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.
Sunday, May 20, 2007
Thursday, May 17, 2007
Silence
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.
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.
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.
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.
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.
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
Forgiveness
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.
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
Poppies
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.
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.
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.
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.
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.
Monday, April 30, 2007
taqiyya
This strange word is an anglicization of an Arabic word, meaning dissimulation (which is a long word meaning telling lies). I got it from a publication I have just received from The Barnabus Fund. Patrick Sookhdeo, the Director, is a Pakistani who has converted from Islam to Christianity.
Lying in Islam appears to be an anomaly. One of the 99 names of Allah is 'al-Haqq' meaning 'the reality, the supreme truth'. In the Qur'an truth is commended and lies condemned. How is it that anyone can suggest that Muslims tell lie?
The doctrine of taqiyya developed from a time of religious persecution where Muslims could save their lives by concealing their true beliefs. I don't think that there is any obligation on an honorable man to tell the truth to tyrants. Thus, we would commend those brave souls who concealed allied airmen from the SS in the second world war. In the Bible Moses concealed from Pharoah his true purpose of leading the Israelites out of Egypt. Neither the SS nor Pharoah deserved to be told the truth.
All well and good, but in Islam that principle has been extended so that it seems that Muslims can hardly be trusted by Christians and Jews to keep their word - the possiblity of taqiyya always exists. Obviously some Muslims are honorable men, but if many Muslims conceal the truth from Christians and Jews those many jeopardize the integrity of the many who are honest. As Hamid Enayat, a Muslim historian who was a Fellow of St Anthony's College Oxford states, "Taqiyya has in practice become the norm in public behaviour among all Muslims - both Sunni and Shi'a - whenever there is a conflict between faith and expediency."
The devlopment of the doctrine was as a cloak of protection for the Shi'a minority who passed themselves off as Sunnis to protect themselves from harm. Muslim's interpret the Qur'an to say that they have a duty to save life, honor and property from danger and unlawful destruction whenever possible, even if this means dissimulation. This runs to pretended friendship with non-Muslims, a practice condemned by the Qur'an, "Let not the believers take for friends or helpers Unbelievers rather than Believers; if any do that, in nothing will there be help from God:" but there is a get out clause as it continues, "except by way of precaution that ye might guard yourselves from them." In other words pretend to be their friend as a precaution against their harming you.
A famous Hadith (A Hadith was originally an oral tradition relevant to the actions and customs of the Prophet. They are meant to be a secondary source of Islam with the primary source being the Quran.) says, "Lying is allowed in only three cases: falsehood spoken by a man to his wife to please her, falsehood in war, and falsehood to put things right between people." (Al-Tirmidhi #5033: narrated by Asma', daughter of Yazid).
The doctrine of taqiyya is there to defend Islam against its perceived enemies. As a conequence, much of what is said publicly by Muslim's to non-Muslims is likely to be untrue. For example, Hamid Ali, spiritual leader of the Al-Madina mosque in West Yorkshire publicly condemned the 7/7 bombings in London 2005. But in coversation with a Bagladeshi-born undercover reporter of the Sunday Times he said that the 7/7 bombings were a 'good act' and praised the bombers.
This is a quote from Sheikh 'Abdul Rahman 'Abdul Khaliq, a Saudi Salafi scholar taliking about peace treaties made with Israel.
"The first duty is to firmly believe in their invalidity and becuse they contain invalid conditions they were born deadthe very day they were given birth to...
The second duty of the Muslim is to believe that those treaties do not bind him and that it is not lawful for hime to give effect to any of their contents except under compulsion and necessity...
The third duty is to work towards overthrowing these treaties..."
While many Muslims are honest and open in their dealings with non-Muslims the possiblity of taqiyya makes it difficult for non-Muslims to assess the relability of statements made by Muslims to them, says Sookhdeo, it si easier to be sure of what Muslims really think by checking what they say to each other and by what they do.
Lying in Islam appears to be an anomaly. One of the 99 names of Allah is 'al-Haqq' meaning 'the reality, the supreme truth'. In the Qur'an truth is commended and lies condemned. How is it that anyone can suggest that Muslims tell lie?
The doctrine of taqiyya developed from a time of religious persecution where Muslims could save their lives by concealing their true beliefs. I don't think that there is any obligation on an honorable man to tell the truth to tyrants. Thus, we would commend those brave souls who concealed allied airmen from the SS in the second world war. In the Bible Moses concealed from Pharoah his true purpose of leading the Israelites out of Egypt. Neither the SS nor Pharoah deserved to be told the truth.
All well and good, but in Islam that principle has been extended so that it seems that Muslims can hardly be trusted by Christians and Jews to keep their word - the possiblity of taqiyya always exists. Obviously some Muslims are honorable men, but if many Muslims conceal the truth from Christians and Jews those many jeopardize the integrity of the many who are honest. As Hamid Enayat, a Muslim historian who was a Fellow of St Anthony's College Oxford states, "Taqiyya has in practice become the norm in public behaviour among all Muslims - both Sunni and Shi'a - whenever there is a conflict between faith and expediency."
The devlopment of the doctrine was as a cloak of protection for the Shi'a minority who passed themselves off as Sunnis to protect themselves from harm. Muslim's interpret the Qur'an to say that they have a duty to save life, honor and property from danger and unlawful destruction whenever possible, even if this means dissimulation. This runs to pretended friendship with non-Muslims, a practice condemned by the Qur'an, "Let not the believers take for friends or helpers Unbelievers rather than Believers; if any do that, in nothing will there be help from God:" but there is a get out clause as it continues, "except by way of precaution that ye might guard yourselves from them." In other words pretend to be their friend as a precaution against their harming you.
A famous Hadith (A Hadith was originally an oral tradition relevant to the actions and customs of the Prophet. They are meant to be a secondary source of Islam with the primary source being the Quran.) says, "Lying is allowed in only three cases: falsehood spoken by a man to his wife to please her, falsehood in war, and falsehood to put things right between people." (Al-Tirmidhi #5033: narrated by Asma', daughter of Yazid).
The doctrine of taqiyya is there to defend Islam against its perceived enemies. As a conequence, much of what is said publicly by Muslim's to non-Muslims is likely to be untrue. For example, Hamid Ali, spiritual leader of the Al-Madina mosque in West Yorkshire publicly condemned the 7/7 bombings in London 2005. But in coversation with a Bagladeshi-born undercover reporter of the Sunday Times he said that the 7/7 bombings were a 'good act' and praised the bombers.
This is a quote from Sheikh 'Abdul Rahman 'Abdul Khaliq, a Saudi Salafi scholar taliking about peace treaties made with Israel.
"The first duty is to firmly believe in their invalidity and becuse they contain invalid conditions they were born deadthe very day they were given birth to...
The second duty of the Muslim is to believe that those treaties do not bind him and that it is not lawful for hime to give effect to any of their contents except under compulsion and necessity...
The third duty is to work towards overthrowing these treaties..."
While many Muslims are honest and open in their dealings with non-Muslims the possiblity of taqiyya makes it difficult for non-Muslims to assess the relability of statements made by Muslims to them, says Sookhdeo, it si easier to be sure of what Muslims really think by checking what they say to each other and by what they do.
Saturday, April 28, 2007
Retirement looms
After my illness in Canada I have decided to reassess what I am doing. As I was being driven to the hospital by Dr Ronan Foley I said to him, "If someone told me I was going to die tonight, I would say, 'Bring it on; I don't want to suffer any longer'".
Of course, I wasn't anywhere near dying, just in a lot of pain, but it made me think what I was doing with my life.
I am 64 and the normal retirement age is 65. My contract with the University ends in September 2008, and I think that will be time to call it a day. The weather has been beautiful today and the garden marvelous. I think I have done my stint and I ought to take time to be with my wife, enjoying things together. In a few weeks we will have been married 40 years. In that time we will have taken just 24 vacations together, and some of those have really been just long weekends.
As the man says, nobody looks back and says, "I wish I'd spent more time at the office."
I semi-retired four years ago; this time there will be nothing semi- about it. Before I go I have set myself three tasks. I will publish a paper explaining why 98% homology rather than 97% homology is better for the VH gene mutation cut-off. I will finish a book I am writing on CLL for doctors. I will write a book on CLL for patients.
There are other things in my life to do. I should hate someone to write that CLL was all of his life on my obituary.
Of course, I wasn't anywhere near dying, just in a lot of pain, but it made me think what I was doing with my life.
I am 64 and the normal retirement age is 65. My contract with the University ends in September 2008, and I think that will be time to call it a day. The weather has been beautiful today and the garden marvelous. I think I have done my stint and I ought to take time to be with my wife, enjoying things together. In a few weeks we will have been married 40 years. In that time we will have taken just 24 vacations together, and some of those have really been just long weekends.
As the man says, nobody looks back and says, "I wish I'd spent more time at the office."
I semi-retired four years ago; this time there will be nothing semi- about it. Before I go I have set myself three tasks. I will publish a paper explaining why 98% homology rather than 97% homology is better for the VH gene mutation cut-off. I will finish a book I am writing on CLL for doctors. I will write a book on CLL for patients.
There are other things in my life to do. I should hate someone to write that CLL was all of his life on my obituary.
Thursday, April 26, 2007
Don't fence me in.
This picture is of a fence designed to keep out illegal immigrants.
We don't like fences do we? At least Javier Solana doesn't like fences.
"A wall that separates one country from another is not something that I like or that the European Union members like," Solana said at a news conference in Mexico City. "We don't think walls are reasonable instruments to stop people from crossing into a country."
The EU believes immigrants should be treated "like people, not like criminals," he said.
The EU doesn't like fences especially when they keep Mexicans out of the USA or Palestinians out of Israel. This fence is a good 10 feet high with razor wire and is at a place called Ceuta. Where is Cueta? It is in North Africa. This is what Wikipedia says about it
The Ceuta border fence is a separation barrier between Morocco and the Autonomous City of Ceuta, in Spain. Constructed by Spain, its stated purpose is to stop illegal immigration and smuggling.
Construction of the €30-million razor wire barrier was financed by the European Union. It consists of parallel 3-metre (10-foot) fences topped with barbed wire, with regular watchposts and a road running between them to accommodate police patrols or ambulance service in case of need. Underground cables connect spotlights, noise and movement sensors, and video cameras to a central control booth.
Morocco has objected to the construction of the barrier since it does not recognize Spanish sovereignty in Ceuta.
