the marking of goods in imperial and metric would carry on indefinitely.

To my mind this drive towards the imposition of metric measurements derives from that tyrant Napoleon. As with other Napoleonic impositions, like driving on the right, government interference with the individual and the loss of ligatures from the English language (Noah Webster was a disciple of Napoleon), the metric system was a French plot to do down the English.

In a thousand years time this current period will be seen as the heyday of British hegemony. Of course, power has largely passed to a former colony, but their success has largely stemmed from their refusal to be cowed by government and their loyalty to Imperial measurements.

The French do a lot of things right, of course, wine and cheese, especially, but what the British and their former colonials have that allows them to triumph is that they are numerate. Our current areas of great success are all based on the ability to calculate rapidly. Take the London Stock Exchange: it is largely staffed by young men disparagingly called 'barrow boys', men like Steve Thoburn, men who can calculate the price of a pound of bananas in pounds shillings and pence. These are men whose minds are not trapped withing the prison of ten, but who can calculate with base 3 or 4 or 8 or 9 or 12 or 14 or 16 or 20 or 22.

Cricket pitches are one tenth of a furlong (or a chain) long. Unlike Rugby, which has changed the 25 to a 22 to accommodate the metre, cricket has remained true to the Empire. But then the French don't play cricket. (And that's probably the source of the problem.)

I was cheered to see Nicolas Sarkozy as French President. The French have been such lackluster economic performers recently that there has really been no decent competition. I hope that Sarkozy will be able to convince Frenchmen of the value of hard work. When they put their minds to it Frenchmen perform with style, but I fear that their warm climate and pleasant countryside make it too easy for Frenchmen to relax.

I am reminded of an old "Yes, Prime Minister" episode where Jim Hacker wanted to get rid of our nuclear deterrent. "Can you really believe that we would ever bomb Russia?" he asked the generals. And of course we would never bomb Russia or even Iran. The whole, complete and only reason that the British have a nuclear bomb is because the French have one.

Tuesday, May 08, 2007

Why should I get my prognostic markers done?

I think that this is a genuine dilemma for patients with CLL. In one sense whether you know what your prognostic markers say or not is not going to affect the rate of progression of your disease. Your disease will either progress or not, and when and if it does progress there is time enough to consider treatment, but until it does you might as well forget about it. Undoubtedly, some patients are able to put it out of their minds. On the other hand some patients are happier if they can know all there is to know about their disease, be it good news or bad.

Let's go back to the beginning. Before the prognostic markers came along patients were classified according to stage. The Rai system was used in America and the Binet system in Europe. Although they are largely interchangeable there are important differences. Rai stage 0 consists of patients who just have a lymphocytosis. Their lymph nodes are not enlarged and their liver and spleen cannot be felt on clinical examination. They also have normal or near normal hemoglobin and platelet levels. Although such patients are mostly benign, hidden among them are patients who have been picked up early in their disease and within a few weeks will have progressed to stage III or IV, and some who have enlarged lymph nodes, liver or spleen, but they cannot be felt on clinical examination although they would be revealed by a CT. The most benign Binet group, stage A, does allow enlargement of liver, spleen or lymph nodes, but only in 2 of the five possible areas (neck, armpit, groin, spleen or liver). More than this they are stage B. Rai Stage I or II overlaps with Binet stage B, but also contain some patients who are Binet stage A (with enlargement in fewer than 3 areas). So Rai stage 0 is mainly benign, but includes some early stage aggressive diseases. Binet stage A is similar though it contains rather more early stage aggressive diseases. Rai I or II are regarded as an intermediate stage, as is Binet B, but some of these are late stage non-aggressive disease. Someone with 1cm lymph nodes in groin, armpit and neck would be Binet stage B yet may have a very benign disease.

You would think that having anemia or thrombocytopenia (Binet C or Rai III and IV) would automatically be bad news, but this is only true if the cytopenias are due to heavy marrow infiltration. They could be due to an enlarged spleen or to autoimmunity.

In fact most new patients (around 80%) have Binet stage A disease, so these staging systems that have been around since the 1970s are increasingly less helpful for treatment decisions.

