The end justifies the beans – Jack (of Beanstalk fame) – Stephen Sondheim
We are likely to live ten years longer than our parents, but eight of them will be filled with pain or decrepitude. – Jane Miller
What makes a good doctor? - Patients value communication and care, colleagues seek competence and camaraderie, medical students prize cheerfulness. By contrast, admission panels focus on chemistry grades. – The Lancet
"If voting changed anything, they'd make it illegal". Emma Goldman
"Why are you chanting 'Burn!' when you should be chanting 'Learn!' so you can 'Earn!'" – Martin Luther King
“The most incomprehensible thing about the Universe is that it is comprehensible". – Albert Einstein
The laws of physics were so uniquely conducive to human existence that the universe must be "a put-up job". – Fred Hoyle
The planet does not need humans – Al Gore (and James Lee)
“The brain is a wonderful organ; it starts the moment you get up in the morning and does not stop until you get to the office." - Robert Frost.
“We need to get some broad based support, to capture the public's imagination... So we have to offer up scary scenarios, make simplified, dramatic statements and make little mention of any doubts... Each of us has to decide what the right balance is between being effective and being honest." - Prof. Stephen Schneider, Stanford Professor of Climatology, lead author of many IPCC reports
“The data doesn't (sic) matter. We're not basing our recommendations on the data. We're basing them on the climate models.” - Prof. Chris Folland, Hadley Centre for Climate Prediction and Research
"It doesn't matter what is true, it only matters what people believe is true."
- Paul Watson, co-founder of Greenpeace
“These environmentalists are watermelons; green on the outside and red in the middle” - Warren T. Brookes
Monday, September 06, 2010
Saturday, September 04, 2010
Update on FCR
There has been a great kerfuffle about FCR recently. I have to admit that I was very dubious about this drug combination when it first came out. It was extremely popular in America following its introduction by MD Anderson Cancer Canter (MDACC), and produced higher response rates than any previous regimen. However, MDACC doesn't do phase III randomized controlled trials so it wasn't clear whether FCR was the best thing since color television or whether there was special pleading going on.
Looking at the clinical trials it seemed to be the case that the entry criteria weren't particularly stringent, that patients were younger than normal and often of early stage. Moreover, because the patients were sometimes only seen once at MDACC, then the subsequent courses given by local physicians, the long term consequences of FCR were not particularly well documented.
I have long been wary of fludarabine. I was the one who first recognized the severe autoimmine hemolytic anemia it can trigger and our group was one of the first to recognize that rarely it can cause myelodysplastic syndrome. Indeed I wrote an article in Nature Clinical Oncology, a little while ago, which was entitled FCR: No Country for Old Men. This was in response to a summary paper from MDACC on their experience with FCR. I quote from my paper:
"A large, nonrandomized, phase II trial of FCR in patients with CLL was performed at the MD Anderson Cancer Center.6 In this trial, 300 patients were treated every 4 weeks for a planned total of 6 courses of FCR (rituximab 375–500 mg/m2 on day 1, fludarabine 25–30 mg/m2 daily, cyclophosphamide 250–300 mg/m2 daily on days 1 to 3 of each course and days 2 to 4 for the first course only). The patients were followed up for a median of 6 years, and the complete response rate was 72%—far higher than for previous treatments such as fludarabine plus cyclophosphamide
(35%)7 or fludarabine alone (29%). In CLL, a complete response according to the 1996 National Cancer Institute criteria9 allows for a bonemarrow lymphocytosis of 30%, which might represent considerable residual disease. Consequently, methods for the detection of minimal residual disease have been developed that use either flow
cytometry or polymerase chain reaction (PCR). Tam and colleagues used both techniques and found that 35% of patients were negative for residual disease."
"Although their PCR technique achieved the new international standard of detecting
one tumor cell in 10,000, other researchers have described and used flow cytometry
and PCR techniques that are 5–10 times more sensitive. Among patients with a partial response or better (n = 285) the median time to progression was 80 months, with a projected 60% progression-free survival at 6 years. Again, this result is
impressive but it must be seen in the context of the characteristics of the patients treated. Firstly, the patients in this study were relatively young; the median age was 57 years, and only 14% were aged 70 years or older, whereas in the general CLL population, 70 years is the median age of presentation. As a group, patients over the age of 70 years were significantly less likely to complete the optimum six cycles of therapy (46% versus 79%; P <0.001) and significantly less likely to achieve complete remission (P = 0.02). Secondly, most modern prognostic markers such as ZAP-70 expression, IGHV mutational status and fluorescence in situ hybridization were not studied in this trial. CD38 expression was assessed, but only 21% of patients had more than 30% of cells that expressed this marker. The corresponding
percentage of patients treated in our center is 64%."
"Lacking a contemporary comparator group, the main interest in this trial is the long-term safety profile of the FCR regimen. The actuarial risk of Richter syndrome was 2.5% at 6 years – no more than for historical series. Likewise, the actuarial risk of myelodysplastic syndrome was only 2.8% at 6 years. The well-established effect of fludarabine in depleting circulating T cells is certainly responsible for the 10% risk of serious or opportunistic infections during the first year of remission and 4% risk in the second year. Four of the five late deaths from infection, however, were caused by bacteria rather than fungi or viruses."
"The most unexpected toxicity was persistent cytopenia after completion of therapy, which continued for at least 3 months. This effect occurred in 19% of patients; however, following recovery of blood counts, recurrent late cytopenic episodes occurred in 28% of patients, predominantly in the first year of remission. The use of salvage therapy for patients with persistent cytopenias who relapse is particularly demanding, both for the patient and physician."
Despite my reticence there is now clear evidence that FCR is a superior regimen in CLL. This comes from the German CLL8 trial, which still has not been published in a peer reviewed journal, but was presented at ASH in December 2009. This is how I reported what it found:
The German CLL8 trial was a large one, involving 817 patients with CLL that needed treating. They were randomized to either FC or FCR in standard doses. The group receiving FCR had a higher response rate (95.1 vs 88.4%) and more complete remissions (44.1 vs 21.8%; p<0.001) and a longer progression-free survival 51.8 months v 32.8 months (p<0.001). We've seen this sort of result before, but do the patients live any longer? Note that the follow up is relatively short (median just over 3 years). The Overall Survival rate was 84.1% in the FCR arm versus 79.0 % in the FC arm (p=0.01).
They were able to do a multivariate analysis to look for what factors predict poorer survival. Several factors acted as independent prognostic factors for both progression-free survival and overall survival, including age, sex, FCR-treatment v FC treatment, receiving fewer or more than 3 cycles of treatment, response, 17p-deletion, serum levels of thymidine kinase and ß2-microglobulin, and mutational status of the IGVH genes.
Adding rituximab seems to lead to more neutropenia, but this does not lead to more infections. I presume that the neutrophils are consumed by the CD20/anti-CD20 immune complexes. In fact there were more deaths in the FC arm (86/396, 21.7% versus 65/404, 16.1%). Most commonly death was cause by progressive disease (FC 48/86, FCR 33/65), but there were also more deaths from secondary malignancies in the FC arm (13/86 v 5/65). Of course, in this age group there were also deaths from unrelated causes. Treatment related mortality was just 2.0% in each arm.
One strange finding was that the benefit of FCR did not reach statistical significance for stage C patients (Rai stages III and IV). Why this was so is not clear, but it might be due to the relative immaturity of the study or it may be that these patients, with a higher tumor load, need more intensive treatment. Since platelets falling to below 100 or HB falling below 10 are indications for treatment, perhaps a higher threshold for starting treatment should be adopted.
To summarize: FCR is the only regimen that has been shown to lengthen life over what was previously believed to be the gold standard treatment. However, there are other acceptable treatments that have never been compared head-to-head with FCR. These include FR, FCR-lite, Bendamustine-rituximab and PCR. It is not known whether substituting ofatumumab for rituximab would be an improvement.
It is clear that FCR is too toxic for some patients, and in the UK the combination of chlorambucil and rituximab has recently been shown to be very well tolerated with a high response rate.
Looking at the clinical trials it seemed to be the case that the entry criteria weren't particularly stringent, that patients were younger than normal and often of early stage. Moreover, because the patients were sometimes only seen once at MDACC, then the subsequent courses given by local physicians, the long term consequences of FCR were not particularly well documented.
I have long been wary of fludarabine. I was the one who first recognized the severe autoimmine hemolytic anemia it can trigger and our group was one of the first to recognize that rarely it can cause myelodysplastic syndrome. Indeed I wrote an article in Nature Clinical Oncology, a little while ago, which was entitled FCR: No Country for Old Men. This was in response to a summary paper from MDACC on their experience with FCR. I quote from my paper:
"A large, nonrandomized, phase II trial of FCR in patients with CLL was performed at the MD Anderson Cancer Center.6 In this trial, 300 patients were treated every 4 weeks for a planned total of 6 courses of FCR (rituximab 375–500 mg/m2 on day 1, fludarabine 25–30 mg/m2 daily, cyclophosphamide 250–300 mg/m2 daily on days 1 to 3 of each course and days 2 to 4 for the first course only). The patients were followed up for a median of 6 years, and the complete response rate was 72%—far higher than for previous treatments such as fludarabine plus cyclophosphamide
(35%)7 or fludarabine alone (29%). In CLL, a complete response according to the 1996 National Cancer Institute criteria9 allows for a bonemarrow lymphocytosis of 30%, which might represent considerable residual disease. Consequently, methods for the detection of minimal residual disease have been developed that use either flow
cytometry or polymerase chain reaction (PCR). Tam and colleagues used both techniques and found that 35% of patients were negative for residual disease."
"Although their PCR technique achieved the new international standard of detecting
one tumor cell in 10,000, other researchers have described and used flow cytometry
and PCR techniques that are 5–10 times more sensitive. Among patients with a partial response or better (n = 285) the median time to progression was 80 months, with a projected 60% progression-free survival at 6 years. Again, this result is
impressive but it must be seen in the context of the characteristics of the patients treated. Firstly, the patients in this study were relatively young; the median age was 57 years, and only 14% were aged 70 years or older, whereas in the general CLL population, 70 years is the median age of presentation. As a group, patients over the age of 70 years were significantly less likely to complete the optimum six cycles of therapy (46% versus 79%; P <0.001) and significantly less likely to achieve complete remission (P = 0.02). Secondly, most modern prognostic markers such as ZAP-70 expression, IGHV mutational status and fluorescence in situ hybridization were not studied in this trial. CD38 expression was assessed, but only 21% of patients had more than 30% of cells that expressed this marker. The corresponding
percentage of patients treated in our center is 64%."
"Lacking a contemporary comparator group, the main interest in this trial is the long-term safety profile of the FCR regimen. The actuarial risk of Richter syndrome was 2.5% at 6 years – no more than for historical series. Likewise, the actuarial risk of myelodysplastic syndrome was only 2.8% at 6 years. The well-established effect of fludarabine in depleting circulating T cells is certainly responsible for the 10% risk of serious or opportunistic infections during the first year of remission and 4% risk in the second year. Four of the five late deaths from infection, however, were caused by bacteria rather than fungi or viruses."
"The most unexpected toxicity was persistent cytopenia after completion of therapy, which continued for at least 3 months. This effect occurred in 19% of patients; however, following recovery of blood counts, recurrent late cytopenic episodes occurred in 28% of patients, predominantly in the first year of remission. The use of salvage therapy for patients with persistent cytopenias who relapse is particularly demanding, both for the patient and physician."
Despite my reticence there is now clear evidence that FCR is a superior regimen in CLL. This comes from the German CLL8 trial, which still has not been published in a peer reviewed journal, but was presented at ASH in December 2009. This is how I reported what it found:
The German CLL8 trial was a large one, involving 817 patients with CLL that needed treating. They were randomized to either FC or FCR in standard doses. The group receiving FCR had a higher response rate (95.1 vs 88.4%) and more complete remissions (44.1 vs 21.8%; p<0.001) and a longer progression-free survival 51.8 months v 32.8 months (p<0.001). We've seen this sort of result before, but do the patients live any longer? Note that the follow up is relatively short (median just over 3 years). The Overall Survival rate was 84.1% in the FCR arm versus 79.0 % in the FC arm (p=0.01).
They were able to do a multivariate analysis to look for what factors predict poorer survival. Several factors acted as independent prognostic factors for both progression-free survival and overall survival, including age, sex, FCR-treatment v FC treatment, receiving fewer or more than 3 cycles of treatment, response, 17p-deletion, serum levels of thymidine kinase and ß2-microglobulin, and mutational status of the IGVH genes.
Adding rituximab seems to lead to more neutropenia, but this does not lead to more infections. I presume that the neutrophils are consumed by the CD20/anti-CD20 immune complexes. In fact there were more deaths in the FC arm (86/396, 21.7% versus 65/404, 16.1%). Most commonly death was cause by progressive disease (FC 48/86, FCR 33/65), but there were also more deaths from secondary malignancies in the FC arm (13/86 v 5/65). Of course, in this age group there were also deaths from unrelated causes. Treatment related mortality was just 2.0% in each arm.
One strange finding was that the benefit of FCR did not reach statistical significance for stage C patients (Rai stages III and IV). Why this was so is not clear, but it might be due to the relative immaturity of the study or it may be that these patients, with a higher tumor load, need more intensive treatment. Since platelets falling to below 100 or HB falling below 10 are indications for treatment, perhaps a higher threshold for starting treatment should be adopted.
To summarize: FCR is the only regimen that has been shown to lengthen life over what was previously believed to be the gold standard treatment. However, there are other acceptable treatments that have never been compared head-to-head with FCR. These include FR, FCR-lite, Bendamustine-rituximab and PCR. It is not known whether substituting ofatumumab for rituximab would be an improvement.
It is clear that FCR is too toxic for some patients, and in the UK the combination of chlorambucil and rituximab has recently been shown to be very well tolerated with a high response rate.
Thursday, September 02, 2010
Atrocities of God V The seven tribes of Deuteronomy 7
This will be my final journey into the Old Testament looking at the supposed atrocities of God. I shall list a few of them, but I think by now I have covered enough ground to lump them all together and demonstrate why they are not atrocities at all, but examples of God's grace and mercy.
Here are some examples quoted by the website Common Sense Atheism.
In Exodus 12:29, God the baby-killer slaughters all Egyptian firstborn children and cattle because their king was stubborn.
In Numbers 16:41-49, the Israelites complain that God is killing too many of them. So, God sends a plague that kills 14,000 more of them.
In 1 Samuel 6:19, God kills 50,000 men for peeking into the ark of the covenant.
In Numbers 31:7-18, the Israelites kill all the Midianites except for the virgins, whom they are allowed to rape as spoils of war.
In 2 Kings 2:23-24, some kids tease the prophet Elisha, and God sends bears to dismember them.
We could add others: the treatment of the Canaanites, the slaughter of the population of Jericho and the destruction of the Philistines, for example.
All such accusations stem from a misapprehension of God's nature. If you ask the average modern day man what he expects from a god, he would probably answer, a comfortable life, freedom from pain and suffering, prosperity, forgiveness for my misdemeanours, the odd miracle when Nature goes against me (like a cure for cancer and wonderful rescues from earthquakes and Chilean mining disasters) and a long life free from dementia. If you are looking for such a god you won't find one in Christianity.
God is not concerned with our luxury or even our comfort, but with our righteousness. As we have seen from the story of Sodom, God is concerned with justice, and you know, in our heart of hearts, so are we.
For all our best wishes to the copper miners in Chile, what would our feelings be about the mine owners, were it to be proved that they were negligent in ignoring warnings which might have prevented the disaster. Would we not demand justice?
Tony Blair has just published a book, which many people have regarded as self-justifying. They will never forgive him for invading Iraq. Many want him tried as a war criminal. They want their version of justice.
I will never forgive Diego Maradonna for that 'hand of God' goal against England in the 1986 World Cup. I bristle at the injustice of it.