Who was it who paid for the fence?
The European Union.
Who does Mr Solano work for?
The European Union.
Who is it that doesn't like fences?
The European Union.
There used to be a saying in my youth, "Strong fences make good neighbors."
ZAP-70 again.
One of the most pressing topics to come up in Canada was the usefulness or otherwise of ZAP-70 as a prognostic factor. In fact John Byrd said that patients coming to see him with their ZAP-70 assay was the bane of his life.
Now I have already blogged about ZAP-70 once and my views on it have not changed.
ZAP-70 is the signaling molecule for the T cell receptor. The T cells receptor is made up of several chains that protruse from the cell membrane ready to be tweaked by the target molecule which the T cell is programmed to react with. It is the zeta chain that actually reacts with ZAP-70 (which stands for Zeta Associated Protein with a molecular weight of 70 kiloDaltons). When it is twitched, ZAP-70 relays the message to the nucleus of the cell where instructions are issued for the cell to divide or secrete or whatever.
In B cells ZAP-70 is not normally involved. The B cell receptor is also made up of several chains, and the one that does the signaling is called CD79b. This reacts, not with ZAP-70, but with a molecule from the same family, called syk. Syk relays the message to the nucleus in a similar way and instructions are issued for division or secretion or whatever.
In CLL cells ZAP-70 is sometimes present when it shouldn't be. Even in these cells, it's still syk and not ZAP-70 that does the signaling. So what does ZAP-70 do?
All signaling has an on switch and an off switch. When you think about it, there would have to be, wouldn't there? Once a signal is sent, you don't want to keep repeating the same signal do you? In fact there is an automatic damping down of the signal once it has been sent. As syk reacts with downstream molecules, compounds are formed that inhibit syk from passing any more messages for a while. What ZAP-70 does is bind to these inhibitory compounds so that syk signaling can continue unimpaired.
So why is ZAP-70 there in this anomolous way? We don't know why, but we know how. Heat shock protein 90 (HSP90) acts as a molecular chaparone. It sticks close by certain moleculews and protects them from harm. It is a common feature of cancer cells that HSP90 binds to molecules that are supposed to be destroyed by natural processes and allows them to persist. ZAP-70 in some CLLs is one of these molecules with 'protection'. Why it gets this protection no-one knows. It's certainly not because it knows Tony Soprano.
A trial of treatment to remove the protection is under way in San Diego. They do this with a derivative of the antibiotic geldanamycin, known as 17-AAG.
The presence of ZAP-70 in some CLLs was discovered by the NIH group of Lou Staudt. After we had discovered the difference between mutated and unmutated CLLs other workers began looking for an easier assay. CD38 had proved to be only 71% concordant with VH gene mutations. The NIH group developed something they called a lymphochip (this was about the same time that FISH was getting popular and teh headline writers had fun with FISH and chips). The lymphochip allows thousands of genes to be examined at the same time for whether they are switched on or off. The glow red if on and green if off. They compared patients with mutated and unmutated VH genes - eventually using 70 of our patients for confirmation. The result was that of all the genes they examined the closest correlation was with ZAP-70. At the same time they began to look for antibodies that would detect the protein ZAP-70 in the cell rather than just the active gene. Both our lab and Montserrat's lab developed assays for ZAP-70 using flow cytometry. We presented our results at the same ASH meeting, but they were rather quicker in getting them into print - we were waiting for rather larger numbers. Both our methods were similar.
There are problems with the assay. First, unlike most flow methods we were trying to detect a molecule inside the cell rather than on its surface. This means that the cell has to be made permeable to the antibody with something like paraformaldehyde. Then ZAP-70 is only one of several proteins that belong to the syk family. They are all rather alike, and an antibody made against one tends to have some reactivity against the others. Then antibodies are selected because they give a clear reaction in a particular test. When used in a different test they may not show the same characteristics. We were looking at antibodies that showed reactions by immunohistochemistry or gel diffusion or immunoprecipitation. We looked at 8 different antibodies before we found one that was both sensitive and specific by flow.
The Spanish group chose a different way of expressing the results to us. The problem is that T cells and NK cells contain a lot of ZAP-70 and CLL blood has a lot of T cells and NK cells. We needed to separate the two populations, so you have to stain the T cells with anti-CD2 stained with a different color so that they appear in a different quadrant. The Spanish group used the most positive T cells as the zero, whereas we put in a negative control. Nevertheless, we got very similar results with 94% and 95% concordance with VH genes.
It would be more satisfactory to use a directly labelled antibody to do the test. The Spanish group and we used a fluorescently labelled second anti-antibody to detect the presence of the primary antibody. Using a single antibody would make it easier to commercialize the test. However, when you directly labelled our antibody, you got false positive results. The San Diego group eventually produced a test using a new antibody that seems to give reproducible results, and this paper later came out in the New England Journal of Medicine. Unfortunately, the concordance with VH genes was only 77%, hardly better than CD38. What they did suggest was that patients who were mutated/ZAP-70 positive did better than those that were unmutated ZAP-70 negative, and this seems to hold now they have accumulated over 1000 cases.
There is a difference, though. Our results were based on overall survival, the Rassenti results are based on length of first remission.
Although, I said that a direct test would be easier to commercialize, when Quest and other labs took up the challenge, there were problems. Reports started coming back that patients were getting different results from different labs. Because of this a workshop was organized by teh journal, Cytometry B. A lot of labs partcipated, and it was clear that there was a lot of disagreement on what was important. Results were different when heparin was used as an anticoagulant compared with EDTA. How much time passed between drawing the blood and testing it was important. and there were lots of technical differences. As a result ZAP-70 testing by flow is back in the melting pot. Individual research labs are fairly sure what there own test means, but there is no comercial test that is reliable, and my advice today is don't pay good money for a ZAP-70 test.
Finally, there has been a paper which tries to explain the animalous results between VH genes and ZAP-70. The Germans say that the VH mutated/ZAP-70 positive cases are the V3-21s, and the VH unmutated/ZAP-70 negative cases are thaose with p53 or ATM problems. All I can say to this is I have our examined this hypothesis in teh light of our own cases, and it does not hold water.
Now I have already blogged about ZAP-70 once and my views on it have not changed.
ZAP-70 is the signaling molecule for the T cell receptor. The T cells receptor is made up of several chains that protruse from the cell membrane ready to be tweaked by the target molecule which the T cell is programmed to react with. It is the zeta chain that actually reacts with ZAP-70 (which stands for Zeta Associated Protein with a molecular weight of 70 kiloDaltons). When it is twitched, ZAP-70 relays the message to the nucleus of the cell where instructions are issued for the cell to divide or secrete or whatever.
In B cells ZAP-70 is not normally involved. The B cell receptor is also made up of several chains, and the one that does the signaling is called CD79b. This reacts, not with ZAP-70, but with a molecule from the same family, called syk. Syk relays the message to the nucleus in a similar way and instructions are issued for division or secretion or whatever.
In CLL cells ZAP-70 is sometimes present when it shouldn't be. Even in these cells, it's still syk and not ZAP-70 that does the signaling. So what does ZAP-70 do?
All signaling has an on switch and an off switch. When you think about it, there would have to be, wouldn't there? Once a signal is sent, you don't want to keep repeating the same signal do you? In fact there is an automatic damping down of the signal once it has been sent. As syk reacts with downstream molecules, compounds are formed that inhibit syk from passing any more messages for a while. What ZAP-70 does is bind to these inhibitory compounds so that syk signaling can continue unimpaired.
So why is ZAP-70 there in this anomolous way? We don't know why, but we know how. Heat shock protein 90 (HSP90) acts as a molecular chaparone. It sticks close by certain moleculews and protects them from harm. It is a common feature of cancer cells that HSP90 binds to molecules that are supposed to be destroyed by natural processes and allows them to persist. ZAP-70 in some CLLs is one of these molecules with 'protection'. Why it gets this protection no-one knows. It's certainly not because it knows Tony Soprano.
A trial of treatment to remove the protection is under way in San Diego. They do this with a derivative of the antibiotic geldanamycin, known as 17-AAG.
The presence of ZAP-70 in some CLLs was discovered by the NIH group of Lou Staudt. After we had discovered the difference between mutated and unmutated CLLs other workers began looking for an easier assay. CD38 had proved to be only 71% concordant with VH gene mutations. The NIH group developed something they called a lymphochip (this was about the same time that FISH was getting popular and teh headline writers had fun with FISH and chips). The lymphochip allows thousands of genes to be examined at the same time for whether they are switched on or off. The glow red if on and green if off. They compared patients with mutated and unmutated VH genes - eventually using 70 of our patients for confirmation. The result was that of all the genes they examined the closest correlation was with ZAP-70. At the same time they began to look for antibodies that would detect the protein ZAP-70 in the cell rather than just the active gene. Both our lab and Montserrat's lab developed assays for ZAP-70 using flow cytometry. We presented our results at the same ASH meeting, but they were rather quicker in getting them into print - we were waiting for rather larger numbers. Both our methods were similar.
There are problems with the assay. First, unlike most flow methods we were trying to detect a molecule inside the cell rather than on its surface. This means that the cell has to be made permeable to the antibody with something like paraformaldehyde. Then ZAP-70 is only one of several proteins that belong to the syk family. They are all rather alike, and an antibody made against one tends to have some reactivity against the others. Then antibodies are selected because they give a clear reaction in a particular test. When used in a different test they may not show the same characteristics. We were looking at antibodies that showed reactions by immunohistochemistry or gel diffusion or immunoprecipitation. We looked at 8 different antibodies before we found one that was both sensitive and specific by flow.
The Spanish group chose a different way of expressing the results to us. The problem is that T cells and NK cells contain a lot of ZAP-70 and CLL blood has a lot of T cells and NK cells. We needed to separate the two populations, so you have to stain the T cells with anti-CD2 stained with a different color so that they appear in a different quadrant. The Spanish group used the most positive T cells as the zero, whereas we put in a negative control. Nevertheless, we got very similar results with 94% and 95% concordance with VH genes.
It would be more satisfactory to use a directly labelled antibody to do the test. The Spanish group and we used a fluorescently labelled second anti-antibody to detect the presence of the primary antibody. Using a single antibody would make it easier to commercialize the test. However, when you directly labelled our antibody, you got false positive results. The San Diego group eventually produced a test using a new antibody that seems to give reproducible results, and this paper later came out in the New England Journal of Medicine. Unfortunately, the concordance with VH genes was only 77%, hardly better than CD38. What they did suggest was that patients who were mutated/ZAP-70 positive did better than those that were unmutated ZAP-70 negative, and this seems to hold now they have accumulated over 1000 cases.