Oncologists have known about this for a long time and have been looking for something better. Two of the most relied upon are bone marrow biopsy and lymphocyte doubling time.

Bone marrow biopsy is unnecessary for diagnosis. It is useful to distinguish the cause of a cytopenia - diffuse infiltration implies that this is the cause, and compared to any other pattern it is a poor prognostic feature. Bone marrow biopsy can help with prognosis, and in the context of a clinical trial can be used before and after treatment to assess response, though these days tests for minimal residual disease give more information. But it can be a painful investigation and it is not cheap. Its use as a prognostic indicator could easily be replaced by a better test.

Lymphocyte doubling time is a simple and cheap test that just needs regular CBCs. But it has its drawbacks. You need several tests showing an upward trend. The tests have to be done at the same lab, because of inter-lab variation. Allowance has to be made for infection or vaccination and other things that can transiently raise the lymphocyte count. The increase has to be measured on a meaningful part of the curve. An increase from 4 to 8 is not significant, while an increase from 40 to 80 probably is.

Other tests like the measurement of serum LDH or beta-2 microglobulin have their advocates, but they are often difficult to interpret. Both these and other substances (like CD23, thrombopoietin, IL-8 etc) are made by CLL cells, so measuring how much there is, is dependent on how many CLL cells there are and how quickly they are growing. You can get the same result from a large slow growing tumor or a small rapidly-growing tumor. They are also affected by how well the kidneys work in excreting the surplus.

At this time CLL was regarded as a continuum. We didn't know when it started - it was diagnosed at an arbritary time during its progression and its rate of progression was a closed book. Any patient could suddenly change from being stable to progressive, and all patients needed to be watched carefully for when that happened.

In this context the two papers that appeared in Blood in 1999 (Hamblin et al and Damle et al) were remarkable. They appeared to say that CLL was not really a continuum, but there were two different types, one relatively benign and one relatively aggressive, determined by something set in stone, the kind of cell that the leukemia had developed from. If you were benign from the beginning, you remained benign. If you were aggressive now, you had always been aggressive. Far from being a marker of prognosis, to know your VH gene mutational status was part of the diagnostic procedure; did you have this type of CLL or that type? It was as important as knowing whether you had follicular lymphoma or diffuse large cell lymphoma.

As time has passed, we have learned that things are more complicated than that. In 2000 Dohner et al published in New England Journal of Medicine how the FISH test for chromosomal abnormalities could be used as a prognostic factor. In a sense this was 10 year old news. In 1990 Juliusson et al had published in New England Journal of Medicine about the importance of chromosomal abnormalities. The problem at that time was the technique of karyotyping was unsuccessful in most laboratories. (In fact most of the patients in this paper came from our series; although we are able to detect an abnormal karyotype in about 90% of patients where one is present, only one other laboratory can match this, and most have results of around 40%). FISH testing allowed laboratories to detect thye 4 commonest chromosomal abnormalities (trisomy 12 and deletions on chromosomes 11, 13 and 17) easily and reproducibly.

The Dohner lab have demonstrated that del 17p is particularly evil. Patients who have this had (in 2000) an average survival of 2 and a half years. This is because they lack one copy of the p53 gene, and lacking this the cells are not protected from further genetic damage. Fortunately, only about 5% of patients have this deletion at presentation. Not quite as bad, but still worse than just having unmutated VH genes, is having del 11q. This implies a lack of one copy of the ATM gene. (ATM stands for 'ataxia telangectasis mutated'. It is the gene that is mutated in the rare congenital disease ataxia telangectasia). The ATM gene is part of the same biochemical pathway as p53. The reason we think it isn't as bad as a p53 deletion is that you need both ATM genes to be knocked out to lose its function in the cell, whereas knocking out just one p53 gene is sufficient. Preliminary work by Tanya Stankovic in Birmingham suggests that this is so. About 15-20% of CLL patients have del 11q at presentation. Del 11q is almost always associated with unmutated VH genes, del 17p usually so.

