Somehow people seem to believe that Christians shouldn’t suffer. I’m not sure where the idea comes from, certainly not the Bible. All the disciples met violent deaths apart from John and he died in exile, abandoned on a small island. As the writer to the Hebrews explained some of God’s chosen ones were tortured, some faced jeers and flogging, others were chained and put in prison, they were stoned, they were sawn in two, they were put to death by the sword, they went about in sheepskins and goatskins, destitute, persecuted and ill-treated. They wandered in deserts and mountains, and in caves and holes in the ground.
It’s not exactly the carefree life with a large house, luxurious car and hot and cold running golf courses that we aspire to. No mention of trophy wives and holidays in the Seychelles in that lot.
This silly couplet sums it up:
The Lord maketh it to rain upon the just and the unjust fella.
But more upon the just, because the unjust man usually has the just man’s umbrella.
As well as the slings and arrows of outrageous fortune, Christians suffer because they are Christians. Only last week a Christian schoolgirl aged 16 received 50 lashes in Sudan because she was wearing a knee length skirt. Quite apart from the fact that Sudanese law bars anyone under 18 from receiving lashes, this was an outrageous persecution. Bonhoeffer said that suffering is the badge of the Christian. When we think of some of the heroes of the faith, like Lord Shaftesbury, General Booth and William Wilberforce, we should not forget that successful though they were, they were ridiculed and jeered at in their day.
But when we suffer we are to bear it well, for we are following in the footsteps of the suffering servant.
Today’s passage in 1Peter 2:21-25 points to Jesus as our example. To this you were called, because Christ suffered for you, leaving you an example that you should follow in his steps. "He committed no sin, and no deceit was found in his mouth. When they hurled their insults at him, he did not retaliate; when he suffered, he made no threats. Instead, he entrusted himself to him who judges justly. He himself bore our sins in his body on the tree, so that we might die to sins and live for righteousness; by his wounds you have been healed. For you were like sheep going astray, but now you have returned to the Shepherd and Overseer of your souls.
There is a liberal trap that uses this passage to suggest that the crucifixion was all about Jesus being an example to us. It seeks to deny all that stuff about substitutionary atonement. That is clearly stated in this passage. “He bore our sins in his body on the tree.” and “By his wounds we have been healed.” But for that reason, evangelicals have tended to downplay the notion of Christ as an example, but here it is in black and white. Certainly, he was our substitute, but he was also our example.
We should note that his suffering was undeserved – he committed no sin. But he did not retaliate. Some years ago there was a fashion for vigilante films. We would feel good when the police were weak and ineffectual, the hero gunned down the drug addicts who raped and murdered his wife. But in real life the adage is true that two wrongs don’t make a right. We don’t defeat evil by continuing the cycle of evil; rather evil is vanquished by smothering it. If we soak it up like a sponge, its force is lost.
We leave it to a just judge. As it says in 2 Thessalonians 1:6-10: God is just: He will pay back trouble to those who trouble you and give relief to you who are troubled, and to us as well. This will happen when the Lord Jesus is revealed from heaven in blazing fire with his powerful angels. He will punish those who do not know God and do not obey the gospel of our Lord Jesus. They will be punished with everlasting destruction and shut out from the presence of the Lord and from the majesty of his power on the day he comes to be glorified in his holy people and to be marveled at among all those who have believed. This includes you, because you believed our testimony to you.
Submission seems like weakness. It seems an unmanly thing to do, but Jesus was not unmanly. He was meek not weak, and meekness is strength under control. A huge Jumbo Jet touches down on the runway without the slightest judder. The passengers applaud. They recognize that the pilot has got this huge beast under fingertip control.
Anger is a huge beast within us that cries out, “It’s unfair! I want my revenge!” That is not the Christian way. That is the astray, way. Return control to the shepherd and overseer of our souls.
Monday, November 30, 2009
Saturday, November 28, 2009
Placebo, nocebo.
Just now, Parliament is taking evidence on alternative medicine. One piece of evidence was given by Boots the Chemist, the largest pharmacy chain in the UK. When asked why they sold alternatives medicines alongside real ones, they replied that it was not because they worked, but because they were popular.