How do we define justice? When it comes down to it we are always too self-interested to be truly just. Were the Americans right to declare independence from Britain in 1776? One man's freedom fighter is another man's terrorist. Today the Director General of the BBC admitted that the BBC was biased against Mrs Thatcher. He claims that the BBC no longer has a left-leaning agenda. The website Biased BBC disagrees. Yet Abraham declares, "Shall not the judge of all teh earth do right?" Somewhere, somehow, there has to be an absolute standard by which we judge everything else.
If you read through the Old Testament, especially in the first five books you will see that standard spelled out. We all know about the Ten Commandments, but read through Leviticus - I know many people have tried but few have succeeded. Law is piled upon law. The whole purpose of the Law of Moses is to demonstrate that by keeping the Law you cannot please God. I don't know whether you have ever tried - I have. It is just impossible. You keep falling short.
In the first Century AD a group of Jews gave it everything they had to try and keep the Law of Moses. They even tithed the herbs that grew wild in their gardens. They were called Pharisees. But just as they though they were making it, along came Jesus with a new interpretation of the Law which knocked them back. They were happy about not committing murder, but Jesus told them that even if they were angry with their brother they had already murdered him in their hearts, and although they might abstain from the physical act of adultery, if they looked at a woman lustfully they had already committed adultery with her in their hearts (remember how Playboy caught out Jimmy Carter with that one?) Then there was the question of camels and the eye of a needle so that all around him people were saying, "But that's impossible!"
And that is precisely what the Law is about. It is impossible to keep.
If you see this world as the main purpose of life - you are born, you live, you die, you rot - then there is no point in trying to justify God. God does not inhabit the atheist's universe.
I agree. Life is nasty, messy, unfair and short. But God sees things differently. The purpose of this life is to learn to be dependent on Him. From the time that Adam disobeyed God, the whole world has been laboring under a curse. No wonder everything seems unfair. That is the consequence of Adam's sin. Everyone deserves to die. A fair God cannot just wink at sin as if it never happened. That would be grossly unfair. It would mean that everything was founded on a lie. Instead, the world is founded on a great act of generosity and justice, on sacrifice and love. God himself took the punishment that was due to us so that He could look on us and not see our filthy rags, but the spotless garments of Jesus.
So what about those atrocities in the Old Testament? These people were atrociously wicked. "It is not for your righteousness or for the uprightness of your heart that you are going to possess their land, but it is because of the wickedness of these nations that the LORD your God is driving them out before you, in order to confirm the oath which the LORD swore to your fathers, to Abraham, Isaac and Jacob. (Deuteronomy 9:5)
For those multiculturists who think that every culture has its value and we should treat them all equally take a look at this passage from Deuteronomy:
"You shall not behave thus toward the LORD your God, for every abominable act which the LORD hates they have done for their gods; for they even burn their sons and daughters in the fire to their gods. (Deuteronomy 12:31)
The wickedness of these people is confirmed in other verses of the Bible (for example: "and the Avvites made Nibhaz and Tartak; and the Sepharvites burned their children in the fire to Adrammelech and Anammelech the gods of Sepharvaim. (2 Kings 17:31)".
So we see that these people are not quite as innocent as the atheists would like you to believe. God was not swift to judge. The book of Jonah describes how a nation can stave off their judgement by repentance. But for the Canaanites no such reprieve was forthcoming In Genesis 15:16 God tells Abraham in Canaan that his descendents will return to Canaan because ‘the sin of the Amorites (a name used for Canaanites) has not yet reached its full measure.’ When they did return under Joshua it was in part to wreak God’s wrath upon the Amorites.
God's judgment of people groups found in the Old Testament actually pales in comparison to the judgment He will render at the end of time. According to the New Testament Book of Revelation, God will judge and kill billions of people who reject Him when Jesus returns. But God is still patient. He has given time for today’s generation to repent.
If you do not acknowledge a God who judges according to His own standards then you either believe with Macbeth that life ‘is a tale told by an idiot, full of sound and fury, signifying nothing’, or you are a moral relativist who believes that right and wrong vary according to the situation. The Bible describes such a situation in the book of the Judges when ‘everyone did what was right in his own eyes’. Such a belief leads inevitably to chaos and conflict.
Dear reader, I urge you now to acknowledge Jesus as your Savior. There is still time. Surely, if you have seen what God can do, you must acknowledge that His wrath is real.
Here are some examples quoted by the website Common Sense Atheism.
In Exodus 12:29, God the baby-killer slaughters all Egyptian firstborn children and cattle because their king was stubborn.
In Numbers 16:41-49, the Israelites complain that God is killing too many of them. So, God sends a plague that kills 14,000 more of them.
In 1 Samuel 6:19, God kills 50,000 men for peeking into the ark of the covenant.
In Numbers 31:7-18, the Israelites kill all the Midianites except for the virgins, whom they are allowed to rape as spoils of war.
In 2 Kings 2:23-24, some kids tease the prophet Elisha, and God sends bears to dismember them.
We could add others: the treatment of the Canaanites, the slaughter of the population of Jericho and the destruction of the Philistines, for example.
All such accusations stem from a misapprehension of God's nature. If you ask the average modern day man what he expects from a god, he would probably answer, a comfortable life, freedom from pain and suffering, prosperity, forgiveness for my misdemeanours, the odd miracle when Nature goes against me (like a cure for cancer and wonderful rescues from earthquakes and Chilean mining disasters) and a long life free from dementia. If you are looking for such a god you won't find one in Christianity.
God is not concerned with our luxury or even our comfort, but with our righteousness. As we have seen from the story of Sodom, God is concerned with justice, and you know, in our heart of hearts, so are we.
For all our best wishes to the copper miners in Chile, what would our feelings be about the mine owners, were it to be proved that they were negligent in ignoring warnings which might have prevented the disaster. Would we not demand justice?
Tony Blair has just published a book, which many people have regarded as self-justifying. They will never forgive him for invading Iraq. Many want him tried as a war criminal. They want their version of justice.
I will never forgive Diego Maradonna for that 'hand of God' goal against England in the 1986 World Cup. I bristle at the injustice of it.
How do we define justice? When it comes down to it we are always too self-interested to be truly just. Were the Americans right to declare independence from Britain in 1776? One man's freedom fighter is another man's terrorist. Today the Director General of the BBC admitted that the BBC was biased against Mrs Thatcher. He claims that the BBC no longer has a left-leaning agenda. The website Biased BBC disagrees. Yet Abraham declares, "Shall not the judge of all teh earth do right?" Somewhere, somehow, there has to be an absolute standard by which we judge everything else.
If you read through the Old Testament, especially in the first five books you will see that standard spelled out. We all know about the Ten Commandments, but read through Leviticus - I know many people have tried but few have succeeded. Law is piled upon law. The whole purpose of the Law of Moses is to demonstrate that by keeping the Law you cannot please God. I don't know whether you have ever tried - I have. It is just impossible. You keep falling short.
In the first Century AD a group of Jews gave it everything they had to try and keep the Law of Moses. They even tithed the herbs that grew wild in their gardens. They were called Pharisees. But just as they though they were making it, along came Jesus with a new interpretation of the Law which knocked them back. They were happy about not committing murder, but Jesus told them that even if they were angry with their brother they had already murdered him in their hearts, and although they might abstain from the physical act of adultery, if they looked at a woman lustfully they had already committed adultery with her in their hearts (remember how Playboy caught out Jimmy Carter with that one?) Then there was the question of camels and the eye of a needle so that all around him people were saying, "But that's impossible!"
And that is precisely what the Law is about. It is impossible to keep.
If you see this world as the main purpose of life - you are born, you live, you die, you rot - then there is no point in trying to justify God. God does not inhabit the atheist's universe.
I agree. Life is nasty, messy, unfair and short. But God sees things differently. The purpose of this life is to learn to be dependent on Him. From the time that Adam disobeyed God, the whole world has been laboring under a curse. No wonder everything seems unfair. That is the consequence of Adam's sin. Everyone deserves to die. A fair God cannot just wink at sin as if it never happened. That would be grossly unfair. It would mean that everything was founded on a lie. Instead, the world is founded on a great act of generosity and justice, on sacrifice and love. God himself took the punishment that was due to us so that He could look on us and not see our filthy rags, but the spotless garments of Jesus.
So what about those atrocities in the Old Testament? These people were atrociously wicked. "It is not for your righteousness or for the uprightness of your heart that you are going to possess their land, but it is because of the wickedness of these nations that the LORD your God is driving them out before you, in order to confirm the oath which the LORD swore to your fathers, to Abraham, Isaac and Jacob. (Deuteronomy 9:5)
For those multiculturists who think that every culture has its value and we should treat them all equally take a look at this passage from Deuteronomy:
"You shall not behave thus toward the LORD your God, for every abominable act which the LORD hates they have done for their gods; for they even burn their sons and daughters in the fire to their gods. (Deuteronomy 12:31)
The wickedness of these people is confirmed in other verses of the Bible (for example: "and the Avvites made Nibhaz and Tartak; and the Sepharvites burned their children in the fire to Adrammelech and Anammelech the gods of Sepharvaim. (2 Kings 17:31)".
So we see that these people are not quite as innocent as the atheists would like you to believe. God was not swift to judge. The book of Jonah describes how a nation can stave off their judgement by repentance. But for the Canaanites no such reprieve was forthcoming In Genesis 15:16 God tells Abraham in Canaan that his descendents will return to Canaan because ‘the sin of the Amorites (a name used for Canaanites) has not yet reached its full measure.’ When they did return under Joshua it was in part to wreak God’s wrath upon the Amorites.
God's judgment of people groups found in the Old Testament actually pales in comparison to the judgment He will render at the end of time. According to the New Testament Book of Revelation, God will judge and kill billions of people who reject Him when Jesus returns. But God is still patient. He has given time for today’s generation to repent.
If you do not acknowledge a God who judges according to His own standards then you either believe with Macbeth that life ‘is a tale told by an idiot, full of sound and fury, signifying nothing’, or you are a moral relativist who believes that right and wrong vary according to the situation. The Bible describes such a situation in the book of the Judges when ‘everyone did what was right in his own eyes’. Such a belief leads inevitably to chaos and conflict.
Dear reader, I urge you now to acknowledge Jesus as your Savior. There is still time. Surely, if you have seen what God can do, you must acknowledge that His wrath is real.
Wednesday, September 01, 2010
Pakistan and cricket
The cricketing story at the moment is the revelation in the News of the World that a betting syndicate had suborned some Pakistani cricketers to influence the outcome of the Lord's Test Match against England. The allegation is that the individual, Mazhar Majeed, offered to fix matches for a payment of £150,000. As an earnest of his ability to arrange this, he offered to predict three no-balls in particular overs.
A no-ball occurs when a bowler gets too close to the batsman when delivering the ball. To control this a whitewashed line is drawn in front of the wicket (called the batting crease) Some part of the bowlers front foot must be behind that line when the ball is bowled, and if it is not, the umpire calls, "No-ball!" and the ball has to be delivered again and an extra run awarded to the batting side. On most occasions when a no-ball is balled the bowler's foot is a fraction of an inch over the line and sometimes the umpire misses the offence, so difficult is it to judge. In fact the cricketers have this part of the game well sorted and no-balls are a rarity in the game. Fewer than 1% of the balls bowled are no-balls.
Unfortunately for Mazhar Majeed the people that he was trying to sell his influence to were undercover reporters of the News of the World. He was being subjected to a sting. He claimed on film that he had control of 7 members of the Pakistani team. His boast that he could produce no-balls at will was confirmed when no-balls were bowled at precisely the predicted points. Such a coincidence could not have been produced without collusion.
In this particular Test Match England scored 233 more runs in one innings than Pakistan scored in two innings, so the defeat was overwhelming and three no-balls hardly affected the outcome. It seems like a trivial offence and so it would be were it not for the advent of spot-betting. Rather than gamble on the outcome of a match. punters bet on trivial events like whether rain will stop play during the second session of the day, or whether a particular player will be wearing sunscreen of how many wide balls will be bowled in an innings. If you can predict that the third ball of the fifth over will be a no-ball, you could easily get odds of 50 to one with bookmakers from the Indian subcontinent.
At the moment three Pakistani cricketers, captain of the Test team Salman Butt and fast bowlers Mohammad Asif and Mohammad Amir have been interrogated by Scotland Yard detectives. We have to be careful to continue to refer to 'alleged' offences, but TV replays of the no-ball show that the fast bowlers were over-stepping the crease not by fractions of an inch but by feet, so that there was no question of the umpire missing the offence.
There is some sympathy especially for Mohammad Amir who is only 18 and a fine prospect, but this is not the first time that the Pakistani team has been involved in cheating. Tampering with the ball to make it behave unpredictably when it is bowled has become very common, leading to Pakistan forfeiting a Test Match in 2006 and in 1987, before they introduced neutral umpires there was an an outrageous incident of partisanship by Pakistani umpire Shakoor Rana.
One feels for Pakistan. Following the machine-gunning of the bus of the Sri Lankan Test team, Test Matches are no longer played in Pakistan. With terrorists controling the North West frontier and an area the size of England submerged beneath the flooded Indus river, Pakistan is not a happy place. Cricket is the national game in Pakistan and for many years one of their players, Hanif Mohammed, held the world record for the highest score (365) in Test cricket. They are a proud nation and this incident has been the final straw in a bleak year.
The background to this story is that gambling is illegal in Pakistan - which does not allow bookmakers legal redress. Pakistani cricketers earn much less than their counterparts in other cricketing nations, which leaves players more open to temptation. Corruption is rife in Pakistani life. It is said that fifty families exert feudal control over everything that happens in Pakistan and each has its fingers in the corruption pie. In the past Pakistan has made examples of individuals with life bans for cheating cricketers, but by toppling a fallen idol, the authorities are not dealing with the foundations of the problem.
I might imply that this problem as its roots in Islam, but that would be unfair. The most notorious example of match fixing was by the South African captain Hansie Cronje, who was supposedly a devout Christian.
A no-ball occurs when a bowler gets too close to the batsman when delivering the ball. To control this a whitewashed line is drawn in front of the wicket (called the batting crease) Some part of the bowlers front foot must be behind that line when the ball is bowled, and if it is not, the umpire calls, "No-ball!" and the ball has to be delivered again and an extra run awarded to the batting side. On most occasions when a no-ball is balled the bowler's foot is a fraction of an inch over the line and sometimes the umpire misses the offence, so difficult is it to judge. In fact the cricketers have this part of the game well sorted and no-balls are a rarity in the game. Fewer than 1% of the balls bowled are no-balls.
Unfortunately for Mazhar Majeed the people that he was trying to sell his influence to were undercover reporters of the News of the World. He was being subjected to a sting. He claimed on film that he had control of 7 members of the Pakistani team. His boast that he could produce no-balls at will was confirmed when no-balls were bowled at precisely the predicted points. Such a coincidence could not have been produced without collusion.
In this particular Test Match England scored 233 more runs in one innings than Pakistan scored in two innings, so the defeat was overwhelming and three no-balls hardly affected the outcome. It seems like a trivial offence and so it would be were it not for the advent of spot-betting. Rather than gamble on the outcome of a match. punters bet on trivial events like whether rain will stop play during the second session of the day, or whether a particular player will be wearing sunscreen of how many wide balls will be bowled in an innings. If you can predict that the third ball of the fifth over will be a no-ball, you could easily get odds of 50 to one with bookmakers from the Indian subcontinent.
At the moment three Pakistani cricketers, captain of the Test team Salman Butt and fast bowlers Mohammad Asif and Mohammad Amir have been interrogated by Scotland Yard detectives. We have to be careful to continue to refer to 'alleged' offences, but TV replays of the no-ball show that the fast bowlers were over-stepping the crease not by fractions of an inch but by feet, so that there was no question of the umpire missing the offence.