FISH testing is very useful, but it misses all the less common abnormalities and especially missed translocations. Ideally I would have both FISH and conventional karyotyping, but at the moment conventional karyotyping is only reliable in about two laboratories in the world.

CD38 and ZAP-70 started out as quick and easy ways to get the same information as the VH gene mutations, but both have proved to be unsatisfactory surrogates. CD38 proved to be an independent prognostic factor but if VH genes and FISH were both done CD38 added nothing extra. ZAP-70 is unsatisfactory because there isn't a standardised assay. With some laboratories it doesn't differ very much from VH genes, but the assay done at Tom Kipps lab actually seems to be a better predictor than VH genes. This is the one that commercial labs have tried to copy, but in commercial hands it is much less successful and gives unreliable results.

Until recently the evaluation of prognostic factors has been retrospective. They were tested on samples that were sometimes more than 20 years old from patients who were treated in many different ways, often suboptimally. However since 1999 the tests have been applied in many prospective trials to see how they perform when patients are given standard treatments. So how do they do?

The most important finding has been for FISH for del 17p. These patients do uniformly badly in clinical trials. In particular patients who fail the fludarabine + cyclophosphamide combination have a very poor survival. One of the commonest causes for this is p53 deletion. It is not the only reason. P53 function can be abnormal in the presence of a normal chromosome 17, and what is needed is a functional test of p53. Andy Pettitt at Liverpool has developed one of these and it is a good candidate for being evaluated in the next round of clinical trials. In the meantime it seems foolhardy to begin conventional treatment without doing the FISH test. The 5% with del 17p should be treated in a different way. Treatments that may be effective in p53 deficient CLL include high dose steroids, Campath, flavopiridol, revlimid and allograft. This is important for patients receiving their first treatment, but even more so for patients receiving subsequent treatments. As many as 30% of patients in clinical trials eventually develop p53 abnormalities.

For del 11q the picture isn't so clear. In some clinical trials it is an independent adverse predictive factor while in others it doesn't show, disappearing into the adverse effect of unmutated VH genes. In general the response rate is the same as with other treated cased, but respopnses appear to be shorter. At the moment there is no justification for offering a different treatment from that given to other unmutated cases.

In most trials unmutated VH genes seems to be an independent adverse factor. Overall survival is better for those with mutated VH genes who receive the same treatment. It seems to me that these is justification for stratifying treatment according to VH gene mutations. I envision trials comparing standard treatment with something less aggressive for those with mutated VH genes and standard treatment versus something more aggrtessive for those with unmutated VH genes.

What about doing these tests at presentation? I still think that this is a matter of patient choice. It is important to remember that the median is not the message. Median survival is simply the time at which half the patients are alive and half are dead. Obviously if 0% are dead at two years, 50% dead at three years and 100% dead at four years, the median is very important, but if the first death occurs at 1 year, the last death at 30 years and the 50% cut off is at 15 years, then the median survival figure is not much use to the individual patient who might die this year or in 30 years time.

VH genes are a bit better than that. In a clinical trial the difference in survival after treatment at 5 years between patients with mutated and unmutated VH genes was 16%. But added to that is the fact that around half of the patients with mutated VH genes never need any treatment whereas nearly all those with unmutated VH genes do.

I recently studied 150 patients with Binet stage A disease whose lymphocyte count was less than 30. 50 had poor prognostic markers and all of them needed treatment. All had eventually died of their CLL even though one of them lived beyond 20 years. On the other hand 100 had good prognostic markers. Only 10% ever needed treatment and none have died of CLL so far. In this case the best single marker at predicting the future was CD38 with a 30% cut off.

As I said, some patients relish this sort of information; some disdain it. I am not going to judge between them. However, I think that everybody should be able to access it if they want it.

Monday, May 07, 2007


I somehow the missed the news of the atrocity in Turkey on April 18th. An event took place in Malatya, a Turkish province 300 miles northeast of Antioch, the city where believers were first called Christians. Ten young men all under 20 years old put into place final arrangements for their ultimate act of faith, living out their love for Allah and hatred of infidels who they felt undermined Islam. The young men got guns, bread knives, ropes and towels ready for their final act of service to Allah. They knew there would be a lot of blood.