To quote Ben Goldacre of the Guardian, "The best moment was Dr Peter Fisher from the (NHS-funded) Royal London Homeopathic hospital explaining that homeopathic sugar pills have physical side-effects – so they must be powerful."
This association of bad effects with the administration of small amounts of ingested water is known as the nocebo effect - the opposite of the placebo effect
People tend to dismiss the placebo effect as if it did not matter or could not effect cures. This is silly. Any number of people will come forward and testify that they were made better by homeopathy, acupuncture, foot massage, drinking their own urine and all the other imaginative procedures that collectively are known as alternative or complimentary medicine. In clinical trials it is seldom that these treatments have no effect, but that is also the case when deliberately chosen agents with assuredly no activity are used. Patients are often unable to distinguish between the real drug and dummy drug; they can get both beneficial effects and side effects from the placebo.
The placebo effect is enhanced by time spent with the patient, a sympathetic manner, touching, smiling, self-confidence and listening - things that alternative practitioners are good at. When I was a young doctor we didn't have many drugs that worked. We had morphine and aspirin, but none of the non-steroidal drugs except indomethacin and phenylbutazone, which were pretty toxic. We had a few antibiotics, but not the wide array of kill-anything drugs that we have now; we were still using chloramphenicol, which destroyed the bone marrow of a predictable number of patients and tetracycline, which gave you brown teeth. We had no decent diuretic, and digitalis was the only heart drug. The drugs we had for high blood pressure made everyone ill, one way or another. We had a few cytotoxic drugs, but we gave them in tiny doses because we had no way of keeping patients alive if we had used today's doses. We had to rely on our bedside manner.
Thankfully, most illnesses get better by themselves and the doctor relied on his bedside manner to convince the patient that it was he, and not time, that had effected the cure. So, by all means, let's make use of the placebo effect,
But we run into a problem. Isn't it deceitful to give the patient the impression that sticking pins in them or manipulating their neck or rubbing their feet will make them better? Yes it is. Alternative practitioners either lie to themselves or lie to their patients. Does this matter? I leave the reader to judge.
But doctors can make use of the placebo effect. Not by lying to patients but by spending time with them and having a sympathetic manner. Often I hear of doctors who do not get up when the patients enters the room, do not make eye contact, but stare at their computer screen and type out a prescription almost as soon as the patient's bottom has hit the seat.
Certainly in oncology it pays to spend time with patients. When I was treating kidney cancer with interleukin-2 I was impressed with the results obtained by a doctor in New York. Then I saw that the dose that he used was many times greater than I was using. I couldn't believe that it was possible to get this very toxic drug into patients. I asked him how he did it. He replied that he sat with the patient throughout the whole infusion, holding their hand.
A good bedside manner will enable patients to take full rather than attenuated doses of toxic drugs. Often single center clinical trials produce much better results than when the drug is used in the community. I believe this is in part because of the placebo effect of going to a world-renowned center and being greeted by a kindly old gentleman with a beard who gives you a bear hug when he greets you.
To quote Ben Goldacre of the Guardian, "The best moment was Dr Peter Fisher from the (NHS-funded) Royal London Homeopathic hospital explaining that homeopathic sugar pills have physical side-effects – so they must be powerful."
This association of bad effects with the administration of small amounts of ingested water is known as the nocebo effect - the opposite of the placebo effect
People tend to dismiss the placebo effect as if it did not matter or could not effect cures. This is silly. Any number of people will come forward and testify that they were made better by homeopathy, acupuncture, foot massage, drinking their own urine and all the other imaginative procedures that collectively are known as alternative or complimentary medicine. In clinical trials it is seldom that these treatments have no effect, but that is also the case when deliberately chosen agents with assuredly no activity are used. Patients are often unable to distinguish between the real drug and dummy drug; they can get both beneficial effects and side effects from the placebo.
The placebo effect is enhanced by time spent with the patient, a sympathetic manner, touching, smiling, self-confidence and listening - things that alternative practitioners are good at. When I was a young doctor we didn't have many drugs that worked. We had morphine and aspirin, but none of the non-steroidal drugs except indomethacin and phenylbutazone, which were pretty toxic. We had a few antibiotics, but not the wide array of kill-anything drugs that we have now; we were still using chloramphenicol, which destroyed the bone marrow of a predictable number of patients and tetracycline, which gave you brown teeth. We had no decent diuretic, and digitalis was the only heart drug. The drugs we had for high blood pressure made everyone ill, one way or another. We had a few cytotoxic drugs, but we gave them in tiny doses because we had no way of keeping patients alive if we had used today's doses. We had to rely on our bedside manner.