There is a difference, though. Our results were based on overall survival, the Rassenti results are based on length of first remission.
Although, I said that a direct test would be easier to commercialize, when Quest and other labs took up the challenge, there were problems. Reports started coming back that patients were getting different results from different labs. Because of this a workshop was organized by teh journal, Cytometry B. A lot of labs partcipated, and it was clear that there was a lot of disagreement on what was important. Results were different when heparin was used as an anticoagulant compared with EDTA. How much time passed between drawing the blood and testing it was important. and there were lots of technical differences. As a result ZAP-70 testing by flow is back in the melting pot. Individual research labs are fairly sure what there own test means, but there is no comercial test that is reliable, and my advice today is don't pay good money for a ZAP-70 test.
Finally, there has been a paper which tries to explain the animalous results between VH genes and ZAP-70. The Germans say that the VH mutated/ZAP-70 positive cases are the V3-21s, and the VH unmutated/ZAP-70 negative cases are thaose with p53 or ATM problems. All I can say to this is I have our examined this hypothesis in teh light of our own cases, and it does not hold water.
Next time I'll look at the Falls.
I've been 'off air' for some time. For those who don't know, I have been to Niagara to speak to North American CLL sufferers. The Canadian CLL group did a great job in organizing the meeting in a luxurious hotel complex at White Oaks, Niagara on the Lake. Apart from myself, the other medical speakers were John Byrd, Ronan Foley, Graeme Fraser and Susan Leclair. Bill Evans, the Chairman of Cancer at the Juravinski Cancer Centre in Hamilton gave an overview of cancer services in Ontario and Stephen Segar spoke about complementary medicine. In addition there was a patient advocacy session run by my old friend Laura Cleveland and Ryan Clarke.
The Friday was mainly for doctors and the Saturday mainly for patients.
I did in fact visit the Falls on the Friday morning. Since I was last there about 12 years ago there has been a lot of spending on luxury hotels and a couple of Casinos. The Falls themselves seemed unchanged. Pretty spectacular, but good for a day-trip rather than a week's vacation.
All seemed to be going well until around 10 pm on the Friday when I began vomiting.
I remember as a student, a consultant asked his assistant on a ward round (slyly criticizing a student's spelling), "Do you spell 'vomiting' with two 't's, Keith?"
Keith replied, "Only if it is particularly severe, sir."
This was vomitting.
It went on until the early hours accompanied by equally liquid diarrhea. I was weak and exhausted, hardly able to raise myself from the bathroom floor. The thing about luxury hotels is that they have telephones in the bathroom. I never knew why until now. I was able to contact the night porter, who summoned my host, Dr Foley. Don't tell his patients, but the kind Dr Foley does house calls at night. Ronan helped me back to bed, got me an anti-emetic and some fluid in the form of one of those Sports drinks that his high in electrolytes to replenish what I had lost.
I slept for a while, then started bringing up the Sports drink, then slept again. I had hoped to give my second talk on the Saturday afternoon but as the day wore on I was getting worse, not better. Eventually, Dr Foley had to get me admitted to hospital for intravenous fluids. I was so dry that I could not speak. Dr Foley negotiated me through the beaurocracy of the Niagara Falls hospital. It was a smart facility, newly built (with Casino money?). The Emergency physician just happened to be someone who was at Med school with Dr Foley and my time in hospital could not have gone smoother. I was given two anti-emetics and an anti-spasmodic iv together with two liters of iv fluids and allowed back to the hotel by 9 pm. Dr Foley stayed with me the whole time. The conference organizers booked me into the hotel for another night and put all my travel arangements back 24 hours. I spent the extra time in bed. The flight home was smooth and I have been taking it easy back here in England.
What caused it is anybody's guess. Was there a bug in the Niagara spray that I inhaled? Nobody else at the meeting was ill (apart from with CLL) so it is unlikely to have been the hotel food, and I did not eat anywhere else. Was it the food on the plane? Or perhaps the bar of chocolate that I purchased at Heathrow airport. Perhaps it was a virus?
I have lost 8 pounds. Every silver lining comes wrapped in a cloud. The Canadians were great hosts. Anyone can entertain a visiting speaker. It takes special qualities to care for a sick one.
The Friday was mainly for doctors and the Saturday mainly for patients.
I did in fact visit the Falls on the Friday morning. Since I was last there about 12 years ago there has been a lot of spending on luxury hotels and a couple of Casinos. The Falls themselves seemed unchanged. Pretty spectacular, but good for a day-trip rather than a week's vacation.
All seemed to be going well until around 10 pm on the Friday when I began vomiting.
I remember as a student, a consultant asked his assistant on a ward round (slyly criticizing a student's spelling), "Do you spell 'vomiting' with two 't's, Keith?"
Keith replied, "Only if it is particularly severe, sir."
This was vomitting.
It went on until the early hours accompanied by equally liquid diarrhea. I was weak and exhausted, hardly able to raise myself from the bathroom floor. The thing about luxury hotels is that they have telephones in the bathroom. I never knew why until now. I was able to contact the night porter, who summoned my host, Dr Foley. Don't tell his patients, but the kind Dr Foley does house calls at night. Ronan helped me back to bed, got me an anti-emetic and some fluid in the form of one of those Sports drinks that his high in electrolytes to replenish what I had lost.
I slept for a while, then started bringing up the Sports drink, then slept again. I had hoped to give my second talk on the Saturday afternoon but as the day wore on I was getting worse, not better. Eventually, Dr Foley had to get me admitted to hospital for intravenous fluids. I was so dry that I could not speak. Dr Foley negotiated me through the beaurocracy of the Niagara Falls hospital. It was a smart facility, newly built (with Casino money?). The Emergency physician just happened to be someone who was at Med school with Dr Foley and my time in hospital could not have gone smoother. I was given two anti-emetics and an anti-spasmodic iv together with two liters of iv fluids and allowed back to the hotel by 9 pm. Dr Foley stayed with me the whole time. The conference organizers booked me into the hotel for another night and put all my travel arangements back 24 hours. I spent the extra time in bed. The flight home was smooth and I have been taking it easy back here in England.
What caused it is anybody's guess. Was there a bug in the Niagara spray that I inhaled? Nobody else at the meeting was ill (apart from with CLL) so it is unlikely to have been the hotel food, and I did not eat anywhere else. Was it the food on the plane? Or perhaps the bar of chocolate that I purchased at Heathrow airport. Perhaps it was a virus?
I have lost 8 pounds. Every silver lining comes wrapped in a cloud. The Canadians were great hosts. Anyone can entertain a visiting speaker. It takes special qualities to care for a sick one.
Tuesday, April 17, 2007
Eye of the beholder.
I am actually quite fond of Brian Ferry and Roxy Music. Some of his interpretations of Bob Dylan's songs are outstanding. I see he has apologized for his approving comments about Nazi iconography. Ferry is an artist not a politician. He has a great eye for style. Those who criticize him are like the ignorant mob who beseiged the home of a pediatrician not realizing that a pediatrician is not the same thing as a pedophile. Ferry said that the banners and buildings of Riefensthal and Speer were “beautiful.”
So they were. Nazism was extremely popular in Germany in the 1930s. The attractive presentational style disguised the horror of the content. We are very prone to confuse style and content. Very beautiful people, darlings of the media, do terrible deeds and ugly people go around doing good.
So they were. Nazism was extremely popular in Germany in the 1930s. The attractive presentational style disguised the horror of the content. We are very prone to confuse style and content. Very beautiful people, darlings of the media, do terrible deeds and ugly people go around doing good.
Lions and donkeys
I have been away from my blogging desk for some time, but I must comment on the goings on in Iraq and Iran. Whatever way you spin it, the capture of the sailors and marines in the Gulf was a humiliation for Britain. Niall Ferguson has some apt comments here I suspect that the hapless Des Browne should and will carry the can for it. His career can be summed up by this quotation from HMS Pinafore:
When I was a lad I served a term
As office boy to an Attorney's firm.
I cleaned the windows and I swept the floor,
And I polished up the handle of the big front door.
I polished up that handle so carefullee
That now I am the Ruler of the Queen's Navee!
It was crass mismanagement to get captured in the first place. This is the second time that the Iranians have picked up hostages from Royal Navy personnel trying to intercept smugglers. Such missions must be conducted with sufficient force, and especially with enough helicopters.
Britain is trying to carry on a war on two fronts – Iraq and Afghanistan – with insufficient men and inadequate arms. Since it is the duty of the Minister of Defence to provide for his troops it is the Minister of Defence who must fall on his sword when mishaps like this occur.
Worse was to follow. The hostages were given permission to sell their stories to the highest bidder, in an attempt to counter the lying propaganda from Iran about how well they had been treated (they were captured in Iraqi waters by an act of piracy and far from being an act of generosity by the Iranian politicians, their release was a face-saving exercise when the Iranians came under international pressure). A sympathetic eye might regard this as a naïve attempt to influence the media by young civil servants, until we learn that the decision was made by the second Sea Lord, and that Des Browne was not around to approve it because he had left early before his Easter break – a habit that was not his alone, but commonplace in government offices and seen as a perk. I don’t suppose he will be paying back his salary for the half day that he didn’t work.
So Des Browne should go, but the guilt wasn’t his alone. Why were they short of helicopters?
You can do a lot without helicopters as this report from Basra demonstrates but if you read the comments that follow a recurring question is: why did they have to do it without helicopter cover? The answer seems to be in the hands of Mr Browne’s namesake Gordon Brown., the man most likely to be our next Prime Minister.
He has a reputation for sound financial management, but it may be that he has happened to be in charge through a period of long standing house-price inflation, which has put money without cost into the back-pocket of electors. This may keep the country happy for a while, but while many people are individually richer, money has not been spent where it needed to be. In today’s modern warfare that means helicopters.
I heard yesterday of a company that sells luxury items. They buy a particular item from their wholesalers for £3, put their own label on it and sell it for £75. You pay £72 for the label. Why don’t people buy direct from the wholesalers? Because it's the label they want.
The label that says, “World beating armed forces” isn’t cheap to print and can’t be bought by cheap media tricks. It is acquired through the blood and guts of brave young men and women. As we leaned in the First World War, it’s easily lost when they are led by donkeys.