On that Wednesday morning a 46 year old German missionary and father of three, Tilman Geske, prepared to go to his office, kissing his wife goodbye taking a moment to hug his son and give him the priceless memory, “Goodbye, son. I love you.”

Tilman rented an office space from Zirve Publishing where he was preparing notes for the new Turkish Study Bible. Zirve was also the location of the Malatya Evangelist Church office. In another area of town, 35 year old Pastor Necati Aydin, father of two, said goodbye to his wife, leaving for the office as well. They had a morning Bible Study and prayer meeting that some other believers in town would also be attending. Ugur Yuksel likewise made his way to the Bible study.

The ten Muslim young men arrived in time for the Bible Study, around 10 o’clock and the Bible study started. After Necati read a chapter from the Bible the assault began. The boys tied Ugur, Necati, and Tilman’s hands and feet to chairs and as they videoed their work on their cellphones, they tortured the Christians for almost three hours.

Tilman was stabbed 156 times, Necati 99 times and Ugur’s stabs were too numerous to count. They were disemboweled, and their intestines sliced up in front of their eyes. They were emasculated and watched as those body parts were destroyed. Fingers were chopped off, their noses and mouths and anuses were sliced open. Possibly the worst part was watching as their brothers were likewise tortured. Finally, their throats were sliced from ear to ear, heads practically decapitated.

Another Christian came to the Bible study but was unable to get in. When he heard strange noises from the room, he phoned the police, and the nearest officer arrived in about five minutes. He pounded on the door, “Police, open up!” Initially the officer thought it was a domestic disturbance. At that point they heard another snarl and a gurgling moan. The police understood that sound as human suffering, prepared the clip in his gun and tried over and over again to burst through the door. One of the frightened assailants unlocked the door for the policeman, who entered to find a grisly scene.

Three assailants in front of the policeman dropped their weapons. Meanwhile there was a sound of yelling in the street. Someone had fallen from their third story office. Running down, they found a man on the ground named Emre Gunaydin. He had massive head trauma. He had tried to climb down the drainpipe to escape, and losing his balance had plummeted to the ground. It seems that he was the main leader of the attackers. Another assailant was found hiding on a lower balcony.

The young men involved in the killing are currently in custody. Today news reported that they would be tried as terrorists, so their age would not affect the strict penalty. Assailant Emre Gunaydin is still in intensive care.

When Susanne Tilman expressed her wish to bury her husband in Malatya, the Governor tried to stop it, and when he realized he could not stop it, a rumor was spread that “it is a sin to dig a grave for a Christian.” In the end the men from the church in Adana (near Tarsus), grabbed shovels and dug a grave for their slain brother in an un-tended hundred year old Armenian graveyard. In an act that hit front pages in the largest newspapers in Turkey, Susanne Tilman in a television interview expressed her forgiveness. She did not want revenge, she told reporters. “Oh God, forgive them for they know not what they do,” she said,

In a country where blood-for-blood revenge is as normal as breathing, many many reports have come to the attention of the church of how this comment of Susanne Tilman has changed lives. One columnist wrote of her comment, “She said in one sentence what 1000 missionaries in 1000 years could never do.”

I have been thinking a lot about forgiveness lately. In another news item Lord Tebbitt was invited on to a radio program to commemorate the Brighton bombing. This happened nearly 23 years ago at the height if the Irish troubles. An IRA bomber planted a bomb at the headquarters hotel at the Tory party conference, killing sveral prominent conservative politicians and maiming several others. Margaret Thatcher was fortunate to escape with her life. Normal Tebbitt's wife was paralysed from the neck down. The bomber was Patrick Magee who was sentenced to 35 years in prison, but was released early in 1999 under the Good Friday agreement.

Tebbitt refused to appear on the radio program because Magee had also been invited to appear. How could Tebbitt be expected to forgive the man who had condemned his wife to be bed-ridden for the past 22 and a half years?