Thankfully, most illnesses get better by themselves and the doctor relied on his bedside manner to convince the patient that it was he, and not time, that had effected the cure. So, by all means, let's make use of the placebo effect,
But we run into a problem. Isn't it deceitful to give the patient the impression that sticking pins in them or manipulating their neck or rubbing their feet will make them better? Yes it is. Alternative practitioners either lie to themselves or lie to their patients. Does this matter? I leave the reader to judge.
But doctors can make use of the placebo effect. Not by lying to patients but by spending time with them and having a sympathetic manner. Often I hear of doctors who do not get up when the patients enters the room, do not make eye contact, but stare at their computer screen and type out a prescription almost as soon as the patient's bottom has hit the seat.
Certainly in oncology it pays to spend time with patients. When I was treating kidney cancer with interleukin-2 I was impressed with the results obtained by a doctor in New York. Then I saw that the dose that he used was many times greater than I was using. I couldn't believe that it was possible to get this very toxic drug into patients. I asked him how he did it. He replied that he sat with the patient throughout the whole infusion, holding their hand.
A good bedside manner will enable patients to take full rather than attenuated doses of toxic drugs. Often single center clinical trials produce much better results than when the drug is used in the community. I believe this is in part because of the placebo effect of going to a world-renowned center and being greeted by a kindly old gentleman with a beard who gives you a bear hug when he greets you.
Friday, November 27, 2009
Keeping the Sabbath
For the last few Sunday evenings we have sat through an extended description of the Tabernacle. I don't know about you, but there are certain passages of the Bible that I find difficult to take very seriously. The Bible has some wonderful stories. David battling against the Philistines, Elijah and the prophets of Baal, Joshua and Jericho, Gideon and the Midianites, Joseph and his brothers, Moses and the bulrushes and Samson and Delilah are but a few of the Old Testament stories that thrill and excite. In the New Testament, Jesus is a great story teller, with The Good Samaritan, the Prodigal Son and the Importunate Widow all making important spiritual points. But there are bits of the Bible that are frankly boring to most of us. The end of Exodus and most of Leviticus stand in the way of anyone who starts to read the Bible from cover to cover. Ezra and Nehemiah have a lot of lists and difficult names to get over, and some of Paul's letters can be hard on the understanding.
I guess that part of the reason that Leviticus is so hard to get to grips with is all those dietary laws and all that stoning going on that most of us find not really relevant to the twenty first century. Still Paul does say that "All Scripture is God-breathed and is useful for teaching, rebuking, correcting and training in righteousness." So we ought to ask ourselves whether we should be taking these instructions more seriously.
We have to remember that the Old Testament law was given to the nation of Israel, not to Christians. The Israelites were given instructions on how to obey and please God (the Ten Commandments, for example), and how to worship God and atone for sin (the sacrificial system). Other laws were to make the Israelites distinct from other nations (the food and clothing rules). But none of the Old Testament law is binding on us today. When Jesus died on the cross, He put an end to the Old Testament law. "Christ is the end of the law so that there may be righteousness for everyone who believes" (Romans 10:4). "Is the law, therefore, opposed to the promises of God? Absolutely not! For if a law had been given that could impart life, then righteousness would certainly have come by the law. But the Scripture declares that the whole world is a prisoner of sin, so that what was promised, being given through faith in Jesus Christ, might be given to those who believe. Before this faith came, we were held prisoners by the law, locked up until faith should be revealed. So the law was put in charge to lead us to Christ that we might be justified by faith. Now that faith has come, we are no longer under the supervision of the law." (Galatians 3:21-25). "But now in Christ Jesus you who once were far away have been brought near through the blood of Christ. For he himself is our peace, who has made the two one and has destroyed the barrier, the dividing wall of hostility, by abolishing in his flesh the law with its commandments and regulations. His purpose was to create in himself one new man out of the two, thus making peace." (Ephesians 2:13-15)
Instead of the Old Testament law, we are under the law of Christ "Carry each other’s burdens, and in this way you will fulfill the law of Christ." (Galatians 6:2), which is to “love the Lord your God with all your heart and with all your soul and with all your mind ... and to love your neighbor as yourself” (Matthew 22:37-39). If we obey those two commands, we will be fulfilling all that Christ requires of us. This does not mean the Old Testament law is irrelevant today; these summaries of law come from Deuteronomy and Leviticus!