When I was a lad I served a term
As office boy to an Attorney's firm.
I cleaned the windows and I swept the floor,
And I polished up the handle of the big front door.
I polished up that handle so carefullee
That now I am the Ruler of the Queen's Navee!
It was crass mismanagement to get captured in the first place. This is the second time that the Iranians have picked up hostages from Royal Navy personnel trying to intercept smugglers. Such missions must be conducted with sufficient force, and especially with enough helicopters.
Britain is trying to carry on a war on two fronts – Iraq and Afghanistan – with insufficient men and inadequate arms. Since it is the duty of the Minister of Defence to provide for his troops it is the Minister of Defence who must fall on his sword when mishaps like this occur.
Worse was to follow. The hostages were given permission to sell their stories to the highest bidder, in an attempt to counter the lying propaganda from Iran about how well they had been treated (they were captured in Iraqi waters by an act of piracy and far from being an act of generosity by the Iranian politicians, their release was a face-saving exercise when the Iranians came under international pressure). A sympathetic eye might regard this as a naïve attempt to influence the media by young civil servants, until we learn that the decision was made by the second Sea Lord, and that Des Browne was not around to approve it because he had left early before his Easter break – a habit that was not his alone, but commonplace in government offices and seen as a perk. I don’t suppose he will be paying back his salary for the half day that he didn’t work.
So Des Browne should go, but the guilt wasn’t his alone. Why were they short of helicopters?
You can do a lot without helicopters as this report from Basra demonstrates but if you read the comments that follow a recurring question is: why did they have to do it without helicopter cover? The answer seems to be in the hands of Mr Browne’s namesake Gordon Brown., the man most likely to be our next Prime Minister.
He has a reputation for sound financial management, but it may be that he has happened to be in charge through a period of long standing house-price inflation, which has put money without cost into the back-pocket of electors. This may keep the country happy for a while, but while many people are individually richer, money has not been spent where it needed to be. In today’s modern warfare that means helicopters.
I heard yesterday of a company that sells luxury items. They buy a particular item from their wholesalers for £3, put their own label on it and sell it for £75. You pay £72 for the label. Why don’t people buy direct from the wholesalers? Because it's the label they want.
The label that says, “World beating armed forces” isn’t cheap to print and can’t be bought by cheap media tricks. It is acquired through the blood and guts of brave young men and women. As we leaned in the First World War, it’s easily lost when they are led by donkeys.
Thursday, April 12, 2007
Banking for the rich alone.
There has been a furore in Canford Cliffs because the local branch of HSBC bank is in future to provide a counter service only for customers who make use of their Premier service. To do this you must have £50,000 in savings or a £200,000 mortgage or a salary in excess of £75,000.
Canford Cliffs is the expensive part of Bournemouth (to be accurate it is part of next-door Poole). This branch serves Canford Cliffs, Branksome Park and Sandbanks, the most affluent part of our conurbation. Most people who live there are millionaires. There are some retired folk who are living on a fixed pension who are property-rich but income-poor.
Now I don't see the problem. Nobody would expect the Rolls Royce showroom which is next door but one to stock Fords for the less well off. If a bank wants to provide a service for its rich customers why should it not? It's not as though it is the only bank in the village; there is a LLoyds bank just across the street. Message to poorer HSBC customers. Change your bank. It's called competition and without it capitalism doesn't work.
Canford Cliffs is the expensive part of Bournemouth (to be accurate it is part of next-door Poole). This branch serves Canford Cliffs, Branksome Park and Sandbanks, the most affluent part of our conurbation. Most people who live there are millionaires. There are some retired folk who are living on a fixed pension who are property-rich but income-poor.
Now I don't see the problem. Nobody would expect the Rolls Royce showroom which is next door but one to stock Fords for the less well off. If a bank wants to provide a service for its rich customers why should it not? It's not as though it is the only bank in the village; there is a LLoyds bank just across the street. Message to poorer HSBC customers. Change your bank. It's called competition and without it capitalism doesn't work.
Wednesday, April 04, 2007
CT scans
When should a CLL patient have a CT scan?
The first thing to say is that for the past 30 years the staging of CLL has been carried out very satisfactorily without CT scans. Indeed all the predictive information that is based on Rai or Binet staging specifically excludes CT scanning. However, it stands to reason that some Rai stage 0 patients will in fact have enlarged retroperitoneal lymph nodes (this means nodes at the back of the tummy)undetectable by clinical examination, and these patients will have the prognosis of stage I patients rather than stage 0 patients, and that in some patients the glands will be of sufficient size as to justify immediate treatment.
If CT scanning is used to stage patients, then patients who are truly stage 0 will have a better prognosis than historical data shows, but we are in the dark about what happens to patients whose only evidence of enlarged lymph nodes is what is detectable by CT scanning.
A new paper from Professor Montserrat's group is about to be published in J C lin Oncol which helps to resolve this.
The Barcelona group did abdominal CT scan on 140 stage 0 patients. 27% had an abnormal CT scan. This correlated with increased bone marrow infiltration, high lymphocyte count, high ZAP-70 expression and short lymphocyte doubling time. Patients with an abnormal CT scan had a shorter time to first treatment than those with normal CT scans (median 3.5 years compared with median not yet reached). In a multivariate analysis only abnormal CT scan and high ZAP-70 correlated with disease progression. (Remember that the Barcelona ZAP-70 is one we believe in - it was published in NEJM under Crespo et al. It correlates very closely with unmutated VH genes).
In the light of this finding the International Working Group in CLL are minded to add to their advice on the management of CLL.
CT scans generally are not required for the initial evaluation, staging, or follow up. A recent study has found that patients in Rai stage 0 but with detectable abdominal disease by CT scans may have a more aggressive disease. Therefore, clinical studies evaluating the use of CT scans in CLL are strongly encouraged.
The IWCLL group are very conservative about changing recommendations, but I certainly think that there are situations where a CT scan would be indicated in the initial evaluation of patients in clinical practice.
Patients who are apparently stage 0 but have a lymphocyte count greater than 50,000 (possibly those greater than 30,000), overweight patients who are difficult to examine for lymph nodes, patients with 'B' symptoms, patients with lymphocyte doubling times of less than a year, patients with unmutated VH genes (or a reliable positive ZAP-70).
I know that some people who are worried by the radiation dose from a CT scan. This worry has been reinforced by an MRI specialist who has been writing on Medscape. I have to say that this is very much a lone view among medical imagers. Most, while recognizing that CT scanning does involve a large dose of radiation compared to that received from a chest X-ray, nevertheless agree that the risk of inducing a second cancer is very small compared to the risk of missing the correct diagnosis.
What about using ultrasound or MRI to diagnose retroperitoneal lymph nodes?
In some countries, the use of abdominal ultrasound is popular to assess the extent of lymphadenopathy and organomegaly in CLL. While it may be used in the clinical management of individual patients, this methodology is strongly investigator-dependent and should therefore not be used for the response evaluation in clinical trials. - so say IWCLL and I agree with them. Measurement of nodes on successive ultrasound scans is nigh on impossible, because you cannot really produce comparable views.
Similarly, the IWCLL view of MRI is this - "nuclear magnetic resonance imaging and other imaging techniques are generally not useful in the management of CLL." Again I agree, the view of lymph nodes is not precise enough.
While we are on the subject of imaging, the IWCLL say, "Positron emission tomography (PET) scans do not provide information that is useful in the management of CLL. PET scans, however, might become useful in the diagnostic evaluation and follow up of known or suspected Richter's transformation."
In clinical trials, the latest German trials demonstrate that the use of CT scans to evaluate how good a response is, is very worthwhile. Apparent complete remissions are nothing of the sort in many cases when CT scans are used to evaluate them. The IWCLL recommend, "In clinical trials where the treatment intent is to maximize complete remissions, neck, chest, abdominal and pelvic CT scans are recommended to evaluate the response to therapy. CT scans should be performed prior to the start of therapy and at the first restaging following therapy if previously abnormal".
Like all imaging examinations the doctor must first ask himselftheh question, "Why am I doing this?" and then answer the question, "How will it alter my management if I have this information?" If the answer to the first is, "Idon't know or because it is in the protocol" or the answer to the second is "Not at all or I don't know," then the CT scan should not be done.
The first thing to say is that for the past 30 years the staging of CLL has been carried out very satisfactorily without CT scans. Indeed all the predictive information that is based on Rai or Binet staging specifically excludes CT scanning. However, it stands to reason that some Rai stage 0 patients will in fact have enlarged retroperitoneal lymph nodes (this means nodes at the back of the tummy)undetectable by clinical examination, and these patients will have the prognosis of stage I patients rather than stage 0 patients, and that in some patients the glands will be of sufficient size as to justify immediate treatment.
If CT scanning is used to stage patients, then patients who are truly stage 0 will have a better prognosis than historical data shows, but we are in the dark about what happens to patients whose only evidence of enlarged lymph nodes is what is detectable by CT scanning.
A new paper from Professor Montserrat's group is about to be published in J C lin Oncol which helps to resolve this.
The Barcelona group did abdominal CT scan on 140 stage 0 patients. 27% had an abnormal CT scan. This correlated with increased bone marrow infiltration, high lymphocyte count, high ZAP-70 expression and short lymphocyte doubling time. Patients with an abnormal CT scan had a shorter time to first treatment than those with normal CT scans (median 3.5 years compared with median not yet reached). In a multivariate analysis only abnormal CT scan and high ZAP-70 correlated with disease progression. (Remember that the Barcelona ZAP-70 is one we believe in - it was published in NEJM under Crespo et al. It correlates very closely with unmutated VH genes).
In the light of this finding the International Working Group in CLL are minded to add to their advice on the management of CLL.
CT scans generally are not required for the initial evaluation, staging, or follow up. A recent study has found that patients in Rai stage 0 but with detectable abdominal disease by CT scans may have a more aggressive disease. Therefore, clinical studies evaluating the use of CT scans in CLL are strongly encouraged.
The IWCLL group are very conservative about changing recommendations, but I certainly think that there are situations where a CT scan would be indicated in the initial evaluation of patients in clinical practice.
Patients who are apparently stage 0 but have a lymphocyte count greater than 50,000 (possibly those greater than 30,000), overweight patients who are difficult to examine for lymph nodes, patients with 'B' symptoms, patients with lymphocyte doubling times of less than a year, patients with unmutated VH genes (or a reliable positive ZAP-70).