There is some sympathy especially for Mohammad Amir who is only 18 and a fine prospect, but this is not the first time that the Pakistani team has been involved in cheating. Tampering with the ball to make it behave unpredictably when it is bowled has become very common, leading to Pakistan forfeiting a Test Match in 2006 and in 1987, before they introduced neutral umpires there was an an outrageous incident of partisanship by Pakistani umpire Shakoor Rana.
One feels for Pakistan. Following the machine-gunning of the bus of the Sri Lankan Test team, Test Matches are no longer played in Pakistan. With terrorists controling the North West frontier and an area the size of England submerged beneath the flooded Indus river, Pakistan is not a happy place. Cricket is the national game in Pakistan and for many years one of their players, Hanif Mohammed, held the world record for the highest score (365) in Test cricket. They are a proud nation and this incident has been the final straw in a bleak year.
The background to this story is that gambling is illegal in Pakistan - which does not allow bookmakers legal redress. Pakistani cricketers earn much less than their counterparts in other cricketing nations, which leaves players more open to temptation. Corruption is rife in Pakistani life. It is said that fifty families exert feudal control over everything that happens in Pakistan and each has its fingers in the corruption pie. In the past Pakistan has made examples of individuals with life bans for cheating cricketers, but by toppling a fallen idol, the authorities are not dealing with the foundations of the problem.
I might imply that this problem as its roots in Islam, but that would be unfair. The most notorious example of match fixing was by the South African captain Hansie Cronje, who was supposedly a devout Christian.
Tuesday, August 31, 2010
New blood vessels in CLL
We are too readily seduced by what is going on in the blood in CLL. The real deal is what is happening in the lymph nodes. Like in other cancers, a major factor in the progression of the disease is the formation of new blood vessels. In last week's Blood a paper from Italy explores the relationship between blood levels of Angiopoietin-2 and prognosis. Angiopoietin-2 is a glycoprotein which destabilizes blood vessels causing them to revert to a more plastic state and making them more succeptible to the effect of vascular endothelial growth factor (VEGF). It is secreted by CLL cells, especially those that are CD38 positive. unsurprisingly, this paper finds that high levels of Angiopoietin-2 correlate with a poor prognosis.
My friend and colleague, Steve Devereux, suggested to me a couple of years ago that CLL might benefit from treatment with Avastin. Alas, he couldn't raise a grant to study the question, but this is further evidence that he may have been right.
My friend and colleague, Steve Devereux, suggested to me a couple of years ago that CLL might benefit from treatment with Avastin. Alas, he couldn't raise a grant to study the question, but this is further evidence that he may have been right.
More on Scientific Fraud
From Today's New Scientist:
HARVARD University has confirmed that it has found evidence of misconduct by Marc Hauser, one of the leading lights in the field of animal cognition.
In a letter to Harvard researchers on 20 August, dean of arts and sciences Michael Smith said that Hauser was “solely responsible” for eight instances of scientific misconduct. Three were in papers already identified as targets for a three-year probe by the university. The other five were in studies corrected before being published or which did not lead to papers.
The letter says that “there were problems involving data acquisition, data analysis, data retention, and the reporting of research methodologies and results”. Harvard says it has moved to “impose appropriate sanctions”, but does not say what they are.
Following Harvard's announcement, Hauser also commented for the first time. “I am deeply sorry for the problems this case has caused to my students, my colleagues, and my university,” he wrote, in a statement emailed to New Scientist.
Federal agencies that provided grants for Hauser's work and the US Attorney for the District of Massachusetts are still investigating.
HARVARD University has confirmed that it has found evidence of misconduct by Marc Hauser, one of the leading lights in the field of animal cognition.
In a letter to Harvard researchers on 20 August, dean of arts and sciences Michael Smith said that Hauser was “solely responsible” for eight instances of scientific misconduct. Three were in papers already identified as targets for a three-year probe by the university. The other five were in studies corrected before being published or which did not lead to papers.
The letter says that “there were problems involving data acquisition, data analysis, data retention, and the reporting of research methodologies and results”. Harvard says it has moved to “impose appropriate sanctions”, but does not say what they are.
Following Harvard's announcement, Hauser also commented for the first time. “I am deeply sorry for the problems this case has caused to my students, my colleagues, and my university,” he wrote, in a statement emailed to New Scientist.
Federal agencies that provided grants for Hauser's work and the US Attorney for the District of Massachusetts are still investigating.
Saturday, August 28, 2010
Sharia Law
In 2008 the Archbishop of Canterbury was quoted as saying, "There is a place for finding what would be a constructive accommodation with some aspects of Muslim law, as we already do with some other aspects of religious law."
Suhaib Hasan, Secretary General of the Islamic Sharia Council, has stated, "If Sharia law is implemented, then you can turn this country (the UK) into a haven of peace because once a thief's hand is cut off nobody is going to steal. Once, just only once, if an adulterer is stoned nobody is going to commit this crime at all. We want to offer it to the British society. If they accept it, if they accept it, it is for their good and if they don't accept it they'll need more and more prisons.
Just imagine if a revered cleric had made the Archbishop's statement in Saudi Arabia or Pakistan, substituting the word 'Christian' for 'Muslim'. Would the revered cleric's head still be in contact with his body?
Just imagine if the Archbishop had made Suhaib Hasan's statement in the UK. He would have been pilloried as a Nazi.
Here are some of the tenets of Sharia law. See if you are keen for any to be adopted.
In the Civil code:
A woman's testimony is worth only half of a man's; though in some sharia cases it is completely unacceptable.
A man can have four wives and can divorce his wife by a simple declaration.
A woman can have only one husband at a time and must give justifications for requesting a divorce, some of which are extremely difficult to prove.
The father regains custody of his children when they reach a certain age, or sooner if the woman remarries.
Sons are entitled to double inheritance compared to daughters.
In the Penal code:
Married adulterers are to be stoned to death.
Theft is punishable by amputation.
Drinking alcohol is punishable by flogging.
Highway robbery is punishable by crucifixion.
Apostasy (leaving Islam) is punishable by death. Although some schools believe that this does not apply to women and children, all schools believe it applies to adult males.
Homosexual behaviour is punishable by death.
Eating during daytime during Ramadan is punishable by imprisonment or flogging.
Improper veiling of a woman is punishable by fines, imprisonment or threats.
The pressure to introduce Sharia law into Britain is being opposed by a Human Rights group, One Law for All who have issued a report, Sharia Law in Britain: A threat to One Law for All and Equal Rights.
As the report states: Sharia law is practiced in Britain primarily by Sharia Councils and Muslims Arbitration Tribunals. Both operate on religious principles and are harmful to women although Muslim Arbitration Tribunals are wrongly regarded as being of more concern because they operate as tribunals under the Arbitration Act 1996, making their rulings binding in law.
Sharia Councils, on the other hand, claim to mediate on family issues but in practice often this differs little from arbitration: they frequently ask those appearing before them to sign an agreement to abide by their decisions; they call themselves courts, and the presiding imams, judges. Their decisions are then imposed and regarded as having the weight of legal judgements.
There is neither control over the appointment of “judges” in Sharia Councils or Tribunals nor an independent mechanism for monitoring them. Clients often do not have access to legal advice and representation. The proceedings are not recorded, nor are there any searchable legal judgements, nor any real right of appeal.
Sharia law cannot be compared to secular legal systems because it is considered sacred law that cannot be challenged. There is no scope to look at the interests of the individuals involved, as required by UK family law.
These legal processes ignore both common law and due process, far less Human Rights, and provide little protection and safety for women in violent situations.
There is a general assumption that those who attend Sharia courts do so voluntarily and that unfair decisions can be challenged in a British court. Many of the principles of Sharia law are contrary to British law and public policy, and would in theory therefore be unlikely to be upheld in a British court. In reality, however, women are often pressured by their families into going to these courts and adhering to unfair decisions, and may lack knowledge of English and their rights under British law. Moreover, refusal to settle a dispute in a Sharia court can give rise to threats and intimidation, or at best being ostracised.
According to Maryam Namazie, spokesperson of the One Law for All Campaign and an author of the report, “The existence of a parallel legal system that is denying a large section of the British population their fundamental human rights is scandalous. Our findings show that it is essential to abolish all religious courts in the UK. Their very existence and legitimisation puts pressure on vulnerable women not to assert their civil rights in a British court. As long as Sharia Councils and Tribunals are allowed to continue to make rulings on issues of family law, women will be pressured into accepting decisions which are prejudicial to them and their children.”
Richard Dawkins is certainly no favourite of mine but even he laments the decline of Christianity in this country. I quote, "There are no Christians, as far as I know, blowing up buildings. I am not aware of any Christian suicide bombers. I am not aware of any major Christian denomination that believes the penalty for apostasy is death. I have mixed feelings about the decline of Christianity, insofar as Christianity might be a bulwark against something worse."
Suhaib Hasan, Secretary General of the Islamic Sharia Council, has stated, "If Sharia law is implemented, then you can turn this country (the UK) into a haven of peace because once a thief's hand is cut off nobody is going to steal. Once, just only once, if an adulterer is stoned nobody is going to commit this crime at all. We want to offer it to the British society. If they accept it, if they accept it, it is for their good and if they don't accept it they'll need more and more prisons.
Just imagine if a revered cleric had made the Archbishop's statement in Saudi Arabia or Pakistan, substituting the word 'Christian' for 'Muslim'. Would the revered cleric's head still be in contact with his body?
Just imagine if the Archbishop had made Suhaib Hasan's statement in the UK. He would have been pilloried as a Nazi.
Here are some of the tenets of Sharia law. See if you are keen for any to be adopted.
In the Civil code:
A woman's testimony is worth only half of a man's; though in some sharia cases it is completely unacceptable.
A man can have four wives and can divorce his wife by a simple declaration.
A woman can have only one husband at a time and must give justifications for requesting a divorce, some of which are extremely difficult to prove.
The father regains custody of his children when they reach a certain age, or sooner if the woman remarries.
Sons are entitled to double inheritance compared to daughters.
In the Penal code:
Married adulterers are to be stoned to death.
Theft is punishable by amputation.
Drinking alcohol is punishable by flogging.
Highway robbery is punishable by crucifixion.
Apostasy (leaving Islam) is punishable by death. Although some schools believe that this does not apply to women and children, all schools believe it applies to adult males.
Homosexual behaviour is punishable by death.
Eating during daytime during Ramadan is punishable by imprisonment or flogging.
Improper veiling of a woman is punishable by fines, imprisonment or threats.
The pressure to introduce Sharia law into Britain is being opposed by a Human Rights group, One Law for All who have issued a report, Sharia Law in Britain: A threat to One Law for All and Equal Rights.
As the report states: Sharia law is practiced in Britain primarily by Sharia Councils and Muslims Arbitration Tribunals. Both operate on religious principles and are harmful to women although Muslim Arbitration Tribunals are wrongly regarded as being of more concern because they operate as tribunals under the Arbitration Act 1996, making their rulings binding in law.
Sharia Councils, on the other hand, claim to mediate on family issues but in practice often this differs little from arbitration: they frequently ask those appearing before them to sign an agreement to abide by their decisions; they call themselves courts, and the presiding imams, judges. Their decisions are then imposed and regarded as having the weight of legal judgements.
There is neither control over the appointment of “judges” in Sharia Councils or Tribunals nor an independent mechanism for monitoring them. Clients often do not have access to legal advice and representation. The proceedings are not recorded, nor are there any searchable legal judgements, nor any real right of appeal.
Sharia law cannot be compared to secular legal systems because it is considered sacred law that cannot be challenged. There is no scope to look at the interests of the individuals involved, as required by UK family law.
These legal processes ignore both common law and due process, far less Human Rights, and provide little protection and safety for women in violent situations.
There is a general assumption that those who attend Sharia courts do so voluntarily and that unfair decisions can be challenged in a British court. Many of the principles of Sharia law are contrary to British law and public policy, and would in theory therefore be unlikely to be upheld in a British court. In reality, however, women are often pressured by their families into going to these courts and adhering to unfair decisions, and may lack knowledge of English and their rights under British law. Moreover, refusal to settle a dispute in a Sharia court can give rise to threats and intimidation, or at best being ostracised.
According to Maryam Namazie, spokesperson of the One Law for All Campaign and an author of the report, “The existence of a parallel legal system that is denying a large section of the British population their fundamental human rights is scandalous. Our findings show that it is essential to abolish all religious courts in the UK. Their very existence and legitimisation puts pressure on vulnerable women not to assert their civil rights in a British court. As long as Sharia Councils and Tribunals are allowed to continue to make rulings on issues of family law, women will be pressured into accepting decisions which are prejudicial to them and their children.”
Richard Dawkins is certainly no favourite of mine but even he laments the decline of Christianity in this country. I quote, "There are no Christians, as far as I know, blowing up buildings. I am not aware of any Christian suicide bombers. I am not aware of any major Christian denomination that believes the penalty for apostasy is death. I have mixed feelings about the decline of Christianity, insofar as Christianity might be a bulwark against something worse."
Friday, August 27, 2010
How does rituximab work?
There is no doubt that rituximab was the drug of the decade as far as sufferers from lymphoid malignancies are concerned, but the big question is why does it work? After all, I spent nearly thirty years testing monoclonal antibodies as treatments for lymphoma with very disappointing results. Studies using anti-idiotype, anti-CD5, anti-CD19, anti-CD22, anti-CD23 and anti-CD37 were all very disappointing, but by a lucky chance the anti-CD20s were effective. Why?
We know that the CD20 molecule is an unusual one, but there is one loop that stands out from the cell surface, though it never gets far from the surface. It is against this loop that most of the antibodies (including rituximab) react. There is a much smaller loop (on the left in the diagram) that hardly protrudes from the surface at all and it is against this that the antibody ofatumumab reacts.
My ex-colleagues in Southampton, Mark Cragg and Martin Glennie have been beavering away at this topic for years and in three recent papers that have described what they think is going on (Lim et al Haematologica 2010; 95:135-143; Beers et al Blood 2010; 115:5191-5201; and Beers et al Semin Hematol 2010; 47:107-114.). In this article I will try to distill what they have discovered into simple language.
Simply binding an antibody to a leukemia cell isn't enough to kill that cell. Usually some sort of effector mechanism is necessary to kill the cell. When we experiment with B cells and antibody in a test tube, it becomes apparent that there are a number of means of killing those cells. The easiest to demonstrate is Complement Dependent Cytotoxicity (CDC). Complement is a series of proteins labelled C1 to C9 which form a cascade of reactions eventually ending up by punching holes in the target cell. When you have a blood transfusion and get the wrong blood group it is CDC that destroys your blood cells (and may kill you), but it is not clear that this is an important mechanism inside the body even if it does work in the test tube.
You can destroy Complement by heating serum to 56 degrees Celsius or in an animal by injecting Cobra Venom Factor. In this way you can determine whether CDC is an important mechanism. In general terms, most investigators do not think it is an important mechanism in human antibody therapy.
Not all anti-CD20 antibodies permit CDC and Cragg and Glennie have divided monoclonal anti-CD20s into those that do (Type I) and those that don't (Type II). Rituximab is a Type I antibody. Type I antibodies have other characteristics, chief of which is to redistribute CD20 into lipid rafts which are then internalized, thus clearing the antigen from the surface. This process is known as antigenic modulation, which I have written about earlier.
There was much confusion about antigenic modulation, and it has always been said that CD20 is one of the few antigens that doesn't modulate, which is why antibodies against it work so well. That turns out to be true for some types of lymphocytes and not for others. Cells from diffuse large B-cell lymphoma and from follicular lymphoma and from some lymphoblastoid cell lines are poor at antigenic modulation, whereas other cell lines and cells from mantle cell lymphoma are much better at it. Best of all are CLL cells. Normal B cells are also good modulators.
Antigenic modulation is distinct from antigen shaving in which the antigen/antibody complex is skimmed from the surface of the malignant B cell by macrophages, usually in the spleen. With antigenic modulation the antibody is internalized by the malignant B cells. Note that both these mechanisms consume the monoclonal antibody and may account for the more rapid than expected clearance of antibody from the circulation.