Late at night last week I listened to a sermon preached in London last year by RT Kendall. He preached on Genesis chapter 45, the story of Joseph, sold into slavery by his brothers. Yet when he finally confronts his brothers in Egypt he does not condemn them. RT related a story of how he had been terribly hurt by some people at Westminster Chapel, where he was pastor. Not knowing what to do he told the story to Romanian pastor Joseph Ton.

Ton told him, "RT, you must forgive them."

"But you don't realise how badly they have hurt me."

"RT, you must forgive them."

"Perhaps, if they came an apologised and asked forgiveness, I might be able to forgive them."

"RT, you must forgive them anyway. They may not even know that they have hurt you. You need to forgive them, not for their sake, but for your sake. Until you forgive them, your ministry will be worthless."

So RT forgave them and immdiately a great load lifted from his life.

Joseph forgave his brothers. He did it secretly (v 1) so that the brothers' crime was not broadcast (and neither was Joseph's generosity).

He did it gently, so as not to raise feelings of guilt or shame (v 5).

He did it forgetfully. He asked them to bring their father down to Egypt and gave them the very words to say to him so that they would not incriminate themselves (v9). There is a wonderful verse in I Corinthians ch 13 v5. "Love keeps no record of wrongs".

Forgiveness is terribly hard. Evil men deserve punishment. Those who love justice are outraged when the guilty go free. Why should we forgive?

Only because we have been forgiven much more than we are being asked to forgive. While we were still in our sin, Christ died for us. It is not our business to punish sinners. "Vengeance is mine," says the Lord,"I will repay."

When we think of the story of Jonah, don't we think Jonah is being churlish when he gives as his reason for not going to Nineveh the fact that God is likely to forgive them and Jonah doen't want them forgiven? But aren't we like that. There is joy in heaven over one sinner that repents, but how do we feel ifthat one sinner is someone who has sinned against us, and now isn't going to burn in Hell fire like we think he ought to? What about those who think we ought to burn in Hell fire?

We think we want justice, but we don't want justice for ourselves; we want mercy.

We forgive because the love of Christ compels us.

Friday, May 04, 2007


One of the reasons that the NATO forces are in Afghanistan is to reduce the production of opium. Afghanistan is the major supplier of illegal heroin. These figures from a written parliamentary answer from the British Foreign Office therefore make interesting reading.

The United Nations Office on Drugs and Crime's 2005 Afghanistan Opium Survey reported that 109,103 hectares of land was used to cultivate opium poppy in 2005, of which 5,103 hectares was eradicated. Their 2006 Afghanistan Opium Survey reported that 180,300 hectares of land was used to cultivate opium poppy in 2006, of which 15,300 hectares was eradicated.

Thursday, May 03, 2007

What I have been reading

For a long time I got stuck on the Historian by Elizabeth Kostova. This is a doorstep of a book about three generations seeking the grave of Dracula. It sounds trashy, but it's not. Kostova grounds the narrative in excellent historical research and has a fine sense of place and time. She is particularly good at behind the iron curtain stuff in the height of the cold war. There are three love stories here intermingled with quite graphic terror and the inevitable supernatural seems quite believable in the primitive village communities in Romania, Bulgaria and Turkey. I was put off from reading it by the Stoker stuff, but I'm glad I persevered.

Before that I read the Righteous Men by Sam Bourne. This is an unusual thriller set amongst the Hascidic comminity on the lower east side of New York. A bit of a puzzle book like Da Vinci Code, but much better written. It doesn't rattle along at Da Vinci pace, but all the better for that.

Then the latest two episodes of the Bernard Cornwell King Alfred series. Sharpe a thousand years before his time if you like, but a rattling good read.

The other nine

One in ten Christians live with persecution. What is the responsibility of the other nine?

You live in daily fear of violence, kidnap, rape or even death: up to 350,000 Iraqi Christians have fled their homes since 2003. Al-Qaeda says << We will destroy the cross... then all that will be accepted will be conversion or the sword>>

Talking to a non-Christian friend about Jesus could land you in jail: a possibility in countries like Malaysia, Morocco and Uzbekistan.