I know that some people who are worried by the radiation dose from a CT scan. This worry has been reinforced by an MRI specialist who has been writing on Medscape. I have to say that this is very much a lone view among medical imagers. Most, while recognizing that CT scanning does involve a large dose of radiation compared to that received from a chest X-ray, nevertheless agree that the risk of inducing a second cancer is very small compared to the risk of missing the correct diagnosis.
What about using ultrasound or MRI to diagnose retroperitoneal lymph nodes?
In some countries, the use of abdominal ultrasound is popular to assess the extent of lymphadenopathy and organomegaly in CLL. While it may be used in the clinical management of individual patients, this methodology is strongly investigator-dependent and should therefore not be used for the response evaluation in clinical trials. - so say IWCLL and I agree with them. Measurement of nodes on successive ultrasound scans is nigh on impossible, because you cannot really produce comparable views.
Similarly, the IWCLL view of MRI is this - "nuclear magnetic resonance imaging and other imaging techniques are generally not useful in the management of CLL." Again I agree, the view of lymph nodes is not precise enough.
While we are on the subject of imaging, the IWCLL say, "Positron emission tomography (PET) scans do not provide information that is useful in the management of CLL. PET scans, however, might become useful in the diagnostic evaluation and follow up of known or suspected Richter's transformation."
In clinical trials, the latest German trials demonstrate that the use of CT scans to evaluate how good a response is, is very worthwhile. Apparent complete remissions are nothing of the sort in many cases when CT scans are used to evaluate them. The IWCLL recommend, "In clinical trials where the treatment intent is to maximize complete remissions, neck, chest, abdominal and pelvic CT scans are recommended to evaluate the response to therapy. CT scans should be performed prior to the start of therapy and at the first restaging following therapy if previously abnormal".
Like all imaging examinations the doctor must first ask himselftheh question, "Why am I doing this?" and then answer the question, "How will it alter my management if I have this information?" If the answer to the first is, "Idon't know or because it is in the protocol" or the answer to the second is "Not at all or I don't know," then the CT scan should not be done.
Monday, April 02, 2007
Above all powers
I have been asked to write a second stanza for LeBlanc and Baloche's well known hymn, to take it past the crucifixion so as to tell the whole Easter story.
Above all powers, above all kings,
Above all nature and all created things;
Above all wisdom and all the ways of man,
You were here before the world began.
Above all kingdoms, above all thrones,
Above all wonders the world has ever known;
Above all wealth and treasures of the earth,
There's no way to measure what You're worth.
Crucified, laid behind the stone;
You lived to die, rejected and alone;
Like a rose trampled on the ground,
You took the fall and thought of us,
Above all.
Here's what I came up with in the wee small hours of trying to adjust back to European time.
Above all victories, above all joy,
Above all baseness that evil men employ;
Above all science and wisdom of the hour,
You have conquered death and all its power.
Above all triumphs, above the clouds,
Above all wonder that grips the watching crowds
Above all champions and battles ever won
You eclipsed the glory of the sun
Raised to life; darkness left behind
You died to live, a gift for all mankind
When you rose, glorious from the grave
You broke the Fall and rescued us
Above all.
Above all powers, above all kings,
Above all nature and all created things;
Above all wisdom and all the ways of man,
You were here before the world began.
Above all kingdoms, above all thrones,
Above all wonders the world has ever known;
Above all wealth and treasures of the earth,
There's no way to measure what You're worth.
Crucified, laid behind the stone;
You lived to die, rejected and alone;
Like a rose trampled on the ground,
You took the fall and thought of us,
Above all.
Here's what I came up with in the wee small hours of trying to adjust back to European time.
Above all victories, above all joy,
Above all baseness that evil men employ;
Above all science and wisdom of the hour,
You have conquered death and all its power.
Above all triumphs, above the clouds,
Above all wonder that grips the watching crowds
Above all champions and battles ever won
You eclipsed the glory of the sun
Raised to life; darkness left behind
You died to live, a gift for all mankind
When you rose, glorious from the grave
You broke the Fall and rescued us
Above all.
April fool: Psalm 14
The fool says in his heart there is no God.
Psalm 14 is almost identical to Psalm 53. In David's day atheists were thin on the ground and it is not the man who believes that there is no God that the psalmist is referring to. The Hebrew word translated as 'fool' means more than mentally deficient; it means someone who is morally deficient. Like the chap is Psalm 10 who says to himself, "God has forgotten. He covers His face and never sees." David is talking about the practical atheist. In all his thoughts there is no room for God. His ways are always prosperous; he is haughty and God's ways are far from him. He says to himself, "Nothing will shake me. I will always be happy and never have trouble."
Do you recognize this modern man? Because Psalm 14 tells us that when God looks down on the world he finds that all have turned aside and have together become corrupt. There is no-one who does good, not even one. How redolent that is of the New Testament. In his letter to the Romans, St Paul quotes from this very psalm. The classic text that demonstrates a universal need of a Saviour is Romans 3:23. "For all have sinned and fallen short of the glory of God."
Evildoers frustrate the plans of the poor, says David in Psalm 14. They revile God with the taunt, "He won't call me to account". But God's forebearance will not last forever.
David calls for the salvation of Israel to come out of Zion. And so it did, for those very ones who have fallen short are "justified freely by his grace through the redemption that came in Christ Jesus God presented him as a sacrifice of atonement through faith in his blood. He did this to demonstrate his justice because in his forebearance he had left the sins committed beforehand unpunished - he did it to demonstrate his justice at the present time, so as to be just and the one who justifies those who have faith in Jesus."
This great grace is available to all but limited to those with faith in Jesus.
This great doctrine is substitutionary atonement. Christ died for the sins of the world. Sins remain unpunished for a while because God punishes them in Christ. Those who refuse his offer must pay their bills themselves.
Substitutionary atonement is one of the core beliefs of Christians. Mel Gibson’s film may have been flawed but it attempted to demonstrate how foul, vile and evil was Christ’s crucifixion. How could God subject anyone to that sort of death unless it was absolutely necessary? He subjected not just anyone but his own completely innocent son to that horror. And Christian doctrine holds and the Bible teaches that father and son are one. As Jesus suffered so suffered God the father.
I don’t suppose I am unique in having a sense of justice. If I see wicked men set free without punishment for their crimes then I am outraged. For the guilty to go free, someone must pay the price.
As Paul tells us “At just the right time, when we were still powerless, Christ died for the ungodly. Very rarely will anyone die for a righteous man, though for a good man someone might possibly dare to die. But God demonstrates his own love for us in this: While we were still sinners, Christ died for us.” (Romans 5:6-8)
Psalm 14 is almost identical to Psalm 53. In David's day atheists were thin on the ground and it is not the man who believes that there is no God that the psalmist is referring to. The Hebrew word translated as 'fool' means more than mentally deficient; it means someone who is morally deficient. Like the chap is Psalm 10 who says to himself, "God has forgotten. He covers His face and never sees." David is talking about the practical atheist. In all his thoughts there is no room for God. His ways are always prosperous; he is haughty and God's ways are far from him. He says to himself, "Nothing will shake me. I will always be happy and never have trouble."
Do you recognize this modern man? Because Psalm 14 tells us that when God looks down on the world he finds that all have turned aside and have together become corrupt. There is no-one who does good, not even one. How redolent that is of the New Testament. In his letter to the Romans, St Paul quotes from this very psalm. The classic text that demonstrates a universal need of a Saviour is Romans 3:23. "For all have sinned and fallen short of the glory of God."
Evildoers frustrate the plans of the poor, says David in Psalm 14. They revile God with the taunt, "He won't call me to account". But God's forebearance will not last forever.
David calls for the salvation of Israel to come out of Zion. And so it did, for those very ones who have fallen short are "justified freely by his grace through the redemption that came in Christ Jesus God presented him as a sacrifice of atonement through faith in his blood. He did this to demonstrate his justice because in his forebearance he had left the sins committed beforehand unpunished - he did it to demonstrate his justice at the present time, so as to be just and the one who justifies those who have faith in Jesus."
This great grace is available to all but limited to those with faith in Jesus.
This great doctrine is substitutionary atonement. Christ died for the sins of the world. Sins remain unpunished for a while because God punishes them in Christ. Those who refuse his offer must pay their bills themselves.
Substitutionary atonement is one of the core beliefs of Christians. Mel Gibson’s film may have been flawed but it attempted to demonstrate how foul, vile and evil was Christ’s crucifixion. How could God subject anyone to that sort of death unless it was absolutely necessary? He subjected not just anyone but his own completely innocent son to that horror. And Christian doctrine holds and the Bible teaches that father and son are one. As Jesus suffered so suffered God the father.
I don’t suppose I am unique in having a sense of justice. If I see wicked men set free without punishment for their crimes then I am outraged. For the guilty to go free, someone must pay the price.
As Paul tells us “At just the right time, when we were still powerless, Christ died for the ungodly. Very rarely will anyone die for a righteous man, though for a good man someone might possibly dare to die. But God demonstrates his own love for us in this: While we were still sinners, Christ died for us.” (Romans 5:6-8)
Sunday, April 01, 2007
Freakonomics
What is truth? said jesting Pilate; and would not stay for an answer. So wrote Francis Bacon in the 16th Century, quoting from St John's Gospel. Pilate was responding to Jesus' assertion "I came into the world to testify to the truth. Everyone on the side of truth listens to me."
A primary school teacher, an engineer and an accountant each answered the question, "What is the sum of 2 plus 2?"
The teacher answered, "Four."
The engineer was more specific, "If by two, you mean 2.00, then the answer is 4.00, but if your twos are really 2.28s rounded down to 2 to zero decimal places, then the correct answer is five, or 4.56 rounded up to 5."
The accountant was worldly-wise, "How much would you like it to be?"
I have been thinking about truth ever since reading a book called 'Freakonomics' by Steven Levitt and Stephen Dubner. This book hit the headlines when it made the astonishing claim that the falling crime rate in America was a direct consequence of Roe v Wade.
Freakonomics is about challenging the conventional wisdom. Between 1975 and 1990 violent crime in America had risen by 80%. Experts were predicting a bloodbath. Fueled by crack cocaine, the black areas of inner cities were exploding. Then in the nineties it all began to go away. Crime levels have fallen back to the levels of 1960. Why?