Most people believe that the most important method of killing that rituximab uses is ADCC which stands for Antibody Dependent Cellular Cytoxicity. This process uses other cells (either NK cells or macrophages) to kill the tumor cell. When the antibody latches on to the CD20, the other end of the molecule sticks out away from the cell surface. This is known as the Fc portion of the molecule (the name comes from the 1950s when immunoglobulin molecules were broken up by various chemicals; the Fc portion was the fraction that could be crystalized). NK cells and macrophages have receptors that recognize Fc (called Fc receptors and labelled CD16, CD32 and CD64). Certain individuals have minor molecular variations (polymorphisms) of CD16 and CD32 which make their Fc receptors less effective. If these people get follicular lymphoma then rituximab works less well than in people without the polymorphisms. However these polymorphisms do not affect the outcome of CLL patients treated with FCR, suggesting that rituximab may act differently in CLL.
However, Complement activation may still be important. It seems likely that activation of Complement is the cause of the acute 'allergic' reaction caused by the first dose of rituximab, which is especially bad where there is a high white count. It is my opinion that the anaphylactoid fragments of Complement, C3a and C5a are responsible. Furthermore, there is evidence that both C3b and C5b inhibit ADCC.
What about Type II antibodies? There aren't very many. The best known is tositumomab, the antibody that is labelled with radioactive iodine in Bexxar. These antibodies do not activate complement and do not push CD20 into lipid rafts. Neither do they cause antigenic modulation. But do they kill tumor cells? They can certainly activate ADCC, but they also have another mechanism of cytotoxicity. This form of killing involves homotypic adhesion, which simply means that two tumor cells stick together. It is known that the process requires cholesterol and is energy dependent. It involves mitochondria moving within the cells to the area where they are in contact. Cell death is caspase independent, which means that it doesn't use apoptosis and is therefore likely to be effective in p53 deficient tumors. The killing requires lysosomes which swell and release their contents into the cytoplasm and extracellular space. Lysosomes are spherical organelles that contain enzymes (acid hydrolases) that break up endocytized materials and cellular debris. If they release their enzymes into the cytoplasm, it's like letting a tiger out of its cage. Something's going to die - in this case, the cell.
Of the new antibodies available in the clinic or in trials, ofatumumab is a Type I antibody whose ability to stay on the surface (because it goes for the little loop, not the big one) for a long time negates the negative effect of antigenic modulation. On the other hand, GA101 is a type II antibody. It has good direct cell killing and its Fc has been optimized by adding the correct sugars to the amino acids so that ADCC has been improved.
We know that the CD20 molecule is an unusual one, but there is one loop that stands out from the cell surface, though it never gets far from the surface. It is against this loop that most of the antibodies (including rituximab) react. There is a much smaller loop (on the left in the diagram) that hardly protrudes from the surface at all and it is against this that the antibody ofatumumab reacts.My ex-colleagues in Southampton, Mark Cragg and Martin Glennie have been beavering away at this topic for years and in three recent papers that have described what they think is going on (Lim et al Haematologica 2010; 95:135-143; Beers et al Blood 2010; 115:5191-5201; and Beers et al Semin Hematol 2010; 47:107-114.). In this article I will try to distill what they have discovered into simple language.
Simply binding an antibody to a leukemia cell isn't enough to kill that cell. Usually some sort of effector mechanism is necessary to kill the cell. When we experiment with B cells and antibody in a test tube, it becomes apparent that there are a number of means of killing those cells. The easiest to demonstrate is Complement Dependent Cytotoxicity (CDC). Complement is a series of proteins labelled C1 to C9 which form a cascade of reactions eventually ending up by punching holes in the target cell. When you have a blood transfusion and get the wrong blood group it is CDC that destroys your blood cells (and may kill you), but it is not clear that this is an important mechanism inside the body even if it does work in the test tube.
You can destroy Complement by heating serum to 56 degrees Celsius or in an animal by injecting Cobra Venom Factor. In this way you can determine whether CDC is an important mechanism. In general terms, most investigators do not think it is an important mechanism in human antibody therapy.
Not all anti-CD20 antibodies permit CDC and Cragg and Glennie have divided monoclonal anti-CD20s into those that do (Type I) and those that don't (Type II). Rituximab is a Type I antibody. Type I antibodies have other characteristics, chief of which is to redistribute CD20 into lipid rafts which are then internalized, thus clearing the antigen from the surface. This process is known as antigenic modulation, which I have written about earlier.
There was much confusion about antigenic modulation, and it has always been said that CD20 is one of the few antigens that doesn't modulate, which is why antibodies against it work so well. That turns out to be true for some types of lymphocytes and not for others. Cells from diffuse large B-cell lymphoma and from follicular lymphoma and from some lymphoblastoid cell lines are poor at antigenic modulation, whereas other cell lines and cells from mantle cell lymphoma are much better at it. Best of all are CLL cells. Normal B cells are also good modulators.
Antigenic modulation is distinct from antigen shaving in which the antigen/antibody complex is skimmed from the surface of the malignant B cell by macrophages, usually in the spleen. With antigenic modulation the antibody is internalized by the malignant B cells. Note that both these mechanisms consume the monoclonal antibody and may account for the more rapid than expected clearance of antibody from the circulation.
Most people believe that the most important method of killing that rituximab uses is ADCC which stands for Antibody Dependent Cellular Cytoxicity. This process uses other cells (either NK cells or macrophages) to kill the tumor cell. When the antibody latches on to the CD20, the other end of the molecule sticks out away from the cell surface. This is known as the Fc portion of the molecule (the name comes from the 1950s when immunoglobulin molecules were broken up by various chemicals; the Fc portion was the fraction that could be crystalized). NK cells and macrophages have receptors that recognize Fc (called Fc receptors and labelled CD16, CD32 and CD64). Certain individuals have minor molecular variations (polymorphisms) of CD16 and CD32 which make their Fc receptors less effective. If these people get follicular lymphoma then rituximab works less well than in people without the polymorphisms. However these polymorphisms do not affect the outcome of CLL patients treated with FCR, suggesting that rituximab may act differently in CLL.
However, Complement activation may still be important. It seems likely that activation of Complement is the cause of the acute 'allergic' reaction caused by the first dose of rituximab, which is especially bad where there is a high white count. It is my opinion that the anaphylactoid fragments of Complement, C3a and C5a are responsible. Furthermore, there is evidence that both C3b and C5b inhibit ADCC.
What about Type II antibodies? There aren't very many. The best known is tositumomab, the antibody that is labelled with radioactive iodine in Bexxar. These antibodies do not activate complement and do not push CD20 into lipid rafts. Neither do they cause antigenic modulation. But do they kill tumor cells? They can certainly activate ADCC, but they also have another mechanism of cytotoxicity. This form of killing involves homotypic adhesion, which simply means that two tumor cells stick together. It is known that the process requires cholesterol and is energy dependent. It involves mitochondria moving within the cells to the area where they are in contact. Cell death is caspase independent, which means that it doesn't use apoptosis and is therefore likely to be effective in p53 deficient tumors. The killing requires lysosomes which swell and release their contents into the cytoplasm and extracellular space. Lysosomes are spherical organelles that contain enzymes (acid hydrolases) that break up endocytized materials and cellular debris. If they release their enzymes into the cytoplasm, it's like letting a tiger out of its cage. Something's going to die - in this case, the cell.
Of the new antibodies available in the clinic or in trials, ofatumumab is a Type I antibody whose ability to stay on the surface (because it goes for the little loop, not the big one) for a long time negates the negative effect of antigenic modulation. On the other hand, GA101 is a type II antibody. It has good direct cell killing and its Fc has been optimized by adding the correct sugars to the amino acids so that ADCC has been improved.
Wednesday, August 25, 2010
Latest on my health
I rang the oncologist yesterday and we agreed that I postpone my appointment with him until I have seen the surgeon at the end of next month. I will have a CT scan midway through September.
My weight is gradually creeping back up - I am now 182 pounds having been 200 before the operation and 177 at my lowest. I still get a bit of colic and I take antispasmodics, but on the whole my anastomosis is working fine. Most evenings I feel quite bloated by bedtime. My strength is returning and I no longer need an afternoon nap. I am driving short distances - my first trip to the bank this morning and I polished the wood block floor that extends through most of the ground floor of out house today. I plan to attend a lecture in Southampton next week. This will entail a 60 mile round trip in the Jaguar.
I hope that I might be fit enough to attend the UKCLL Forum meeting in London in September.
I have restarted editing Leukemia Research and am refereeing for Blood and British Journal of Haematology.
The CT scan and appointment with the oncologist will determine whether I am to have further chemotherapy
My weight is gradually creeping back up - I am now 182 pounds having been 200 before the operation and 177 at my lowest. I still get a bit of colic and I take antispasmodics, but on the whole my anastomosis is working fine. Most evenings I feel quite bloated by bedtime. My strength is returning and I no longer need an afternoon nap. I am driving short distances - my first trip to the bank this morning and I polished the wood block floor that extends through most of the ground floor of out house today. I plan to attend a lecture in Southampton next week. This will entail a 60 mile round trip in the Jaguar.
I hope that I might be fit enough to attend the UKCLL Forum meeting in London in September.
I have restarted editing Leukemia Research and am refereeing for Blood and British Journal of Haematology.
The CT scan and appointment with the oncologist will determine whether I am to have further chemotherapy
Monday, August 23, 2010
Iron deficiency in CLL
I am grateful to correspondent,Lynn, for drawing attention to something that had passed me by while I was ill. In distinguishing between iron deficiency and the anemia of chronic disorders, it is usually sufficient to measure the serum iron, the total iron binding capacity and the serum ferritin. In both, the serum iron will be low, but the iron binding capacity goes up in iron deficiency and down in the anemia of chronic disorders. Serum ferritin goes down in iron deficiency and is normal or raised in chronic disorders.
Sometimes patients have both iron deficiency and a chronic disorder, so how do you decide whether they should be given iron?
A few years ago the serum soluble transferrin receptor assay became available. This goes up in iron deficiency but is unaffected by chronic disorders.
However, this is not true for some hematological malignancies, especially for CLL. The serum soluble transferrin receptor level goes up in CLL and indeed is a measurement of tumor burden. So if you really are not sure whether someone with CLL is also iron deficient and the other tests won't help you, then the only way to find out for sure is to do a bone marrow biopsy and stain it for iron.
Sometimes patients have both iron deficiency and a chronic disorder, so how do you decide whether they should be given iron?
A few years ago the serum soluble transferrin receptor assay became available. This goes up in iron deficiency but is unaffected by chronic disorders.
However, this is not true for some hematological malignancies, especially for CLL. The serum soluble transferrin receptor level goes up in CLL and indeed is a measurement of tumor burden. So if you really are not sure whether someone with CLL is also iron deficient and the other tests won't help you, then the only way to find out for sure is to do a bone marrow biopsy and stain it for iron.
Sunday, August 22, 2010
What I've been reading
In the past week I have read two books.
Rose Tremain's novel The Road Home tells the story of an Eastern European immigrant to England. He finds that the streets of London are not paved with gold, that £20 a day is not enough to live on and that Englishmen are not tall, ascetic and witty, fellows with bowler hats and umbrellas, but mostly denizens of the Commonwealth and fat. Reduced to sleeping in doorways, he takes jobs delivering fliers for a kebab stall, picking asparagus in Lincolnshire and washing dishes in a smart restaurant. The people he meets include an Irish drunk, a couple of Chinese homosexuals, a curmudgeonly farmer, a sweet old lady abandoned to a residential home by uncaring children, and many from the London art scene whom Tremain lampoons for their being dressed in the Emperor's New Clothes. Lev, the immigrant, has just lost his wife to leukemia and is emotionally stifled because of this, yet he manages to negotiate his way through the minefield to a happy ending.
No such happy ending for Marcus Trescothick. I am not normally a fan of sporting biographies, but this one is a bit different. Coming back to me tells the story of England's opening batsman, who at the height of his success succumbs to an acute anxiety neurosis. It makes him unable to tour other countries and signals the end of his career as an international cricketer. Frankly I could do with out the, "I scored 47 and 63 in the two innings at Lords but after that I reached my highest test score against the Bangladeshis of 197 at Edgbaston." You can skip all that; just take it for read that he was a very good batsman. What is interesting is how he handled the anxiety and depression and how unaware the cricket management were of the problem. The press were vile, assuming that the problem was a sexual peccadillo of him or his wife.
I liked the explanation given to him by his counsellor. "Depressive illness, caused by stress, nearly always happens to one sort of person. He or she will have the following characteristics; moral strength, reliability, diligence, strong conscience, strong sense of responsibility, a tendency to focus on the needs of others before one's own, sensitivity, vulnerability to criticism, and self-esteem dependent on the evaluation of others. This person is the sort to whom you would turn if you had a problem to sort out upon which your house depended, a safe pair of hands you can trust with your life, though often taken somewhat for granted. People are very surprised when he gets ill; indeed he is the last person you would expect to have a breakdown."
Rose Tremain's novel The Road Home tells the story of an Eastern European immigrant to England. He finds that the streets of London are not paved with gold, that £20 a day is not enough to live on and that Englishmen are not tall, ascetic and witty, fellows with bowler hats and umbrellas, but mostly denizens of the Commonwealth and fat. Reduced to sleeping in doorways, he takes jobs delivering fliers for a kebab stall, picking asparagus in Lincolnshire and washing dishes in a smart restaurant. The people he meets include an Irish drunk, a couple of Chinese homosexuals, a curmudgeonly farmer, a sweet old lady abandoned to a residential home by uncaring children, and many from the London art scene whom Tremain lampoons for their being dressed in the Emperor's New Clothes. Lev, the immigrant, has just lost his wife to leukemia and is emotionally stifled because of this, yet he manages to negotiate his way through the minefield to a happy ending.
No such happy ending for Marcus Trescothick. I am not normally a fan of sporting biographies, but this one is a bit different. Coming back to me tells the story of England's opening batsman, who at the height of his success succumbs to an acute anxiety neurosis. It makes him unable to tour other countries and signals the end of his career as an international cricketer. Frankly I could do with out the, "I scored 47 and 63 in the two innings at Lords but after that I reached my highest test score against the Bangladeshis of 197 at Edgbaston." You can skip all that; just take it for read that he was a very good batsman. What is interesting is how he handled the anxiety and depression and how unaware the cricket management were of the problem. The press were vile, assuming that the problem was a sexual peccadillo of him or his wife.
I liked the explanation given to him by his counsellor. "Depressive illness, caused by stress, nearly always happens to one sort of person. He or she will have the following characteristics; moral strength, reliability, diligence, strong conscience, strong sense of responsibility, a tendency to focus on the needs of others before one's own, sensitivity, vulnerability to criticism, and self-esteem dependent on the evaluation of others. This person is the sort to whom you would turn if you had a problem to sort out upon which your house depended, a safe pair of hands you can trust with your life, though often taken somewhat for granted. People are very surprised when he gets ill; indeed he is the last person you would expect to have a breakdown."
More scientific fraud
In the 1980s I was very interested in scientific fraud which was then rife in the Ivy League institutions in America. I wrote an article, Fake! , which details the many frauds that were then revealed. The article is available for free if you want to download it. At about the same time New Scientist published a cartoon which showed an old tramp playing a violin for pennies on a street corner with a caption which read, "He learned his trade fiddling at Harvard."
Another Harvard fraud has apparently now surfaced. It concerns the psychologist Marc Hauser who is on a year's leave of absence while the dodgy data are investigated. Hauser's research focuses on the evolutionary roots of the human mind. In a letter he wrote to colleagues, he described the inquiry as painful. The letter said that his lab has been under investigation for three years by a Harvard committee, and that evidence of misconduct was found. He alluded to unspecified mistakes and oversights that he had made, and said he will be on leave for the upcoming academic year.