Nine of the Ten Commandments are clearly repeated in the New Testament (all except the command to observe the Sabbath day). Obviously, if we are loving God, we will not be worshipping false gods or bowing down before idols. If we are loving our neighbors, we will not be murdering them, lying to them, committing adultery against them, or coveting what belongs to them.
It is actually impossible for us to do this perfectly. In the Sermon on the Mount Jesus opens up exactly what it means to love God and love your neighbor. Being angry with your brother and looking lustfully at a woman? Who doesn't fall short? The purpose of the Old Testament law is to convict people of our inability to keep the law and point us to our need for Jesus Christ as Savior "What shall we say, then? Is the law sin? Certainly not! Indeed I would not have known what sin was except through the law. For I would not have known what coveting really was if the law had not said, Do not covet.”(Romans 7:7) "So the law was put in charge to lead us to Christ that we might be justified by faith."(Galatians 3:24).
But what about the Sabbath? When I was young I thought Sunday afternoons were set aside for exercises in boredom. I remember a story about a Scottish Presbyterian pastor, who when he was snowed in and unable to get to the kirk because the road was blocked, took the only option open to him and skated across the loch. After the morning service his Elders called him in and accused him of skating on the Lord's day. He explained that it was his only way or getting there to preach the sermon they had all experienced. They took a moment to confer and then asked him, "Can ye assure us that ye dinnae enjoy it?"
In Colossians 2:16-17, Paul states, “Therefore do not let anyone judge you by what you eat or drink, or with regard to a religious festival, a New Moon celebration or a Sabbath day. These are a shadow of the things that were to come; the reality, however, is found in Christ.” Similarly, Romans 14:5 states, “One man considers one day more sacred than another; another man considers every day alike. Each one should be fully convinced in his own mind.” It is clear that, for the Christian, Sabbath-keeping is a matter of spiritual freedom, not a command from God. We should be convinced in our own mind, but we don't get saved by keeping the Sabbath.
Jesus often performed miracles on the Sabbath; it was almost as though he was goading the Pharisees with their excessive legalism. He said that the Sabbath was made for man; not man for the Sabbath. Various experiments have emphasized our need for regular rest and one day in seven seems about right. We should not confuse the Christian Sunday with the Jewish Sabbath. We spend Sunday in worship, the Jews spent the Sabbath resting.
But the Sabbath does have a special meaning for Christians. The origin of the Sabbath goes back to Creation. After creating the heavens and the earth in six days, God “rested on the seventh day from all His work which He had made” (Genesis 2:2). This doesn’t mean that God was tired and needed a rest. He never tires, and His power is not diminished by the hardest work. It simply means that He ceased from His labors.
God used the example of His resting on the seventh day of Creation to establish the principle of the Sabbath day rest for His people. In Exodus 20:8-11 and Deuteronomy 5:12-15, God gave the Israelites the fourth of His Ten Commandments. They were to “remember” the Sabbath day and “keep it holy.” One day out of every seven, they were to rest from their labors and give the same day of rest to their servants and animals.
With the establishment of the Old Testament Law, the Jews were constantly “laboring” to make themselves acceptable to God. Their labors included trying to obey thousands of do’s and don’ts of the ceremonial law, the Temple law, the civil law, etc. Of course, they couldn’t possibly keep all those laws, so God provided an array of sin offerings and sacrifices so they could come to Him for forgiveness and restore fellowship with Him, but only temporarily.
But the sacrifices had be repeated over and over again until the coming of Christ and "after He had offered one sacrifice for sins forever, sat down on the right of God” (Hebrews 10:12). He also ceased from His labors. He rested. So we can see that the Sabbath points forwards to Jesus as our Sabbath rest.