There have many suggestions: The 'broken windows' approach to inner city policing introduced by Rudolph Giuliani and his police commissioner, William Bratton, in New York City has gotten a lot of the credit, but so has simply putting more police on the streets. Tougher gun-control laws, gun buy-back schemes, laws against concealed weapons, all have their advocates. Or is it simply a strong economy cutting down the numbers of unemployed? The devil makes work for idle hands. Is harsher punishment acting as a deterrent - longer prison sentences or the return of capital punishment? Or is it a change in the market for crack? Or simply the greying of the population?
Levitt and Dubner have considered all these possibilities. About a third of the decrease comes from locking up criminals. Prisons are expensive, they often brutalize the inmates, and often it is the inadequate, the addict and the mad that are locked up, but there is no getting away from it; career criminals commit no crime when incarcerated. On the other hand capital punishment, as it is practised, makes little difference. The truth is it turns out to be safer for a criminal on death row than it is selling crack on a street corner in Chicago. He is less likely to die.
Criminals didn't march to jail by themselves; someone had to put them there. Homicide rates in New York City fell from 30.7 per 100,000 in 1990 to 8.4 per 100,000 in 2000. However, the fall began before the broken windows strategy began. It began when the previous Mayor, David Dinkins, started increasing police numbers in response to Mayoral contender Guiliani's law and order campaign, four years before 'broken windows' was instituted. In fact the homicide rate fell in other cities that increased their police numbers and didn't adopt the Bratton philosophy of policing. Increased police numbers accounts for about 10% of the drop in crime; less unemployement on the other hand cannot be responsible for more than 1% or 2% of the total fall.
Tougher gun laws have had little effect. Indeed, in Britain where all hand guns are banned, gun crime is increasing. Surprisingly, criminals don't obey gun control laws any more than they obey the laws of property.
More important was the fall in the price of crack cocaine. Most of the inner city murders were not by crackheads but part of the intense competition for prime selling sites. Gang member shot gang member. These were turf wars. The use of crack has not diminished since 1990. The supply has become more available, but roughly the same number of users are able to obtain more for their money. The profits have diminished, the street corners aren't so valuable and not worth dying for. The change in the crack economy accounts for 15% of the fall in crime.
The greying of the population accounts for the rest - about 40% of the fall. On the whole the over-65s tend not to commit violent crimes. But why are there fewer young people? Obviously contaception is part of it, but abortion available to all is the major component. Every year in America over one and a half milion babies are aborted. By and large these are the children of the young, unemployed, unmarried, inner city poor. These are the characteristics of those most likely to become criminals. Unintentionally, America has been aborting its potential criminals.
Lies, damned lies and statistics! Statistics are notoriously misused to mislead. Levitt and Dubner's assertion received a bad response from those on both sides of the abortion debate. However, the figures seem to me to be true. The greatest contribution to the fall in crime in America is the fall in the number of those likely to become criminals and the reason for this is the increased availability of abortion. Since Roe v Wade conceptions have risen by 30% but live births have fallen by 6%.
Consider this. Had the American government, as a solution to the crime wave, brought in a law that ordered the killing of a large proportion of babies born to unmarried, teenage, black mothers who were poor and unemployed, the world would rightly have been in uproar. Headlines would have screamed George W Herod (or William J Herod - take your pick). Instead, women of America have freely chosed to abort these babies before they were born.
Try as I might I have difficulty in seeing a fundamental difference between killing a developing fetus and killing a newborn. I know that a certain proportion of fetuses will not reach term, but nobody is concerned about them; the reason for an abortion is to kill the fetus that will come to term. I know about a woman's right to choose, but that presupposes that she harms no-one but herself. It presupposes that the developing fetus is not an individual in its own right. When does it become an individual? At 8 weeks or 13 weeks or 24 weeks or 28 weeks or when it is born or when it begins to talk? Legislation in the UK forbids experimentaion on an embryo after 14 days, when the primitive neural streak appears.
As a man I struggle with this area. To bear a child is a particularly female thing; no man can begin to understand the intimate relationship between a mother and child. Of course there is a difference between killing a fetus and killing a baby. It is an esthetic difference; it is an emotional difference; but is it an ethical difference? And should we beguided by ethics or esthetics or emotions?
I suspect that I will have responses from both sides of the debate. I have my views, but I'm not calling anyone by a rude name. Please refrain from calling me by one. However, the debate is enhanced by facts that allow us see clearly what is actually happening.
If you haven't read Freakonomics than I recommend that you do. There are other topics like why do drug dealers live with their mothers, and how you detect a cheating Sumo wrestler. And the next time you move house or sell your car you might want to ponder on the power of experts to rig the market against you.
A primary school teacher, an engineer and an accountant each answered the question, "What is the sum of 2 plus 2?"
The teacher answered, "Four."
The engineer was more specific, "If by two, you mean 2.00, then the answer is 4.00, but if your twos are really 2.28s rounded down to 2 to zero decimal places, then the correct answer is five, or 4.56 rounded up to 5."
The accountant was worldly-wise, "How much would you like it to be?"
I have been thinking about truth ever since reading a book called 'Freakonomics' by Steven Levitt and Stephen Dubner. This book hit the headlines when it made the astonishing claim that the falling crime rate in America was a direct consequence of Roe v Wade.
Freakonomics is about challenging the conventional wisdom. Between 1975 and 1990 violent crime in America had risen by 80%. Experts were predicting a bloodbath. Fueled by crack cocaine, the black areas of inner cities were exploding. Then in the nineties it all began to go away. Crime levels have fallen back to the levels of 1960. Why?
There have many suggestions: The 'broken windows' approach to inner city policing introduced by Rudolph Giuliani and his police commissioner, William Bratton, in New York City has gotten a lot of the credit, but so has simply putting more police on the streets. Tougher gun-control laws, gun buy-back schemes, laws against concealed weapons, all have their advocates. Or is it simply a strong economy cutting down the numbers of unemployed? The devil makes work for idle hands. Is harsher punishment acting as a deterrent - longer prison sentences or the return of capital punishment? Or is it a change in the market for crack? Or simply the greying of the population?
Levitt and Dubner have considered all these possibilities. About a third of the decrease comes from locking up criminals. Prisons are expensive, they often brutalize the inmates, and often it is the inadequate, the addict and the mad that are locked up, but there is no getting away from it; career criminals commit no crime when incarcerated. On the other hand capital punishment, as it is practised, makes little difference. The truth is it turns out to be safer for a criminal on death row than it is selling crack on a street corner in Chicago. He is less likely to die.
Criminals didn't march to jail by themselves; someone had to put them there. Homicide rates in New York City fell from 30.7 per 100,000 in 1990 to 8.4 per 100,000 in 2000. However, the fall began before the broken windows strategy began. It began when the previous Mayor, David Dinkins, started increasing police numbers in response to Mayoral contender Guiliani's law and order campaign, four years before 'broken windows' was instituted. In fact the homicide rate fell in other cities that increased their police numbers and didn't adopt the Bratton philosophy of policing. Increased police numbers accounts for about 10% of the drop in crime; less unemployement on the other hand cannot be responsible for more than 1% or 2% of the total fall.
Tougher gun laws have had little effect. Indeed, in Britain where all hand guns are banned, gun crime is increasing. Surprisingly, criminals don't obey gun control laws any more than they obey the laws of property.
More important was the fall in the price of crack cocaine. Most of the inner city murders were not by crackheads but part of the intense competition for prime selling sites. Gang member shot gang member. These were turf wars. The use of crack has not diminished since 1990. The supply has become more available, but roughly the same number of users are able to obtain more for their money. The profits have diminished, the street corners aren't so valuable and not worth dying for. The change in the crack economy accounts for 15% of the fall in crime.
The greying of the population accounts for the rest - about 40% of the fall. On the whole the over-65s tend not to commit violent crimes. But why are there fewer young people? Obviously contaception is part of it, but abortion available to all is the major component. Every year in America over one and a half milion babies are aborted. By and large these are the children of the young, unemployed, unmarried, inner city poor. These are the characteristics of those most likely to become criminals. Unintentionally, America has been aborting its potential criminals.
Lies, damned lies and statistics! Statistics are notoriously misused to mislead. Levitt and Dubner's assertion received a bad response from those on both sides of the abortion debate. However, the figures seem to me to be true. The greatest contribution to the fall in crime in America is the fall in the number of those likely to become criminals and the reason for this is the increased availability of abortion. Since Roe v Wade conceptions have risen by 30% but live births have fallen by 6%.
Consider this. Had the American government, as a solution to the crime wave, brought in a law that ordered the killing of a large proportion of babies born to unmarried, teenage, black mothers who were poor and unemployed, the world would rightly have been in uproar. Headlines would have screamed George W Herod (or William J Herod - take your pick). Instead, women of America have freely chosed to abort these babies before they were born.
Try as I might I have difficulty in seeing a fundamental difference between killing a developing fetus and killing a newborn. I know that a certain proportion of fetuses will not reach term, but nobody is concerned about them; the reason for an abortion is to kill the fetus that will come to term. I know about a woman's right to choose, but that presupposes that she harms no-one but herself. It presupposes that the developing fetus is not an individual in its own right. When does it become an individual? At 8 weeks or 13 weeks or 24 weeks or 28 weeks or when it is born or when it begins to talk? Legislation in the UK forbids experimentaion on an embryo after 14 days, when the primitive neural streak appears.
As a man I struggle with this area. To bear a child is a particularly female thing; no man can begin to understand the intimate relationship between a mother and child. Of course there is a difference between killing a fetus and killing a baby. It is an esthetic difference; it is an emotional difference; but is it an ethical difference? And should we beguided by ethics or esthetics or emotions?
I suspect that I will have responses from both sides of the debate. I have my views, but I'm not calling anyone by a rude name. Please refrain from calling me by one. However, the debate is enhanced by facts that allow us see clearly what is actually happening.
If you haven't read Freakonomics than I recommend that you do. There are other topics like why do drug dealers live with their mothers, and how you detect a cheating Sumo wrestler. And the next time you move house or sell your car you might want to ponder on the power of experts to rig the market against you.
Friday, March 30, 2007
Traveling through time and space.
The large mountain sometimes seen from Seattle is called Mount Rainier (pronounced 'raneer'). If you can't see the mountain it's raining; if you can see it, don't worry, it will be rainier later. (Boom, boom!)
We had a wet and overcast trip to America but it was dry almost half the time we were there and when the sun came out it was very pleasant.