According to the Boston Globe, "Hauser’s work falls at the intersection of psychology, evolutionary biology, and neuroscience, and he has studied everything from the cognitive and evolutionary underpinnings of language to the idea that morality is innate. He began teaching at Harvard in 1992 and several times has been voted one of Harvard’s most popular professors by graduating students, according to his CV. He is writing a book titled 'Evilicious: Explaining Our Evolved Taste for Being Bad.’"
"A paper in the journal Cognition has been withdrawn. The paper tested cotton-top tamarin monkeys’ ability to learn generalized patterns, an ability that human infants had been found to have, and that may be critical for learning language. The paper found that the monkeys were able to learn patterns, suggesting that this was not the critical cognitive building block that explains humans’ ability to learn language. In doing such experiments, researchers videotape the animals to analyze each trial and provide a record of their raw data. The Harvard investigation, said video records and field notes of one of the co-authors were incomplete. The investigation also raised questions about two other papers co-authored by Hauser. The journal Proceedings of the Royal Society B published a correction last month to a 2007 study. Science, another top journal, was notified of the Harvard investigation in late June and told that questions about record-keeping had been raised. Science has requested a copy of Harvard’s report of its investigation and will “move with utmost efficiency in light of the seriousness of issues of this type."
This isn’t the first time Hauser’s work has been challenged.
"In 1995, he was the lead author of a paper in the Proceedings of the National Academy of Sciences that looked at whether cotton-top tamarins are able to recognize themselves in a mirror. Self-recognition was something that set humans and other primates, such as chimpanzees and orangutans, apart from other animals, and no one had shown that monkeys had this ability."
"Gordon G. Gallup Jr., a professor of psychology at State University of New York at Albany, questioned the results and requested videotapes that Hauser had made of the experiment. “When I played the videotapes, there was not a thread of compelling evidence — scientific or otherwise — that any of the tamarins had learned to correctly decipher mirrored information about themselves," Gallup said in an interview.""
What strikes me now and what struck me in 1981 was how many of these frauds seem to concern evolution. Starting with Piltdown Man, scientists have fabricated data so as to get out from under a creator God. If we have been created by God then we owe him submission and obedience, something that modern man can't abide.
Another Harvard fraud has apparently now surfaced. It concerns the psychologist Marc Hauser who is on a year's leave of absence while the dodgy data are investigated. Hauser's research focuses on the evolutionary roots of the human mind. In a letter he wrote to colleagues, he described the inquiry as painful. The letter said that his lab has been under investigation for three years by a Harvard committee, and that evidence of misconduct was found. He alluded to unspecified mistakes and oversights that he had made, and said he will be on leave for the upcoming academic year.
According to the Boston Globe, "Hauser’s work falls at the intersection of psychology, evolutionary biology, and neuroscience, and he has studied everything from the cognitive and evolutionary underpinnings of language to the idea that morality is innate. He began teaching at Harvard in 1992 and several times has been voted one of Harvard’s most popular professors by graduating students, according to his CV. He is writing a book titled 'Evilicious: Explaining Our Evolved Taste for Being Bad.’"
"A paper in the journal Cognition has been withdrawn. The paper tested cotton-top tamarin monkeys’ ability to learn generalized patterns, an ability that human infants had been found to have, and that may be critical for learning language. The paper found that the monkeys were able to learn patterns, suggesting that this was not the critical cognitive building block that explains humans’ ability to learn language. In doing such experiments, researchers videotape the animals to analyze each trial and provide a record of their raw data. The Harvard investigation, said video records and field notes of one of the co-authors were incomplete. The investigation also raised questions about two other papers co-authored by Hauser. The journal Proceedings of the Royal Society B published a correction last month to a 2007 study. Science, another top journal, was notified of the Harvard investigation in late June and told that questions about record-keeping had been raised. Science has requested a copy of Harvard’s report of its investigation and will “move with utmost efficiency in light of the seriousness of issues of this type."
This isn’t the first time Hauser’s work has been challenged.
"In 1995, he was the lead author of a paper in the Proceedings of the National Academy of Sciences that looked at whether cotton-top tamarins are able to recognize themselves in a mirror. Self-recognition was something that set humans and other primates, such as chimpanzees and orangutans, apart from other animals, and no one had shown that monkeys had this ability."
"Gordon G. Gallup Jr., a professor of psychology at State University of New York at Albany, questioned the results and requested videotapes that Hauser had made of the experiment. “When I played the videotapes, there was not a thread of compelling evidence — scientific or otherwise — that any of the tamarins had learned to correctly decipher mirrored information about themselves," Gallup said in an interview.""
What strikes me now and what struck me in 1981 was how many of these frauds seem to concern evolution. Starting with Piltdown Man, scientists have fabricated data so as to get out from under a creator God. If we have been created by God then we owe him submission and obedience, something that modern man can't abide.
Saturday, August 21, 2010
IQ
When I was a medical student there was a fellow student who stood out by being older. He was a dentist who had decided to retrain as a doctor to fulfil his ambition of becoming a facio-maxillary surgeon. He was in his thirties, drove a smart car and always had money that the rest of us couldn't imagine. He had an expression that he used whenever any of the year behaved as 'medical students' (drinking, partying, going to bed at dawn). He would murmur with disdain, "Top two per-cent."
What he was getting at was the fact that the exam system weeded out those with the top two per-cent of IQs to go to medical school. However, having a higher yet IQ doesn't win you any coconuts. You need a certain threshold IQ (say 120), but above that, other things mater for success in life.
Christopher Langan, with an IQ of 200, (my IQ is apparently 163 according to my parents; Einstein's was only 150) is supposed to be the cleverest man in America. He came to fame as a winner on the TV show One versus One Hundred. From a very young age he read and re-read ever more complicated books. He put in the 10,000 hours required to make himself an expert. Ask him anything and he has the answer.
Yet Chris Langan is a failure in life. He has never achieved anything of note during his lifetime (apart from winning quiz shows). He has twice dropped out of College. His background was terrible. His mother had four boys with four different fathers. The man who stayed with her longest was a drunk who beat up both mother and children. He won a scholarship, but lost it because his mother was too indolent to fill in the forms. He lived in poverty which caused him to miss classes and he was insufficiently persuasive with the college administration for them to make allowances for him despite his high intellect.
Robert Oppenheimer was a similar child prodigy, but he came from a privileged background. There were books at home, intellectual conversation, and a social mores that taught you how to behave. He went to Harvard and the as a PhD student to the other Cambridge University in England. In England he deliberately tried to poison his tutor, Patrick Blackett (who would later win the 1948 Nobel prize for physics). Oppenheimer was carpeted, but after protracted negotiations he was put on probation and booked into sessions with a Harley Street psychiatrist; not the usual punishment for attempted murder in England (which at that time retained the death penalty).
Later, Oppenheimer went on to head up the Manhattan project which produced the first two nuclear devices. He was a long-shot for this post. He was just 38, junior to many of the scientists he would have to manage. He was a theorist in a job that called for experimenters and engineers. He had many communist friends. He had no administrative experience. He was very impractical, he walked about in a funny hat and knew nothing about equipment. one of his colleagues said, "He couldn't run a hamburger stand."
What he did have was charm. He could charm the birds from the trees and his charm worked on General Groves, the rather stiff and disciplinarian engineer whose approval he needed to implement his ideas.
The particular skill that enables you to talk your way out of an attempted murder rap is called by psychologists, 'practical intelligence'. A lot of politicians have it. It includes knowing what to say and to whom, when to say it, and how to say it with maximum effect. Analytical intelligence is largely genetic, but social savvy is a learned behavior. That's where wealth, good schools and privilege come in. You can't improve analytical intelligence much, but you can improve practical intelligence. You can also improve your ability in divergence tests. Here is a test for you. In the 'Comments' write down how many uses you can imagine for a] a brick, and b] a blanket.
The ideas in this article come directly from Malcolm Gladwell's book Outliers
What he was getting at was the fact that the exam system weeded out those with the top two per-cent of IQs to go to medical school. However, having a higher yet IQ doesn't win you any coconuts. You need a certain threshold IQ (say 120), but above that, other things mater for success in life.
Christopher Langan, with an IQ of 200, (my IQ is apparently 163 according to my parents; Einstein's was only 150) is supposed to be the cleverest man in America. He came to fame as a winner on the TV show One versus One Hundred. From a very young age he read and re-read ever more complicated books. He put in the 10,000 hours required to make himself an expert. Ask him anything and he has the answer.
Yet Chris Langan is a failure in life. He has never achieved anything of note during his lifetime (apart from winning quiz shows). He has twice dropped out of College. His background was terrible. His mother had four boys with four different fathers. The man who stayed with her longest was a drunk who beat up both mother and children. He won a scholarship, but lost it because his mother was too indolent to fill in the forms. He lived in poverty which caused him to miss classes and he was insufficiently persuasive with the college administration for them to make allowances for him despite his high intellect.
Robert Oppenheimer was a similar child prodigy, but he came from a privileged background. There were books at home, intellectual conversation, and a social mores that taught you how to behave. He went to Harvard and the as a PhD student to the other Cambridge University in England. In England he deliberately tried to poison his tutor, Patrick Blackett (who would later win the 1948 Nobel prize for physics). Oppenheimer was carpeted, but after protracted negotiations he was put on probation and booked into sessions with a Harley Street psychiatrist; not the usual punishment for attempted murder in England (which at that time retained the death penalty).
Later, Oppenheimer went on to head up the Manhattan project which produced the first two nuclear devices. He was a long-shot for this post. He was just 38, junior to many of the scientists he would have to manage. He was a theorist in a job that called for experimenters and engineers. He had many communist friends. He had no administrative experience. He was very impractical, he walked about in a funny hat and knew nothing about equipment. one of his colleagues said, "He couldn't run a hamburger stand."
What he did have was charm. He could charm the birds from the trees and his charm worked on General Groves, the rather stiff and disciplinarian engineer whose approval he needed to implement his ideas.
The particular skill that enables you to talk your way out of an attempted murder rap is called by psychologists, 'practical intelligence'. A lot of politicians have it. It includes knowing what to say and to whom, when to say it, and how to say it with maximum effect. Analytical intelligence is largely genetic, but social savvy is a learned behavior. That's where wealth, good schools and privilege come in. You can't improve analytical intelligence much, but you can improve practical intelligence. You can also improve your ability in divergence tests. Here is a test for you. In the 'Comments' write down how many uses you can imagine for a] a brick, and b] a blanket.
The ideas in this article come directly from Malcolm Gladwell's book Outliers
Homeopathy
At the risk of being forced to take this posting down, I reprint the whole of an editorial by Michael Baum, the breast cancer specialist, in today's Lancet. I see no reason why it should be hidden behind a paywall.
Homeopath Waives the Rules.
Evidence-free politics was recently on display when the UK's Department of Health rejected a call by the House of Commons Science and Technology Committee to stop funding the use of homoeopathy in the National Health Service (NHS). This it is claimed will emancipate patients to indulge in choice, even though “His [the Secretary of State for Health] position remains that the evidence of efficacy and the scientific basis of homeopathy is highly questionable”.
Using this kind of logic, why not offer astrology on the NHS to help women decide when to induce labour? It beggars belief that a modern NHS that prides itself on evidence-based medicine should fly in the face of the Science and Technology Committee, which concluded that homoeopathy is nothing other than an elaborate placebo and “involves deceiving the patient every time it is prescribed”. Responding to the Committee, Health Minister Anne Milton said: “We believe in patients being able to make informed choices about their treatment, which includes complementary or alternative treatments such as homeopathy”.
So there you have it: the UK Government supports alternative medicine that by its very nature is nearly all an evidence-free zone. So at a time of financial crisis, Health Minister Andrew Lansley has pledged to continue spending more than £4 million a year to capture the support of a vocal minority. My group has just described a new technique for delivering intraoperative radiotherapy for breast cancer that will save women the 6 weeks of traipsing back and forward to the radiotherapy centre. The sum of money to be spent on homoeopathy over a couple of years could open up this service to all the women in England and Wales who need it, while eventually saving the exchequer about £15 million a year. What's the betting that the introduction of this service will have to wait the approval of the UK's National Institute for Health and Clinical Excellence (NICE) while homoeopathy continues to be allowed to creep under that hurdle? As it transpires the Department of Health refuses to ask NICE to investigate homoeopathy. Shame on you, Health Minister.
Homeopath Waives the Rules.
Evidence-free politics was recently on display when the UK's Department of Health rejected a call by the House of Commons Science and Technology Committee to stop funding the use of homoeopathy in the National Health Service (NHS). This it is claimed will emancipate patients to indulge in choice, even though “His [the Secretary of State for Health] position remains that the evidence of efficacy and the scientific basis of homeopathy is highly questionable”.
Using this kind of logic, why not offer astrology on the NHS to help women decide when to induce labour? It beggars belief that a modern NHS that prides itself on evidence-based medicine should fly in the face of the Science and Technology Committee, which concluded that homoeopathy is nothing other than an elaborate placebo and “involves deceiving the patient every time it is prescribed”. Responding to the Committee, Health Minister Anne Milton said: “We believe in patients being able to make informed choices about their treatment, which includes complementary or alternative treatments such as homeopathy”.
So there you have it: the UK Government supports alternative medicine that by its very nature is nearly all an evidence-free zone. So at a time of financial crisis, Health Minister Andrew Lansley has pledged to continue spending more than £4 million a year to capture the support of a vocal minority. My group has just described a new technique for delivering intraoperative radiotherapy for breast cancer that will save women the 6 weeks of traipsing back and forward to the radiotherapy centre. The sum of money to be spent on homoeopathy over a couple of years could open up this service to all the women in England and Wales who need it, while eventually saving the exchequer about £15 million a year. What's the betting that the introduction of this service will have to wait the approval of the UK's National Institute for Health and Clinical Excellence (NICE) while homoeopathy continues to be allowed to creep under that hurdle? As it transpires the Department of Health refuses to ask NICE to investigate homoeopathy. Shame on you, Health Minister.
Friday, August 20, 2010
God's atrocities: IV The binding of Isaac.
Of all the incidents that might justify the complaints of Dawkins and Hitchens against religion, the Binding of Isaac is at first sight the greatest.
What would you think of a father who deliberately murdered his son as some sort of religious ritual? Yet Judaism, Islam and Christianity make Abraham's aborted sacrifice of his son a major incident in the individual faiths (though Islam has made it about Ishmael rather than Isaac).
If you met a father behaving like that today, who could blame you for calling child protective agencies? Is this faith or fanaticism? In the past few years we’ve seen more than enough people who measure their devotion by their willingness to kill defenseless people. In New York, London, Madrid and Bali we can point the finger at fanatical Islamists, but what about Jonesville and Waco? What about Orissa? Moreover, Muslims, Jews and Christians can find examples in their scriptures to justify that kind of ruthlessness.
In the Jewish view, God was testing Abraham, establishing the depth of the commitment upon which the nation of Israel would be founded. No sooner had Abraham arranged the firewood on the altar, taken the knife and stretched out his hand to slaughter his son, than "an angel of God called out to him from the heavens... 'Lay not your hand upon the lad, neither do anything to him; for now I know that you fear God, as you have not withheld your only child from Me... Thus I shall bless you, and multiply your descendants as the stars of the heaven, and as the sand that is at the shore of the sea...' "
Maimonides, the preeminent Jewish expositor of the twelfth century, explains that the "binding of Isaac" served to establish two key axioms of the Jewish faith: a) the extent of man's capacity to love, fear and serve God; b) the principle of "prophecy" - the fact that God communicates His will to man.
By binding Isaac upon the altar, Abraham demonstrated that man is capable of a love and awe of God that surpasses his every other feeling or commitment. For what greater love is there than the love of a parent for his child? What greater fear is there than a parent's fear for the life of his child? With the binding, Abraham set his commitment to God above these most basic truths of human nature, establishing it as the all-surpassing consideration in the life of man.
The second truth established by the incident is the principle of prophecy.