You live in utter poverty, trapped in a system which limits your opportunity to break free: Christians in Pakistan and India are often forced to live as bonded laborers unable to pay off the loan which desperation made them take from their employers. Bonded labor is often a euphemism for slavery.

You carry a social stigma that affects what job you can get or how your children are treated in school: in as many as 60 countries some Christian children are discriminated against within the education system because of their faith. This can mean they fail their exams or are forced to change their name to one that sounds Islamic.

The police are not interested in protecting you, and may even arrest you even though you are the victim: although there are places where the police will protect minority groups, too often calls for help are ignored if they come from Christians.

Under Shari'a your testimony is worth less than that of a Muslim: thus victim's are not believed and opressors escape blame.

What can we privileged Christians do? Find out here.

Tuesday, May 01, 2007

taqiyya 2

A good example of Muslim dissembling occurred during the recent war between Lebanon and Israel. Most of the world's press labelled Israel as the aggressor, whereas it was Hezbollah who began it. In Israel the press were allowed a fairly free rein, but Hezbollah tightly controlled information, and frankly lied. As I said yesterday a Muslim is allowed to lie in war.

An open society, Israel, is victimized by its own openness," Marvin Kalb and Dr. Carol Saivetz of the Shorenstein Center of Harvard University concluded in their research paper, "The Israeli-Hezbollah War of 2006: The Media as a Weapon in Asymmetrical Conflict"

In the Second Lebanon War, Hezbollah limited access to Western reporters, "orchestrated" events and manipulated journalists with threats of expulsion if they violated its reporting rules. And the press largely complied with the restrictions that were "reminiscent of the Soviet era," Kalb and Saivetz found.

In one example cited by the paper, on a tour of a Shi'ite neighborhood of Beirut damaged by IAF air strikes, Hezbollah warned reporters not to "wander off on their own or speak to residents" and to photograph only approved sights. If the press violated these rules, "cameras would be confiscated, film or tape destroyed, and offending reporters would never be allowed access to Hezbollah officials or Hezbollah-controlled areas."

At one point, apparently on cue, a Hezbollah minder signaled for ambulances to rev up their engines, set off their sirens and drive noisily down the street. The scene was orchestrated, designed to provide a photo op, and reporters went along for the ride."

On August 3, Human Rights Watch specifically accused Israel of war crimes. Few seemed to note that before the war, on May 27, Nasrallah had actually—and publicly—embraced the guerrilla tactic of hiding soldiers among civilians. “[Hezbollah fighters] live in their houses, in their schools, in their churches, in their fields, in their farms and in their factories,” he said, adding, “You can’t destroy them in the same way you would destroy an army.”

Israel defended its military operations by citing two relevant articles in international law: using civilians for military cover was a war crime, and any target with soldiers hiding among civilians was considered a legitimate military target. Israel’s defense, though, fell on deaf ears, not only among diplomats but also reporters, as daily evidence mounted of civilian deaths.

The paper is too long to summarize. I have given the link; click on it and make up your own mind.

You might ask how could the world's press be so gullible? They have come to expect Western politicians to routinely lie to them, surely they should be more skeptical? I guess the answer is that they always tend to favor the underdog. But they should learn the lesson of taqiyya. In war it is regarded as correct for a Muslim to tell lies.

Here are a few well known lies propagated as Islamized knowledge:

Napoleon Bonaparte converted to Islam.
Muslim explorers reached America before Christopher Columbus.
Islam arrived in Australia in the 9th century.
Offa, the 8th century Anglo-Saxon king of Mercia (famous for Offa's Dyke which kept the Welsh out of the British Midlands) was a Muslim.
Women are equal to men in Islam.

This last is often said when Westerners insist that Islam is anti-woman. Yet under Shari'a women receive a smaller inheritance and less compensation for injuries than men and their worth as a witness in atrial is less than that of a male witness. The rules for divorce are biased against women. In most Muslim countries women suffer from second rate status, are more likely to be illiterate and are treated unfairly in divorce and other legal proceedings.