My son is living in an area near Green Lake called Tangletown, where the houses are made of wood and the gardens are impressive. The trees are festooned with blossom and everything is green and heavily scented. The people are friendly, the schools are good, the atmosphere welcoming. We did the Underground Tour and learned that the founders of Seattle were mostly crooks who were not over-concerned about sewage. I had always thought that Flushing Meadows was something to do with tennis, but it seems an apt description of what happened when the tide came in at Puget Sound. (Flushing Meadows was featured in the Hitchcock movie 'Strangers on a Train' the lead actor in which, Farley Granger, came out yesterday as heterosexual after giving the impression for many years that he was gay.)
We went up the Space Needle on a fairly clear day and saw the mountains and we visited the Science Fiction Museaum (of which more later).
My talk to patients went well, I think, though because of computer difficulties many of my carefully prepared slides had to be abandoned and I had to ad-lib a bit. This is only the third time I have spoken just to patients and I still have to perfect how the talk should be given. I probably need to cut down on the data and address the sort of problems that people actually have.
One thing that travel affords is time to read. I managed to finish "The Time Traveler's Wife" by Audrey Niffenegger. If you don't know about this novel you can Google it. It became famous for 15 minutes when Brad Pitt and Jennifer Aniston bought the screen rights, though it now seems that neither wil appear in the movie which is apparently in production.
Time travel is used as a device to explore relationships, and why not? I am a science fiction fan and I had to defend this at a university entrance interview. I said it exposed people to extreme circumstances. Nothing more extreme than meeting your middle aged future husband when you are six or getting pregnant by a younger version of your husband after he had had a vasectomy deliberately to avoid the risk of further miscarriages.
The problem of time travel is changing the future. The famous Ray Bradbury story "Sound of Thunder" (which is featured in the Seattle Science Fiction Museum) has a dinosaur hunter treading on a butterfly and as a consequence America is changed from a democracy to a totalitarian state. Some would say that destroying the World Trade Center is having the same effect. Niffenegger avoids this conundrum, but it was a problem for the hero of the movie that I watched on the plane coming back. 'Deja Vu' was a litle piece of nonsense, but quite fun.
In a sense all travel is time travel. It is said that travel to New Zealand is like going back to 1957 - for me a very good year. In a way travel to Seattle was like going back to 1968; in Seattle at least the equation Iraq = Viet Nam seems self-evident. There are some obvious similarities, but to my mind tremendous differences. It is a false analogy, but it does emphasize how complex are different societies and how unexpected are the consequences of interfering in what you don't understand. A bit like time travel really.
We had a wet and overcast trip to America but it was dry almost half the time we were there and when the sun came out it was very pleasant.
My son is living in an area near Green Lake called Tangletown, where the houses are made of wood and the gardens are impressive. The trees are festooned with blossom and everything is green and heavily scented. The people are friendly, the schools are good, the atmosphere welcoming. We did the Underground Tour and learned that the founders of Seattle were mostly crooks who were not over-concerned about sewage. I had always thought that Flushing Meadows was something to do with tennis, but it seems an apt description of what happened when the tide came in at Puget Sound. (Flushing Meadows was featured in the Hitchcock movie 'Strangers on a Train' the lead actor in which, Farley Granger, came out yesterday as heterosexual after giving the impression for many years that he was gay.)
We went up the Space Needle on a fairly clear day and saw the mountains and we visited the Science Fiction Museaum (of which more later).
My talk to patients went well, I think, though because of computer difficulties many of my carefully prepared slides had to be abandoned and I had to ad-lib a bit. This is only the third time I have spoken just to patients and I still have to perfect how the talk should be given. I probably need to cut down on the data and address the sort of problems that people actually have.
One thing that travel affords is time to read. I managed to finish "The Time Traveler's Wife" by Audrey Niffenegger. If you don't know about this novel you can Google it. It became famous for 15 minutes when Brad Pitt and Jennifer Aniston bought the screen rights, though it now seems that neither wil appear in the movie which is apparently in production.
Time travel is used as a device to explore relationships, and why not? I am a science fiction fan and I had to defend this at a university entrance interview. I said it exposed people to extreme circumstances. Nothing more extreme than meeting your middle aged future husband when you are six or getting pregnant by a younger version of your husband after he had had a vasectomy deliberately to avoid the risk of further miscarriages.
The problem of time travel is changing the future. The famous Ray Bradbury story "Sound of Thunder" (which is featured in the Seattle Science Fiction Museum) has a dinosaur hunter treading on a butterfly and as a consequence America is changed from a democracy to a totalitarian state. Some would say that destroying the World Trade Center is having the same effect. Niffenegger avoids this conundrum, but it was a problem for the hero of the movie that I watched on the plane coming back. 'Deja Vu' was a litle piece of nonsense, but quite fun.
In a sense all travel is time travel. It is said that travel to New Zealand is like going back to 1957 - for me a very good year. In a way travel to Seattle was like going back to 1968; in Seattle at least the equation Iraq = Viet Nam seems self-evident. There are some obvious similarities, but to my mind tremendous differences. It is a false analogy, but it does emphasize how complex are different societies and how unexpected are the consequences of interfering in what you don't understand. A bit like time travel really.
Wednesday, March 21, 2007
Blighty
Tomorrow most of my family will be in America. Diane and I will be visiting Richard in Seattle and David will be in Florida working at some motor car race or other. Only the girls will be left behind in Blighty.
Blighty comes from the Hindi word 'bilayati' meaning foreign, and it was used in the British Raj to refer to things from the homeland. It became a popular term in World War One when a 'blighty wound' was one that meant shipping home to recouperate.
A blighter, on the other hand, is a contemptible person; one who casts a blight on his surroundings. In the 20th Century it lost its perjorative force and became a synonym for 'chap'. Chap, probably doesn't come from British India, despite "CHAP, a cast in BHAKKAR district of PUNJAB" from Wikipedia. It meant a customer from at least as early as 1715 and may derive from 'chapman' a dialect word for customer in the sixteenth Century. A 'chap' was part of the in-crowd in public-school lingo, the rest were 'oiks' or 'yobboes'. There is a lot of 'old-chapping' in Wodehouse. Of course it may have come full circle from the Romany 'chav', nowadays used as a term of abuse. The Wikipedia definition is "a mainly derogatory slang term in the United Kingdom for a subcultural stereotype fixated on fashions such as gold jewellery and 'designer' clothing. They are generally considered to have no respect for society, and be ignorant or unintelligent. The term appeared in mainstream dictionaries in 2005. The defining features of the stereotype include clothing in the Burberry pattern (notably a now-discontinued baseball cap) and from a variety of other casual and sportswear brands. Tracksuits, hoodies, sweatpants and baseball caps are particularly associated with this stereotype. Response to the term has ranged from amusement to criticism that it is a new manifestation of classism.
Chavs used to holiday in Benidorm but affluence has brought on the wanderlust. It is by no means unusual to see them in Barbados or the Seychelles. I doubt that the overcast skies of Seattle will attract them.
Blighty comes from the Hindi word 'bilayati' meaning foreign, and it was used in the British Raj to refer to things from the homeland. It became a popular term in World War One when a 'blighty wound' was one that meant shipping home to recouperate.
A blighter, on the other hand, is a contemptible person; one who casts a blight on his surroundings. In the 20th Century it lost its perjorative force and became a synonym for 'chap'. Chap, probably doesn't come from British India, despite "CHAP, a cast in BHAKKAR district of PUNJAB" from Wikipedia. It meant a customer from at least as early as 1715 and may derive from 'chapman' a dialect word for customer in the sixteenth Century. A 'chap' was part of the in-crowd in public-school lingo, the rest were 'oiks' or 'yobboes'. There is a lot of 'old-chapping' in Wodehouse. Of course it may have come full circle from the Romany 'chav', nowadays used as a term of abuse. The Wikipedia definition is "a mainly derogatory slang term in the United Kingdom for a subcultural stereotype fixated on fashions such as gold jewellery and 'designer' clothing. They are generally considered to have no respect for society, and be ignorant or unintelligent. The term appeared in mainstream dictionaries in 2005. The defining features of the stereotype include clothing in the Burberry pattern (notably a now-discontinued baseball cap) and from a variety of other casual and sportswear brands. Tracksuits, hoodies, sweatpants and baseball caps are particularly associated with this stereotype. Response to the term has ranged from amusement to criticism that it is a new manifestation of classism.
Chavs used to holiday in Benidorm but affluence has brought on the wanderlust. It is by no means unusual to see them in Barbados or the Seychelles. I doubt that the overcast skies of Seattle will attract them.
Monday, March 19, 2007
Life on Mars II
Caves spotted on Mars : Dark 'skylights' could be openings to Martian shelters.
The headline writer in Nature seems to have missed the point. The article refers not to little green men, but to the possiblity that these 'caves' might be places where water ice might collect - a necessary starting point for the generation of primitive 'life forms'.
If I were a betting man I might wager that this will all come to nothing, just like all the previous sightings of life on Mars. Still if you get a chance, do watch the TV program that I referred to earlier.
The headline writer in Nature seems to have missed the point. The article refers not to little green men, but to the possiblity that these 'caves' might be places where water ice might collect - a necessary starting point for the generation of primitive 'life forms'.
If I were a betting man I might wager that this will all come to nothing, just like all the previous sightings of life on Mars. Still if you get a chance, do watch the TV program that I referred to earlier.
Saturday, March 17, 2007
NICE for America
This from New Scientist
NICE, the body the looks at the cost-effectiveness of new treatments, has been operating in the UK for the past 8 years. Now, the US is considering a similar proposal in the shape of a proposed Comparative Effectiveness Board (CEB), which would review the evidence on how well drugs work and whether they are cost-effective. If necessary, the CEB would carry out its own clinical trials. The idea is to break the pharmaceutical industry's stranglehold on drug prices and stop it peddling marginally effective medicines. The drug industry is already expressing its displeasure at the idea of a government body judging a drug's value for money.
Support for such a body is growing in both the public and private healthcare arenas. “There are cultural differences about how the role of government is viewed, and most Americans tend to be on the side of ‘less government’,” says Steve Pearson, of Harvard Medical School and a key proponent of the CEB. “But that's starting to change, as people have problems affording healthcare, and something has to give.”