There are many levels and degrees of human communion with the divine, from the scientist's contemplation of God's creation, to the preacher whose interpretation and exposition of Scripture is guided and molded by divine inspiration. Prophecy, however, is the ultimate divine communication - a revelation that completely transcends the equivocation and subjectivity of its human receiver, so that its truth is absolute, incontestable and immutable. A fundamental principle of the Jewish (and indeed Christian) faith is that God communicates to man in this manner.
When Abraham was told to offer Isaac as a sacrifice to God, this was contrary to everything Abraham was and stood for, contrary to everything he knew and believed about God, and contrary to what God, Himself, had said to him.
Abraham knew and related to God as "the merciful and benevolent One, slow to anger, great in kindness."
According to Jewish tradition, the prohibition of taking a human life is one of the seven basic laws of civilization communicated by God to Adam and Noah (the "Seven Noachide Laws") which Abraham had been laboring for many decades to instill in a world where murder and promiscuity were the staples of religious worship. (For we know that the Canaanites indulged in child sacrifices and the many fertility cults had religious prostitutes as part of their devotions). And God had promised Abraham that Isaac (unmarried and childless at the time of the binding) would father a great nation who would carry on Abraham's work of conveying the truth of the One God to the world.
Certainly, we read in Genesis 9:6 that God tells Noah, "Whoever sheds the blood of man, by man shall his blood be shed; for in the image of God has God made man." Furthermore in Genesis 15:4-5 God tells Abraham "a son coming from your own body will be your heir. " He took him outside and said, "Look up at the heavens and count the stars—if indeed you can count them." Then he said to him, "So shall your offspring be." and in Genesis 21:12 God tells him that "it is through Isaac that your offspring will be reckoned."
So when Abraham heard the words "Take your son... and raise him as an offering," he had many reasons to doubt their divinity, to surmise that not God but some malevolent voice had uttered them in his soul's ears. Had his certainty that God had spoken them been an iota less than absolute, he would not - indeed, could not - have acted on them.
Thus, concludes Maimonides, the binding of Isaac is the ultimate exemplar of the principle of prophecy - that God communicates His will to man in a manner that leaves no doubt as to its origin, meaning, or manner of implementation.
Of course, skeptics will cavil at this. How can a man distinguish the voice of God from the voice of a demon? Or from some weird schizophrenic 'voice'? Is it not a common defence for the murderer to say, "God told me to do it? How can one answer such an objection except to say that from what we read, Abraham was a man who knew the voice of God, who had upped sticks from Ur at God's command, who had believed God when told that he would father a child on a 90-year-old woman and whose belief had been credited to him as righteousness.
Abraham was a man who believed that God worked miracles. For the Christian we have to believe that Abraham believed a greater miracle than an old woman becoming a mother. For we read in Hebrews 11:17-19 - By faith Abraham, when God tested him, offered Isaac as a sacrifice. He who had received the promises was about to sacrifice his one and only son, even though God had said to him, "It is through Isaac that your offspring will be reckoned." Abraham reasoned that God could raise the dead, and figuratively speaking, he did receive Isaac back from death
But more important, for the Christian, this whole episode prefigures the sacrifice of Christ - the doctrine known as substitutionary atonement. God provided a substitute, the ram caught in a thicket. Whereas Abraham is spared from sacrificing his son; God has to sacrifice His son to expunge the sin of His people. Abraham was told to build the alter in the vicinity of Moriah, the very place where Christ was crucified. Abraham figuratively received his son from the grave; Jesus actually rose from the dead.
The aborted sacrifice of Isaac should not act as an example for those who obey God; indeed child sacrifice is roundly condemned in Scripture for example Jeremiah 32:35 They built high places for Baal in the Valley of Ben Hinnom to sacrifice their sons and daughters to Molech (an Ammonite god), though I never commanded, nor did it enter my mind, that they should do such a detestable thing and so make Judah sin.
The important point of the story is that Abraham did not kill his son. God stopped him. Abraham obeyed God. The War Poet Wilfred Owen grieving over so many comrades sent to their deaths needlessly had his own take on the story:
So Abram rose, and clave the wood, and went,
And took the fire with him, and a knife.
And as they sojourned both of them together,
Isaac the first-born spake and said, My Father,
Behold the preparations, fire and iron,
But where the lamb for this burnt-offering?
Then Abram bound the youth with belts and straps,
And builded parapets and trenches there,
And stretchèd forth the knife to slay his son.
When lo! an Angel called him out of heaven,
Saying, Lay not thy hand upon the lad,
Neither do anything to him, thy son.
Behold! Caught in a thicket by its horns,
A Ram. Offer the Ram of Pride instead.
But the old man would not so, but slew his son,
And half the seed of Europe, one by one.
But this was not what happened. Instead, because the taint remained on mankind God took it on himself to slay his own son. Isaac was a bemused and unwilling sacrifice who needed binding to the alter; Christ knew exactly what he was doing: I lay down my life, he said, no-one takes it from me.
O teach me what it meaneth,
That cross uplifted high,
With One - the Man of Sorrows-
Condemned to bleed and die.
O teach me what it cost Thee
To make a sinner whole;
And teach me, Savior, teach me
The value of a soul!
This was not an atrocity of God; this was an atrocity of mankind against God.
What would you think of a father who deliberately murdered his son as some sort of religious ritual? Yet Judaism, Islam and Christianity make Abraham's aborted sacrifice of his son a major incident in the individual faiths (though Islam has made it about Ishmael rather than Isaac).
If you met a father behaving like that today, who could blame you for calling child protective agencies? Is this faith or fanaticism? In the past few years we’ve seen more than enough people who measure their devotion by their willingness to kill defenseless people. In New York, London, Madrid and Bali we can point the finger at fanatical Islamists, but what about Jonesville and Waco? What about Orissa? Moreover, Muslims, Jews and Christians can find examples in their scriptures to justify that kind of ruthlessness.
In the Jewish view, God was testing Abraham, establishing the depth of the commitment upon which the nation of Israel would be founded. No sooner had Abraham arranged the firewood on the altar, taken the knife and stretched out his hand to slaughter his son, than "an angel of God called out to him from the heavens... 'Lay not your hand upon the lad, neither do anything to him; for now I know that you fear God, as you have not withheld your only child from Me... Thus I shall bless you, and multiply your descendants as the stars of the heaven, and as the sand that is at the shore of the sea...' "
Maimonides, the preeminent Jewish expositor of the twelfth century, explains that the "binding of Isaac" served to establish two key axioms of the Jewish faith: a) the extent of man's capacity to love, fear and serve God; b) the principle of "prophecy" - the fact that God communicates His will to man.
By binding Isaac upon the altar, Abraham demonstrated that man is capable of a love and awe of God that surpasses his every other feeling or commitment. For what greater love is there than the love of a parent for his child? What greater fear is there than a parent's fear for the life of his child? With the binding, Abraham set his commitment to God above these most basic truths of human nature, establishing it as the all-surpassing consideration in the life of man.
The second truth established by the incident is the principle of prophecy.
There are many levels and degrees of human communion with the divine, from the scientist's contemplation of God's creation, to the preacher whose interpretation and exposition of Scripture is guided and molded by divine inspiration. Prophecy, however, is the ultimate divine communication - a revelation that completely transcends the equivocation and subjectivity of its human receiver, so that its truth is absolute, incontestable and immutable. A fundamental principle of the Jewish (and indeed Christian) faith is that God communicates to man in this manner.
When Abraham was told to offer Isaac as a sacrifice to God, this was contrary to everything Abraham was and stood for, contrary to everything he knew and believed about God, and contrary to what God, Himself, had said to him.
Abraham knew and related to God as "the merciful and benevolent One, slow to anger, great in kindness."
According to Jewish tradition, the prohibition of taking a human life is one of the seven basic laws of civilization communicated by God to Adam and Noah (the "Seven Noachide Laws") which Abraham had been laboring for many decades to instill in a world where murder and promiscuity were the staples of religious worship. (For we know that the Canaanites indulged in child sacrifices and the many fertility cults had religious prostitutes as part of their devotions). And God had promised Abraham that Isaac (unmarried and childless at the time of the binding) would father a great nation who would carry on Abraham's work of conveying the truth of the One God to the world.
Certainly, we read in Genesis 9:6 that God tells Noah, "Whoever sheds the blood of man, by man shall his blood be shed; for in the image of God has God made man." Furthermore in Genesis 15:4-5 God tells Abraham "a son coming from your own body will be your heir. " He took him outside and said, "Look up at the heavens and count the stars—if indeed you can count them." Then he said to him, "So shall your offspring be." and in Genesis 21:12 God tells him that "it is through Isaac that your offspring will be reckoned."
So when Abraham heard the words "Take your son... and raise him as an offering," he had many reasons to doubt their divinity, to surmise that not God but some malevolent voice had uttered them in his soul's ears. Had his certainty that God had spoken them been an iota less than absolute, he would not - indeed, could not - have acted on them.
Thus, concludes Maimonides, the binding of Isaac is the ultimate exemplar of the principle of prophecy - that God communicates His will to man in a manner that leaves no doubt as to its origin, meaning, or manner of implementation.
Of course, skeptics will cavil at this. How can a man distinguish the voice of God from the voice of a demon? Or from some weird schizophrenic 'voice'? Is it not a common defence for the murderer to say, "God told me to do it? How can one answer such an objection except to say that from what we read, Abraham was a man who knew the voice of God, who had upped sticks from Ur at God's command, who had believed God when told that he would father a child on a 90-year-old woman and whose belief had been credited to him as righteousness.
Abraham was a man who believed that God worked miracles. For the Christian we have to believe that Abraham believed a greater miracle than an old woman becoming a mother. For we read in Hebrews 11:17-19 - By faith Abraham, when God tested him, offered Isaac as a sacrifice. He who had received the promises was about to sacrifice his one and only son, even though God had said to him, "It is through Isaac that your offspring will be reckoned." Abraham reasoned that God could raise the dead, and figuratively speaking, he did receive Isaac back from death
But more important, for the Christian, this whole episode prefigures the sacrifice of Christ - the doctrine known as substitutionary atonement. God provided a substitute, the ram caught in a thicket. Whereas Abraham is spared from sacrificing his son; God has to sacrifice His son to expunge the sin of His people. Abraham was told to build the alter in the vicinity of Moriah, the very place where Christ was crucified. Abraham figuratively received his son from the grave; Jesus actually rose from the dead.
The aborted sacrifice of Isaac should not act as an example for those who obey God; indeed child sacrifice is roundly condemned in Scripture for example Jeremiah 32:35 They built high places for Baal in the Valley of Ben Hinnom to sacrifice their sons and daughters to Molech (an Ammonite god), though I never commanded, nor did it enter my mind, that they should do such a detestable thing and so make Judah sin.
The important point of the story is that Abraham did not kill his son. God stopped him. Abraham obeyed God. The War Poet Wilfred Owen grieving over so many comrades sent to their deaths needlessly had his own take on the story:
So Abram rose, and clave the wood, and went,
And took the fire with him, and a knife.
And as they sojourned both of them together,
Isaac the first-born spake and said, My Father,
Behold the preparations, fire and iron,
But where the lamb for this burnt-offering?
Then Abram bound the youth with belts and straps,
And builded parapets and trenches there,
And stretchèd forth the knife to slay his son.
When lo! an Angel called him out of heaven,
Saying, Lay not thy hand upon the lad,
Neither do anything to him, thy son.
Behold! Caught in a thicket by its horns,
A Ram. Offer the Ram of Pride instead.
But the old man would not so, but slew his son,
And half the seed of Europe, one by one.
But this was not what happened. Instead, because the taint remained on mankind God took it on himself to slay his own son. Isaac was a bemused and unwilling sacrifice who needed binding to the alter; Christ knew exactly what he was doing: I lay down my life, he said, no-one takes it from me.
O teach me what it meaneth,
That cross uplifted high,
With One - the Man of Sorrows-
Condemned to bleed and die.
O teach me what it cost Thee
To make a sinner whole;
And teach me, Savior, teach me
The value of a soul!
This was not an atrocity of God; this was an atrocity of mankind against God.
Tuesday, August 17, 2010
ZAP-70 changes
In order to make this paper available to all.
ZAP-70 levels do change in CLL but not very often.Terry J Hamblin
Abstract
Evidence is accumulating that in some patients with CLL the expression of ZAP-70 changes over time. This diminishes its role as a prognostic marker but increases our understanding of the pathophysiology of the disease.
Commentary
Although the mutational status of the immunoglobulin variable region (IgVH) genes remains the gold standard for prognostic markers in chronic lymphocytic leukaemia (CLL), it is a complicated assay unsuited to routine laboratories. Unfortunately, attempts to find a surrogate have run into several obstacles. CD38 expression measured by flow cytometry was an early contender and initially seemed to have as much predictive value IgVH mutations. Unfortunately, it was subsequently found to give disparate results in 28% and even worse was described as changing over time in 24% (1).
More recently, ZAP-70 expression has attracted great interest. Although transiently expressed during certain stages of B-cell development, most mature peripheral blood B cells do not express ZAP-70, a cytoplasmic tyrosine kinase which is the key signalling molecule for T-lymphocytes and NK-cells. In CLL it acts as an auxiliary molecule for B-cell signalling in the more aggressive cases, probably acting to block inhibitors of signalling through syk. It’s presence in aggressive CLL appears to be due the chaperoning function of heat shock protein 90 (Hsp90). After it was originally identified in gene expression microarrays as a gene differentially expressed in CLL cells with unmutated IgVH genes, several laboratories developed flow cytometric assays that potentially could be used by routine laboratories. Initially, there was 95% concordance with IgVH mutational status, but a later assay using the much more convenient direct immunofluorescence, showed concordance of only 77%, hardly better than CD38, although with this assay ZAP-70 appeared to perform better than IgVH mutations as a prognostic factor (reviewed in 2).
The disparity betweens these assays has prompted a search by several laboratories for an assay that would be reliable, reproducible and of prognostic value. This quest is currently unresolved. The type of anticoagulant to use, allowable storage and transit time, which gating strategy, which monoclonal antibody and which fluorescent dye all remain in dispute and how to express the results is still a contentious issue (3). Nevertheless, several publications have attested to the fact that like IgVH mutations and unlike CD38, ZAP-70 is stable over time.
In today’s issue of Leukemia and Lymphoma, Poulain et al (4) dispute this. Four out of 33 ZAP-70 negative cases subsequently became ZAP-70 positive and this was associated with clinical progression. Two out of 27 ZAP-70 positive patients became negative. In one case this was associated with corticosteroid treatment, a phenomenon that has been observed previously. Although previous publications have reported on the stability of ZAP-70 over time, close scrutiny of these publications confirms that in a small number of patients (around 10%) ZAP-70 expression does change as time passes, although until Poulain et al there has been no indication as to why.
Recently Boelens et al (5) reported that ZAP-70 expression in CLL is higher in lymph node cells than in peripheral blood cells and Cutrona et al (6) demonstrated that within normal germinal centres there is a population of ZAP-70 positive, CD38 positive B cells representing in vivo activated cells.
These observations add to our understanding of ZAP-70 in CLL. It seems likely that both ZAP-70 and CD38 are normal features of activated B cells, rather than markers of neoplastic aberration. In CLL activation events and cell division both take place in proliferation centres and here upregulation of both markers occurs. There seems to be a free exchange of cells between tissue and blood making the presence of both CD38 and ZAP-70 surrogates for the rapidity of cell turnover.
The mutational status of the IgVH genes is fixed in CLL making it unique as a prognostic marker; it assigns cases into one immutable subgroup or the other. Other markers, whether CD38 or ZAP-70 expression or chromosomal abnormalities, can be acquired during the course of the disease. Early stage patients can gain little comfort from knowing that they are not present at diagnosis.
References
1. Hamblin TJ, Orchard JA, Ibbotson RE, Davies Z, Thomas PW, Stevenson FK, Oscier DG. CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease. Blood 2002, 99:1023-1029.
2. Hamblin AD, Hamblin TJ. Functional and prognostic role of ZAP-70 in CLL. Expert Opinion on Therapeutic Targets 2005; 9:1165-1178.
3. Marti G, Orfao A, Goolsby C. ZAP-70 in CLL: Towards standardization of a biomarker for patient management: History of Clinical Cytometry Special Issue. Cytometry Part B Cin Cytometry 2006; 70B:197-200.
4. Poulain S, Benard C, Daudignon A, Le Baron F, Morel P, Duthilleul P. Is ZAP-70 expression stable over time in B chronic lymphocytic leukaemia? Leukemia and Lymphoma, 2007; 48: 1219-21.
5. Boelens J, Philippe J, Offner F. B-CLL cells from lymph nodes express higher ZAP-70 levels than B cells from peripheral blood. Leuk Res 2007; 31:719-20.
6. Cutrona G, Colombo M, Matis S, Reverberi D, Dono M, Tarantino V, Chiorazzi N, Ferrarini M. B lymphocytes in humans express ZAP-70 when activated in vivo.
Eur J Immunol. 2006; 36:558-69.
ZAP-70 levels do change in CLL but not very often.Terry J Hamblin
Abstract
Evidence is accumulating that in some patients with CLL the expression of ZAP-70 changes over time. This diminishes its role as a prognostic marker but increases our understanding of the pathophysiology of the disease.
Commentary
Although the mutational status of the immunoglobulin variable region (IgVH) genes remains the gold standard for prognostic markers in chronic lymphocytic leukaemia (CLL), it is a complicated assay unsuited to routine laboratories. Unfortunately, attempts to find a surrogate have run into several obstacles. CD38 expression measured by flow cytometry was an early contender and initially seemed to have as much predictive value IgVH mutations. Unfortunately, it was subsequently found to give disparate results in 28% and even worse was described as changing over time in 24% (1).
More recently, ZAP-70 expression has attracted great interest. Although transiently expressed during certain stages of B-cell development, most mature peripheral blood B cells do not express ZAP-70, a cytoplasmic tyrosine kinase which is the key signalling molecule for T-lymphocytes and NK-cells. In CLL it acts as an auxiliary molecule for B-cell signalling in the more aggressive cases, probably acting to block inhibitors of signalling through syk. It’s presence in aggressive CLL appears to be due the chaperoning function of heat shock protein 90 (Hsp90). After it was originally identified in gene expression microarrays as a gene differentially expressed in CLL cells with unmutated IgVH genes, several laboratories developed flow cytometric assays that potentially could be used by routine laboratories. Initially, there was 95% concordance with IgVH mutational status, but a later assay using the much more convenient direct immunofluorescence, showed concordance of only 77%, hardly better than CD38, although with this assay ZAP-70 appeared to perform better than IgVH mutations as a prognostic factor (reviewed in 2).
The disparity betweens these assays has prompted a search by several laboratories for an assay that would be reliable, reproducible and of prognostic value. This quest is currently unresolved. The type of anticoagulant to use, allowable storage and transit time, which gating strategy, which monoclonal antibody and which fluorescent dye all remain in dispute and how to express the results is still a contentious issue (3). Nevertheless, several publications have attested to the fact that like IgVH mutations and unlike CD38, ZAP-70 is stable over time.
In today’s issue of Leukemia and Lymphoma, Poulain et al (4) dispute this. Four out of 33 ZAP-70 negative cases subsequently became ZAP-70 positive and this was associated with clinical progression. Two out of 27 ZAP-70 positive patients became negative. In one case this was associated with corticosteroid treatment, a phenomenon that has been observed previously. Although previous publications have reported on the stability of ZAP-70 over time, close scrutiny of these publications confirms that in a small number of patients (around 10%) ZAP-70 expression does change as time passes, although until Poulain et al there has been no indication as to why.
Recently Boelens et al (5) reported that ZAP-70 expression in CLL is higher in lymph node cells than in peripheral blood cells and Cutrona et al (6) demonstrated that within normal germinal centres there is a population of ZAP-70 positive, CD38 positive B cells representing in vivo activated cells.
These observations add to our understanding of ZAP-70 in CLL. It seems likely that both ZAP-70 and CD38 are normal features of activated B cells, rather than markers of neoplastic aberration. In CLL activation events and cell division both take place in proliferation centres and here upregulation of both markers occurs. There seems to be a free exchange of cells between tissue and blood making the presence of both CD38 and ZAP-70 surrogates for the rapidity of cell turnover.
The mutational status of the IgVH genes is fixed in CLL making it unique as a prognostic marker; it assigns cases into one immutable subgroup or the other. Other markers, whether CD38 or ZAP-70 expression or chromosomal abnormalities, can be acquired during the course of the disease. Early stage patients can gain little comfort from knowing that they are not present at diagnosis.
References
1. Hamblin TJ, Orchard JA, Ibbotson RE, Davies Z, Thomas PW, Stevenson FK, Oscier DG. CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease. Blood 2002, 99:1023-1029.
2. Hamblin AD, Hamblin TJ. Functional and prognostic role of ZAP-70 in CLL. Expert Opinion on Therapeutic Targets 2005; 9:1165-1178.
3. Marti G, Orfao A, Goolsby C. ZAP-70 in CLL: Towards standardization of a biomarker for patient management: History of Clinical Cytometry Special Issue. Cytometry Part B Cin Cytometry 2006; 70B:197-200.
4. Poulain S, Benard C, Daudignon A, Le Baron F, Morel P, Duthilleul P. Is ZAP-70 expression stable over time in B chronic lymphocytic leukaemia? Leukemia and Lymphoma, 2007; 48: 1219-21.
5. Boelens J, Philippe J, Offner F. B-CLL cells from lymph nodes express higher ZAP-70 levels than B cells from peripheral blood. Leuk Res 2007; 31:719-20.
6. Cutrona G, Colombo M, Matis S, Reverberi D, Dono M, Tarantino V, Chiorazzi N, Ferrarini M. B lymphocytes in humans express ZAP-70 when activated in vivo.
Eur J Immunol. 2006; 36:558-69.
Monday, August 16, 2010
Immigration
I know it is a major debating point in America, but it is just as much so in the UK. For at least 13 years of Labor government Britain has allowed unfettered immigration with a nod and a wink at the laws of the land. One of the reasons for this has been the growth in the economy started under the Tories in 1995 and continued until 2007 when Gordon Brown was caught with his trousers down. Rather than compelling British layabouts to take work, they were featherbedded by benefits funded by inflation imported from China, while immigrants from Poland, Romania, the Baltic states and Bulgaria were welcomed via their EU status and meantime swathes of people from the Indian sub-continent were admitted as 'students' and family members, all prepared to take poorly paid jobs.
The recession has made the problem worse as jobs have disappeared and more and more benefits claimed; quite apart from the pressure on schools and the NHS that the immigrants bring. Although we do not have the porous southern border that the USA does, it has been relatively easy for visitors to overstay their visas, for bogus marriages to be conducted, for economic migrants to claim asylum and for young men to find ways of crossing the Channel. It would not take Arizona-style laws to close these loopholes, though the European Union remains a thorn in our flesh, especially as countries like Hungary offer passports to various Russians and Moldovans with very tenuous claims to Hungarian citizenship. Heaven help us if Spain offers passports to most of South America. We must certainly close our borders.
After years of not enforcing the law, it would be churlish to turn around to the illegals and kick them out; in any case the European Court would find a way of stopping us. On the other hand to offer an amnesty would just encourage more to come in the hope that they would get one too.
Of all places I found this in USA Today from Richard Land, who is president of the Ethics and Religious Liberty Commission for the Southern Baptist Convention
Immigration reform legislation must:
•Respect the God-given dignity of every person
•Protect the unity of the immediate family
•Respect the rule of law
•Guarantee secure national borders
•Ensure fairness to taxpayers
•Establish a path toward legal status and/or citizenship for those who qualify and wish to become permanent residents.
The government has not controlled the borders. The reality has been that too often, those who desire to enter our country illegally have encountered two apparently contradictory signs at our border: one saying "No Trespassing" and the other saying "Help Wanted."
Once the borders are secure, we should have a grace period where undocumented workers can come forward, register, pay fines and back taxes, undergo a criminal background check, agree to learn to read, write and speak English, and go to the back of the line behind those who have, and are, trying to enter our country legally. Those who do not choose to accept this generous offer should be deported immediately.
This is not amnesty. Amnesty is a pardon, a "free ride," where government forgives your transgressions and pardons it with no obligations or penalties. This proposal would allow undocumented workers to come forward, obtain a probationary state and begin to earn their way to full legal status.
No one is saying that they haven't broken the law and they should not be punished for doing so. The only question is what is to be the nature of the punishment — deportation (which means uprooting huge numbers of people and tearing families apart) or the penalties outlined above.
The recession has made the problem worse as jobs have disappeared and more and more benefits claimed; quite apart from the pressure on schools and the NHS that the immigrants bring. Although we do not have the porous southern border that the USA does, it has been relatively easy for visitors to overstay their visas, for bogus marriages to be conducted, for economic migrants to claim asylum and for young men to find ways of crossing the Channel. It would not take Arizona-style laws to close these loopholes, though the European Union remains a thorn in our flesh, especially as countries like Hungary offer passports to various Russians and Moldovans with very tenuous claims to Hungarian citizenship. Heaven help us if Spain offers passports to most of South America. We must certainly close our borders.
After years of not enforcing the law, it would be churlish to turn around to the illegals and kick them out; in any case the European Court would find a way of stopping us. On the other hand to offer an amnesty would just encourage more to come in the hope that they would get one too.
Of all places I found this in USA Today from Richard Land, who is president of the Ethics and Religious Liberty Commission for the Southern Baptist Convention
Immigration reform legislation must:
•Respect the God-given dignity of every person
•Protect the unity of the immediate family
•Respect the rule of law
•Guarantee secure national borders
•Ensure fairness to taxpayers
•Establish a path toward legal status and/or citizenship for those who qualify and wish to become permanent residents.
The government has not controlled the borders. The reality has been that too often, those who desire to enter our country illegally have encountered two apparently contradictory signs at our border: one saying "No Trespassing" and the other saying "Help Wanted."
Once the borders are secure, we should have a grace period where undocumented workers can come forward, register, pay fines and back taxes, undergo a criminal background check, agree to learn to read, write and speak English, and go to the back of the line behind those who have, and are, trying to enter our country legally. Those who do not choose to accept this generous offer should be deported immediately.
This is not amnesty. Amnesty is a pardon, a "free ride," where government forgives your transgressions and pardons it with no obligations or penalties. This proposal would allow undocumented workers to come forward, obtain a probationary state and begin to earn their way to full legal status.
No one is saying that they haven't broken the law and they should not be punished for doing so. The only question is what is to be the nature of the punishment — deportation (which means uprooting huge numbers of people and tearing families apart) or the penalties outlined above.
Sunday, August 15, 2010
Splenic irradiation for CLL
Splenic irradiation is the forgotten treatment for CLL. Perhaps it is because there is no profit to be made from it by the drug companies, but for certain individuals there are advantages compared to drug treatment. I should say up front that it is not a cure, but then nothing is short of an allograft. Nor is it likely to produce the very long remissions that are possible with FCR, but there are very many patients for whom FCR is too toxic. But there are some patients for whom splenic irradiation is the ideal treatment and CLL physicians are very resistant to using it.
I first came upon it was a young doctor when it was an option in the MRC CLL 1 and 2 Trials which began in 1978. I was actually a co-author of the report of those trials which were published in 1991 (Catovsky D, Richards S, Fooks J, Hamblin TJ. Leukemia and Lymphoma 1991; Supplement pp 105-112). In CLL 1 the overall survival of patients treated with splenic irradiation was 5 years compared to 3.8 years for those treated with chlorambucil. The numbers were small and did not reach statistical significance, and the dose of chlorambucil was only 40mg/sq m. However in CLL 2 the overall survival for those treated with splenic irradiation was 3.4 years compared to 4.1 years for chlorambucil. Again the difference was not statistically significant. The conclusion that we drew was that splenic irradiation was not an inferior treatment to the dose of chlorambucil used in the original fludarabine trial or the recent alemtuzumab trial.
I am grateful to my friend Stacie who has sent me a 2001 paper that reviews several trials of splenic irradiation (SI) in CLL. It is from a journal that I don't normally read. (Weinmann M, Becker G, Einsele H, Bamberg M. Radiotherapy and Oncology 2001; 58:235-246.)
Of late, SI has only been used in patients with hypersplenism who were considered unfit for splenectomy, even if performed by keyhole surgery. But in the past it was used as a therapeutic modality which attempted to control the disease as a whole rather than that which is localized to the spleen. How it was supposed to work is a bit of a mystery, but it certainly did work, with some patients (22-38%) achieving what was then thought of as a complete remission. There are various theories why it works. One suggested that there is a circulation of all malignant cells through the spleen so that they all get a dose of radiation as they are passing through, but experiments with radiolabelled lymphocytes do not seem to confirm that. Other suggestions are that there is an induced change to the array of lymphocyte subpopulations or to the cytokine environment that has an effect on the survival of CLL cells. However, this is still speculation and we don't really know how it works.
Hypersplenism is the effect that a large spleen has on the neutrophil, platelet and red cell count because of pooling in the spleen or active destruction. If you take the spleen out, these levels return to normal or even overshoot. The same effect can be achieved with splenic irradiation. It is seldom so complete as splenectomy, and it may not be long lasting (remissions of 7-18 months have been reported) but the effect can be repeated, up to four times. One advantage is that with the blood count restored some patients are able to go ahead and have the chemotherapy that they were previously denied because of their low counts.
Apart from restoration of the blood count, SI can shrink a painful or uncomfortable spleen and make substantial inroads into the tumor mass, by reducing white counts and shrinking nodes. The rare 'complete remissions' would not be so defined by modern criteria.
The dose of SI has varied in different trials. In our MRC trials, we used 100 cGy weekly up to a total of 1 Gy, but later studies used larger doses. Typical doses would be 0.5 to 1Gy given daily or 1-3 times a week to a total of 5-10 Gy. Larger doses than this seem to confer no extra benefit.
The most severe side effects seem to have been transient thrombocytopenia and neutropenia and these counts need to be monitored to guard against infection or bleeding. Neither neutropenia nor thrombocytopenia is a contraindication to SI and some patients who are refractory to chemotherapy also respond.
Long term toxicity does not seem to be a major problem, and although radiation does damage T cells, a regimen of carefully titrated doses allows the treatment to be monitored. For many countries in which fludarabine is regarded as expensive and rituximab a wistful dream, SI is a very cheap option for treatment.
I first came upon it was a young doctor when it was an option in the MRC CLL 1 and 2 Trials which began in 1978. I was actually a co-author of the report of those trials which were published in 1991 (Catovsky D, Richards S, Fooks J, Hamblin TJ. Leukemia and Lymphoma 1991; Supplement pp 105-112). In CLL 1 the overall survival of patients treated with splenic irradiation was 5 years compared to 3.8 years for those treated with chlorambucil. The numbers were small and did not reach statistical significance, and the dose of chlorambucil was only 40mg/sq m. However in CLL 2 the overall survival for those treated with splenic irradiation was 3.4 years compared to 4.1 years for chlorambucil. Again the difference was not statistically significant. The conclusion that we drew was that splenic irradiation was not an inferior treatment to the dose of chlorambucil used in the original fludarabine trial or the recent alemtuzumab trial.
I am grateful to my friend Stacie who has sent me a 2001 paper that reviews several trials of splenic irradiation (SI) in CLL. It is from a journal that I don't normally read. (Weinmann M, Becker G, Einsele H, Bamberg M. Radiotherapy and Oncology 2001; 58:235-246.)