Although drugs accounted for only about 12 per cent of what the US spent on healthcare in 2003, the cost of drugs has been escalating. Figures released by the Department of Health & Human Services (DHHS) on 31 January show that spending on drugs soared sevenfold from $96 per person in 1980 to $709 in 2003, well ahead of the next highest
The Democrats want to bring the collective bargaining power of Medicare and Medicaid to bear on the pharmaceutical industry by removing 2003 legislation that prevents haggling with the pharmaceutical companies
Not surprisingly, the drug industry is against the idea of a federally funded gatekeeper that might meddle in their negotiations with healthcare providers. A year ago, the Pharmaceutical Research and Manufacturers of America, which represents US drug companies, warned that 400,000 people with Alzheimer's would be denied new drugs, as would 9 million suffering from osteoporosis, if a gatekeeper decided on access to medicines.
NICE, the body the looks at the cost-effectiveness of new treatments, has been operating in the UK for the past 8 years. Now, the US is considering a similar proposal in the shape of a proposed Comparative Effectiveness Board (CEB), which would review the evidence on how well drugs work and whether they are cost-effective. If necessary, the CEB would carry out its own clinical trials. The idea is to break the pharmaceutical industry's stranglehold on drug prices and stop it peddling marginally effective medicines. The drug industry is already expressing its displeasure at the idea of a government body judging a drug's value for money.
Support for such a body is growing in both the public and private healthcare arenas. “There are cultural differences about how the role of government is viewed, and most Americans tend to be on the side of ‘less government’,” says Steve Pearson, of Harvard Medical School and a key proponent of the CEB. “But that's starting to change, as people have problems affording healthcare, and something has to give.”
Although drugs accounted for only about 12 per cent of what the US spent on healthcare in 2003, the cost of drugs has been escalating. Figures released by the Department of Health & Human Services (DHHS) on 31 January show that spending on drugs soared sevenfold from $96 per person in 1980 to $709 in 2003, well ahead of the next highest
The Democrats want to bring the collective bargaining power of Medicare and Medicaid to bear on the pharmaceutical industry by removing 2003 legislation that prevents haggling with the pharmaceutical companies
Not surprisingly, the drug industry is against the idea of a federally funded gatekeeper that might meddle in their negotiations with healthcare providers. A year ago, the Pharmaceutical Research and Manufacturers of America, which represents US drug companies, warned that 400,000 people with Alzheimer's would be denied new drugs, as would 9 million suffering from osteoporosis, if a gatekeeper decided on access to medicines.
Wednesday, March 14, 2007
More on mavericks
Nikola Tesla, 10 July 1856 - 7 January 1943, was a world-renowned inventor, physicist, mechanical engineer and electrical engineer. He was ultimately ostracized and regarded as a mad scientist, and died impoverished and forgotten at the age of 86. An ethnic Serb who later became an American citizen, he is best known for his revolutionary work in electricity and magnetism. His most lasting legacy is the alternating current electric power system, but he also played an important part in the development of radio and television, robotics, remote control, radar and computer science. He laid the foundation for expansions of ballistics, nuclear power and theoretical physics. However, some of his ideas have been taken up by enthusiasts for UFOs and new age occultism. He was a man who constantly thought ‘outside the box’ and was opposed by the scientific establishment. Today he has an SI unit named after him, but in 1943 he was regarded as a maverick.
David Bohm, 20 December 1917- 27 October 1992 was an American-born quantum physicist, who left America under McCarthyism to live variously in Brazil, Israel and England, yet made significant contributions in the fields of theoretical physics, philosophy and neuropsychology, and to the Manhattan Project. None of this is disputed, though by a strange irony, he was denied access to his own PhD thesis, which was classified ‘Top Secret’ as it was used to develop the atom bomb. But an important part of his later work concerned holograms and here despite reverence for his emminence as physicist, his ideas were regarded as crackpot.
Edward Jenner, 17 May 1749 – 26 January 1823 was an English country doctor who studied nature and his natural surroundings from childhood and practiced medicine in Berkeley, Gloucestershire, England. He is famous as the first doctor to introduce and study the smallpox vaccine. Yet his Fellowship of the Royal Society was given for his work on cuckoos. He discovered that it was the fledgling cuckoo that expelled the other eggs from the nest, and that for the first 12 days of its life the fledgling had an egg shaped depression in its back to enable it to do so. When he introduced the practice of vaccination he faced opposition from the medical establishment. “Stick to your cuckoos, Jenner!” the chided him. Not being an MD or an FRCP he couldn’t get it accepted in London, and indeed when it was finally shown to work, the ‘variolation’ cabal attempted to steal it from him.
These are three among many mavericks who dared to challenge the scientific paradigm of the day. Of course, there are hundreds who try and are proved wrong. I am not arguing for the rightness of mavericks, simply that scientists, in being too protective of the current paradigm, put a brake on advances.
Dream the impossible dream, goes the song.
David Bohm, 20 December 1917- 27 October 1992 was an American-born quantum physicist, who left America under McCarthyism to live variously in Brazil, Israel and England, yet made significant contributions in the fields of theoretical physics, philosophy and neuropsychology, and to the Manhattan Project. None of this is disputed, though by a strange irony, he was denied access to his own PhD thesis, which was classified ‘Top Secret’ as it was used to develop the atom bomb. But an important part of his later work concerned holograms and here despite reverence for his emminence as physicist, his ideas were regarded as crackpot.
Edward Jenner, 17 May 1749 – 26 January 1823 was an English country doctor who studied nature and his natural surroundings from childhood and practiced medicine in Berkeley, Gloucestershire, England. He is famous as the first doctor to introduce and study the smallpox vaccine. Yet his Fellowship of the Royal Society was given for his work on cuckoos. He discovered that it was the fledgling cuckoo that expelled the other eggs from the nest, and that for the first 12 days of its life the fledgling had an egg shaped depression in its back to enable it to do so. When he introduced the practice of vaccination he faced opposition from the medical establishment. “Stick to your cuckoos, Jenner!” the chided him. Not being an MD or an FRCP he couldn’t get it accepted in London, and indeed when it was finally shown to work, the ‘variolation’ cabal attempted to steal it from him.
These are three among many mavericks who dared to challenge the scientific paradigm of the day. Of course, there are hundreds who try and are proved wrong. I am not arguing for the rightness of mavericks, simply that scientists, in being too protective of the current paradigm, put a brake on advances.
Dream the impossible dream, goes the song.
Tuesday, March 13, 2007
Academic freedom again
Further to the debate on academic freedom was this from the Sunday Telegraph of March 11th this year.
Scientists who questioned mankind's impact on climate change have received death threats and claim to have been shunned by the scientific community.
They say the debate on global warming has been "hijacked" by a powerful alliance of politicians, scientists and environmentalists who have stifled all questioning about the true environmental impact of carbon dioxide emissions.
Timothy Ball, a former climatology professor at the University of Winnipeg in Canada, has received five deaths threats by email since raising concerns about the degree to which man was affecting climate change.
One of the emails warned that, if he continued to speak out, he would not live to see further global warming.
"Western governments have pumped billions of dollars into careers and institutes and they feel threatened," said the professor.
"I can tolerate being called a skeptic because all scientists should be skeptics, but then they started calling us deniers, with all the connotations of the Holocaust. That is an obscenity. It has got really nasty and personal."
Last week, Professor Ball appeared in The Great Global Warming Swindle, a Channel 4 documentary in which several scientists claimed the theory of man-made global warming had become a "religion", forcing alternative explanations to be ignored.
Richard Lindzen, the professor of Atmospheric Science at Massachusetts Institute of Technology - who also appeared on the documentary - recently claimed: "Scientists who dissent from the alarmism have seen their funds disappear, their work derided, and themselves labeled as industry stooges.
"Consequently, lies about climate change gain credence even when they fly in the face of the science."
Dr Myles Allen, from Oxford University, agreed. He said: "The Green movement has hijacked the issue of climate change. It is ludicrous to suggest the only way to deal with the problem is to start micro managing everyone, which is what environmentalists seem to want to do."
Nigel Calder, a former editor of New Scientist, said: "Governments are trying to achieve unanimity by stifling any scientist who disagrees. Einstein could not have got funding under the present system."
Scientists who questioned mankind's impact on climate change have received death threats and claim to have been shunned by the scientific community.
They say the debate on global warming has been "hijacked" by a powerful alliance of politicians, scientists and environmentalists who have stifled all questioning about the true environmental impact of carbon dioxide emissions.
Timothy Ball, a former climatology professor at the University of Winnipeg in Canada, has received five deaths threats by email since raising concerns about the degree to which man was affecting climate change.
One of the emails warned that, if he continued to speak out, he would not live to see further global warming.
"Western governments have pumped billions of dollars into careers and institutes and they feel threatened," said the professor.
"I can tolerate being called a skeptic because all scientists should be skeptics, but then they started calling us deniers, with all the connotations of the Holocaust. That is an obscenity. It has got really nasty and personal."
Last week, Professor Ball appeared in The Great Global Warming Swindle, a Channel 4 documentary in which several scientists claimed the theory of man-made global warming had become a "religion", forcing alternative explanations to be ignored.
Richard Lindzen, the professor of Atmospheric Science at Massachusetts Institute of Technology - who also appeared on the documentary - recently claimed: "Scientists who dissent from the alarmism have seen their funds disappear, their work derided, and themselves labeled as industry stooges.
"Consequently, lies about climate change gain credence even when they fly in the face of the science."
Dr Myles Allen, from Oxford University, agreed. He said: "The Green movement has hijacked the issue of climate change. It is ludicrous to suggest the only way to deal with the problem is to start micro managing everyone, which is what environmentalists seem to want to do."
Nigel Calder, a former editor of New Scientist, said: "Governments are trying to achieve unanimity by stifling any scientist who disagrees. Einstein could not have got funding under the present system."
Thursday, March 08, 2007
TANK cells.
Have you heard of TANK cells? It stands for tumor activeated natural killer cells. Natural Killer cells are part of the non-specific immune system and are though to play a role in defence against tumors, though we have been very poor at recruiting them in clinical practice. It has now been shown that they can be activated by exposure to the acute lymphoblastic cell-line CTV-1. Once activated they kill acute myeloid leukemia cells with great facility. Indeed, they can each kill more than one leukemia cell; they are wasps not bees: they don't kill themselves while killing teh leukemia. The good thing about them is that they don't need to be matched, so anybody's cells can be harvested and activated and then infused into any patient. To prevent their rejection, the patient has to be given fludarabine and Campath, but they do not cause graft-versus-host disease. Coming soon to a clinical trial near you. I wonder if they kill CLL cells.
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