Of late, SI has only been used in patients with hypersplenism who were considered unfit for splenectomy, even if performed by keyhole surgery. But in the past it was used as a therapeutic modality which attempted to control the disease as a whole rather than that which is localized to the spleen. How it was supposed to work is a bit of a mystery, but it certainly did work, with some patients (22-38%) achieving what was then thought of as a complete remission. There are various theories why it works. One suggested that there is a circulation of all malignant cells through the spleen so that they all get a dose of radiation as they are passing through, but experiments with radiolabelled lymphocytes do not seem to confirm that. Other suggestions are that there is an induced change to the array of lymphocyte subpopulations or to the cytokine environment that has an effect on the survival of CLL cells. However, this is still speculation and we don't really know how it works.
Hypersplenism is the effect that a large spleen has on the neutrophil, platelet and red cell count because of pooling in the spleen or active destruction. If you take the spleen out, these levels return to normal or even overshoot. The same effect can be achieved with splenic irradiation. It is seldom so complete as splenectomy, and it may not be long lasting (remissions of 7-18 months have been reported) but the effect can be repeated, up to four times. One advantage is that with the blood count restored some patients are able to go ahead and have the chemotherapy that they were previously denied because of their low counts.
Apart from restoration of the blood count, SI can shrink a painful or uncomfortable spleen and make substantial inroads into the tumor mass, by reducing white counts and shrinking nodes. The rare 'complete remissions' would not be so defined by modern criteria.
The dose of SI has varied in different trials. In our MRC trials, we used 100 cGy weekly up to a total of 1 Gy, but later studies used larger doses. Typical doses would be 0.5 to 1Gy given daily or 1-3 times a week to a total of 5-10 Gy. Larger doses than this seem to confer no extra benefit.
The most severe side effects seem to have been transient thrombocytopenia and neutropenia and these counts need to be monitored to guard against infection or bleeding. Neither neutropenia nor thrombocytopenia is a contraindication to SI and some patients who are refractory to chemotherapy also respond.
Long term toxicity does not seem to be a major problem, and although radiation does damage T cells, a regimen of carefully titrated doses allows the treatment to be monitored. For many countries in which fludarabine is regarded as expensive and rituximab a wistful dream, SI is a very cheap option for treatment.
Friday, August 13, 2010
Honor killings
Gul and Begum Wazir, from Alum Rock, Birmingham, were reportedly shot after a planned marriage between the couple's daughter and their nephew in Pakistan fell through. Mr Wazir and his family had travelled to the village of Salehana in north Pakistan, which is sometimes referred to as Little Birmingham because of its strong ties with the Pakistani community in the West Midlands.
This is the latest of a long litany of beatings and murder in the name of honor. Harry Potter star, Afshan Azad, was badly beaten by her father Abdul Azad, and his son Ashraf attempted honor killing because of her relationship with a Hindu man.
November 2, '09: Noor Almaleki is dead; run over by her Muslim father for being too "westernized". She lingered for days.
Police in Kingston, Ontario, charged three Montrealers, Mohammed Shafia, his wife Tooba and their 18-year-old son Hamed with mass murder of three of the couple's teenage daughters, including their eldest child, Zainab, 19, and Rona Amir Mohammed, a 50-year-old woman who was Shafia's secret, first wife.
A 15-year-old schoolgirl allegedly murdered for falling in love told her boyfriend that she had been 'tortured' by her father. She was alleged to have been killed by her father Mehmet Goren, after he consulted with his brothers, over her relationship with Halil Unal. A week later Goren plunged an axe into Mr Unal's neck in a desperate bid to restore his family's honor.
A Muslim asylum seeker was sentenced to life in prison after killing his German-born wife because she was 'too independent'. The 27-year-old Kurdish man, identified only as Onder B, was found guilty today of stabbing his wife in the eyes, beating her with a billiard cue and then running over her in his car. His mother-in-law had once told him to be 'strict' with her strong-willed daughter, Mujde - who was also Onder's cousin. On New Year's Eve 2008 he stabbed his 18-year-old wife Mujde 46 times and beat her with a billiard cue. And because she was 'already so disfigured from the stabbing and beating that she would hate me for the rest of her life,' he got into his car and ran over her body several times.
Mohammed Shafii, Hamid Mohammed Shafii and Tooba Mohammad Yahya have been charged with four counts of first-degree murder and four counts of conspiracy to commit murder in Kingston, Canada. The victims were his three teenaged daughters, Zainab Shafia, 19, her sisters Sahari, 17, and Geeti, 13 and a woman originally believed to be their aunt but later found to be a second wife of Shafii, Rona Amir Mohammad. All were found in the family's Nissa Sentra, submerged at the bottom of a Rideau Canal lock near Kingston, Ont. In an interview, Diba Masoomi - a woman described as Mohammad's sister - said that Mr. Shafia "believed his daughter had dishonoured him and the family by having a romance with a young Pakistani man in Montreal."
Shafia first married Mohammad in either 1979 or 1980, and then married Yahya in the late 1980s. Both marriages took place in Afghanistan, where it is legal for a man to have more than one wife. The girls were not allowed to go out alone, neither to the cinema nor to meet friends and they were not able to dress freely. Mr. Shafia often criticized the influence of the Western culture on his family since they were not living in an Islamic country anymore.
A terrified wife who predicted her cheating husband would kill her, was stabbed to death by him just days after he was freed in a legal blunder. Sabina Akhtar, 26, went to police in fear of her life after Malik Mannan subjected her to a string of vicious beatings. The taxi driver was jailed for life today at Manchester Crown Court after being convicted of her murder yesterday. He will serve a minimum of 17 years. Speaking outside court, Ms Akhtar's family accused the Crown Prosecution Service of negligence. Her uncle, Reaz Talukder, said his niece would still be alive if her husband had been charged after being arrested for a second time.
Alright, I think you get the picture. But don't think that this is just a Muslim thing. The clash between Western and Islamic culture has highlighted the problem, but it is not the fault of the Koran that this state of affairs exists. The concept of honor will be familiar to all who fought against the Japanese in the Pacific in World War II. It would have been dishonorable for any Japanese soldier to surrender; hence the needless slaughter of a beaten foe. The only reason that it was necessary to drop nuclear bombs on Japanese cities was because of the Japanese sense of 'honor'.
How about those in Britain and France who fought duels because their 'honor' was affronted? And crusaders who went to the Holy Land in order to protect the honor of their God.
Honor killings are common in the Basque country, in Sicily, and especially in Latin America, but of course we are more familiar today when the killer is called Mohammad, Hamid, Masoomi or Shafiri. But supposing we came across a run of honor killings with perpetrators called Turner, Martin or Smith?
Back in the nineteenth century Kentucky was a pretty lawless state. The area of Harlan county in the Appalachians had been settled by eight families in 1819 and between 1860 and 1900 there were more than a thousand murders in the area. Most were down to family feuds, which didn't really stop until the 1930s. The settlers had come from northern Britain, to be precise, the borders between England and Scotland, and even there they had a reputation for feuding.
We have this report from a newspaperman who was called to jury service on one such murder trial in the Twentieth Century. The case before the jury concerned an irascible gentleman who lived next door to a filling station. For several months he had been the butt of various jokes played by the attendants and miscellaneous loafers who hung around the station, despite his warnings and notorious short temper. One morning he emptied both barrels of his shotgun at his tormentors, killing one, maiming a second permanently and wounding a third.
When the jury was polled by the incredulous judge, the reporter was the only one who recorded his vote as guilty. as one of the others put it, "He wouldn't have been much of a man if he hadn't shot them fellows."
What is even more remarkable is an experiment reported by Malcolm Gladwell in his book, Outliers, from the University of Michigan. The experimenters staged a confrontation for psychology students to see how they would respond to an insult. They found that students who came from that part of Kentucky reacted in an aggressive manner while Northerners laughed it off. The culture of honor that originated in the British borderlands in the Eighteenth Century, still persisted in modern day America. Is there any hope for Middle Eastern immigrants?
Perhaps there is. The historian C John Sommerville has shown how Christianity has changed those honor-based cultures of northern Europe in which pride was valued rather than humility, dominance rather than service, courage rather than peaceableness, glory rather than modesty and loyalty to ones own tribe rather than respect for all. This is not the Christianity of the Crusades and the Inquisition, but the Christianity of the Christ who said "Whoever wants to be first must be the servant of all."
This is the latest of a long litany of beatings and murder in the name of honor. Harry Potter star, Afshan Azad, was badly beaten by her father Abdul Azad, and his son Ashraf attempted honor killing because of her relationship with a Hindu man.
November 2, '09: Noor Almaleki is dead; run over by her Muslim father for being too "westernized". She lingered for days.
Police in Kingston, Ontario, charged three Montrealers, Mohammed Shafia, his wife Tooba and their 18-year-old son Hamed with mass murder of three of the couple's teenage daughters, including their eldest child, Zainab, 19, and Rona Amir Mohammed, a 50-year-old woman who was Shafia's secret, first wife.
A 15-year-old schoolgirl allegedly murdered for falling in love told her boyfriend that she had been 'tortured' by her father. She was alleged to have been killed by her father Mehmet Goren, after he consulted with his brothers, over her relationship with Halil Unal. A week later Goren plunged an axe into Mr Unal's neck in a desperate bid to restore his family's honor.
A Muslim asylum seeker was sentenced to life in prison after killing his German-born wife because she was 'too independent'. The 27-year-old Kurdish man, identified only as Onder B, was found guilty today of stabbing his wife in the eyes, beating her with a billiard cue and then running over her in his car. His mother-in-law had once told him to be 'strict' with her strong-willed daughter, Mujde - who was also Onder's cousin. On New Year's Eve 2008 he stabbed his 18-year-old wife Mujde 46 times and beat her with a billiard cue. And because she was 'already so disfigured from the stabbing and beating that she would hate me for the rest of her life,' he got into his car and ran over her body several times.
Mohammed Shafii, Hamid Mohammed Shafii and Tooba Mohammad Yahya have been charged with four counts of first-degree murder and four counts of conspiracy to commit murder in Kingston, Canada. The victims were his three teenaged daughters, Zainab Shafia, 19, her sisters Sahari, 17, and Geeti, 13 and a woman originally believed to be their aunt but later found to be a second wife of Shafii, Rona Amir Mohammad. All were found in the family's Nissa Sentra, submerged at the bottom of a Rideau Canal lock near Kingston, Ont. In an interview, Diba Masoomi - a woman described as Mohammad's sister - said that Mr. Shafia "believed his daughter had dishonoured him and the family by having a romance with a young Pakistani man in Montreal."
Shafia first married Mohammad in either 1979 or 1980, and then married Yahya in the late 1980s. Both marriages took place in Afghanistan, where it is legal for a man to have more than one wife. The girls were not allowed to go out alone, neither to the cinema nor to meet friends and they were not able to dress freely. Mr. Shafia often criticized the influence of the Western culture on his family since they were not living in an Islamic country anymore.
A terrified wife who predicted her cheating husband would kill her, was stabbed to death by him just days after he was freed in a legal blunder. Sabina Akhtar, 26, went to police in fear of her life after Malik Mannan subjected her to a string of vicious beatings. The taxi driver was jailed for life today at Manchester Crown Court after being convicted of her murder yesterday. He will serve a minimum of 17 years. Speaking outside court, Ms Akhtar's family accused the Crown Prosecution Service of negligence. Her uncle, Reaz Talukder, said his niece would still be alive if her husband had been charged after being arrested for a second time.
Alright, I think you get the picture. But don't think that this is just a Muslim thing. The clash between Western and Islamic culture has highlighted the problem, but it is not the fault of the Koran that this state of affairs exists. The concept of honor will be familiar to all who fought against the Japanese in the Pacific in World War II. It would have been dishonorable for any Japanese soldier to surrender; hence the needless slaughter of a beaten foe. The only reason that it was necessary to drop nuclear bombs on Japanese cities was because of the Japanese sense of 'honor'.
How about those in Britain and France who fought duels because their 'honor' was affronted? And crusaders who went to the Holy Land in order to protect the honor of their God.
Honor killings are common in the Basque country, in Sicily, and especially in Latin America, but of course we are more familiar today when the killer is called Mohammad, Hamid, Masoomi or Shafiri. But supposing we came across a run of honor killings with perpetrators called Turner, Martin or Smith?
Back in the nineteenth century Kentucky was a pretty lawless state. The area of Harlan county in the Appalachians had been settled by eight families in 1819 and between 1860 and 1900 there were more than a thousand murders in the area. Most were down to family feuds, which didn't really stop until the 1930s. The settlers had come from northern Britain, to be precise, the borders between England and Scotland, and even there they had a reputation for feuding.
We have this report from a newspaperman who was called to jury service on one such murder trial in the Twentieth Century. The case before the jury concerned an irascible gentleman who lived next door to a filling station. For several months he had been the butt of various jokes played by the attendants and miscellaneous loafers who hung around the station, despite his warnings and notorious short temper. One morning he emptied both barrels of his shotgun at his tormentors, killing one, maiming a second permanently and wounding a third.
When the jury was polled by the incredulous judge, the reporter was the only one who recorded his vote as guilty. as one of the others put it, "He wouldn't have been much of a man if he hadn't shot them fellows."
What is even more remarkable is an experiment reported by Malcolm Gladwell in his book, Outliers, from the University of Michigan. The experimenters staged a confrontation for psychology students to see how they would respond to an insult. They found that students who came from that part of Kentucky reacted in an aggressive manner while Northerners laughed it off. The culture of honor that originated in the British borderlands in the Eighteenth Century, still persisted in modern day America. Is there any hope for Middle Eastern immigrants?
Perhaps there is. The historian C John Sommerville has shown how Christianity has changed those honor-based cultures of northern Europe in which pride was valued rather than humility, dominance rather than service, courage rather than peaceableness, glory rather than modesty and loyalty to ones own tribe rather than respect for all. This is not the Christianity of the Crusades and the Inquisition, but the Christianity of the Christ who said "Whoever wants to be first must be the servant of all."
David Beckham
The England football manager, Fabio Capello, doesn't speak very good English, so it was probably a misunderstanding that mad him blurt out that it was unlikely that David Beckham would be picked for future England games.
David Beckham has been an England player for about 14 years and was captain for about half that time. He has been idolized by many in the same sort of way that Princess Diana was, though there has been another constituency that has been (and continues) sniping at him in the correspondence columns.
Nevertheless, he is a good example to young men who aspire to footballing greatness. I don't think most people realise how difficult it is to excel at football. The best footballer I ever played with at school, who garnered county, regional and international honours as a schoolboy turned professional and managed to achieve a few seasons with Reading in Division 3 (South).
Beckham was not the best footballer who ever played for England, but there are few if any who showed more enthusiasm for the cause. Whether you are a concert pianist or a brain surgeon it takes 10,000 hours of practice to become an expert in your field. Beckham's expertise was in kicking a football. Remember he featured in a TV advert for Weatabix at the age of 10 doing keepy-upies. Remember that he stayed on after training practising free kicks when the rest of the team went off to the golf course, betting shop or boozer.
The result was that free kick against Greece that stunned the crowd into silence. (And you should not forget that Greece went on to be the next European Champions). Even last season we had an example of Beckham crossing the ball on the volley to make a goal. Remember those two corners that won the European cup in injury time for Manchester United? The stunning long ball to Raul for Real Madrid was typical of his skill and repeated often. Neither Gerrard nor Lampard can rival him in that department.
As a right winger Beckham was neither fast like Walcott nor tricky like Johnson, but by gaining a yard or crossing on the volley he produced an end result that neither of them nor any winger since has produced. His free kicks became a by-word throughout football, and until Ronaldo, no one was better at taking them.
He also kept himself fit. Rooney is already looking dumpy at 23; Beckham has a figure good enough to feature in Gay-mags at 35. People forget that he was London schools cross country champion as a teenager.
Celebrity attaches itself to good footballers - even people like Gareth Southgate. On the whole he has handled it as well as most and has made more money from it. To have done so much without being the best footballer of the century in Britain, demonstrates his ability to make the most of his circumstances.
I can’t say I am much into celebrity culture, but he hasn’t made quite the mess of his life that some of his contemporaries have such as John Terry, Ashley Cole and even Peter Crouch.
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