Hebrews chapter 4 is the definitive passage regarding Jesus as our Sabbath rest. Psalm 95 talks about the disobedient ones who "shall never enter my rest". This is a reference to Deuteronomy 1:35 where the LORD declares that those who came out of Egypt, because of their disobedience, should not, except for Joshua and Caleb, enter the promised land; not even Moses, who struck the rock in his anger, would be allowed to enter in. So is the land of Israel the promised rest? No, rather it is a picture of it. For in Hebrews 4:8 the author of the letter writes, "If Joshua had given them rest, God would not have spoken later about another day" - reference to Psalm 95 written much later and warning the Israelites against disobedience like that of their forefathers.
"There remains, then, a Sabbath-rest for the people of God; for anyone who enters God’s rest also rests from his own work, just as God did from his. Let us, therefore, make every effort to enter that rest, so that no one will fall by following their example of disobedience" (Hebrews 4:9-11) Whereas God rested from the work of creation, the believer ceases his efforts to gain salvation by his own works and rests on the finished work of Christ on the cross.
So the Sabbath points forward to Christ, and like the animal sacrifices that have also ceased because Christ's death has fulfilled them, so the practice of regularly ceasing from work one day in seven has been replaced by the eternal rest that we have in Christ. We do not worship God one day in seven, but like the disciples in Acts 2:46-7, we worship God every day. “Every day they continued to meet together in the temple courts. They broke bread in their homes and ate together with glad and sincere hearts, praising God and enjoying the favor of all the people. And the Lord added to their number daily those who were being saved.”
I guess that part of the reason that Leviticus is so hard to get to grips with is all those dietary laws and all that stoning going on that most of us find not really relevant to the twenty first century. Still Paul does say that "All Scripture is God-breathed and is useful for teaching, rebuking, correcting and training in righteousness." So we ought to ask ourselves whether we should be taking these instructions more seriously.
We have to remember that the Old Testament law was given to the nation of Israel, not to Christians. The Israelites were given instructions on how to obey and please God (the Ten Commandments, for example), and how to worship God and atone for sin (the sacrificial system). Other laws were to make the Israelites distinct from other nations (the food and clothing rules). But none of the Old Testament law is binding on us today. When Jesus died on the cross, He put an end to the Old Testament law. "Christ is the end of the law so that there may be righteousness for everyone who believes" (Romans 10:4). "Is the law, therefore, opposed to the promises of God? Absolutely not! For if a law had been given that could impart life, then righteousness would certainly have come by the law. But the Scripture declares that the whole world is a prisoner of sin, so that what was promised, being given through faith in Jesus Christ, might be given to those who believe. Before this faith came, we were held prisoners by the law, locked up until faith should be revealed. So the law was put in charge to lead us to Christ that we might be justified by faith. Now that faith has come, we are no longer under the supervision of the law." (Galatians 3:21-25). "But now in Christ Jesus you who once were far away have been brought near through the blood of Christ. For he himself is our peace, who has made the two one and has destroyed the barrier, the dividing wall of hostility, by abolishing in his flesh the law with its commandments and regulations. His purpose was to create in himself one new man out of the two, thus making peace." (Ephesians 2:13-15)
Instead of the Old Testament law, we are under the law of Christ "Carry each other’s burdens, and in this way you will fulfill the law of Christ." (Galatians 6:2), which is to “love the Lord your God with all your heart and with all your soul and with all your mind ... and to love your neighbor as yourself” (Matthew 22:37-39). If we obey those two commands, we will be fulfilling all that Christ requires of us. This does not mean the Old Testament law is irrelevant today; these summaries of law come from Deuteronomy and Leviticus!
Nine of the Ten Commandments are clearly repeated in the New Testament (all except the command to observe the Sabbath day). Obviously, if we are loving God, we will not be worshipping false gods or bowing down before idols. If we are loving our neighbors, we will not be murdering them, lying to them, committing adultery against them, or coveting what belongs to them.
It is actually impossible for us to do this perfectly. In the Sermon on the Mount Jesus opens up exactly what it means to love God and love your neighbor. Being angry with your brother and looking lustfully at a woman? Who doesn't fall short? The purpose of the Old Testament law is to convict people of our inability to keep the law and point us to our need for Jesus Christ as Savior "What shall we say, then? Is the law sin? Certainly not! Indeed I would not have known what sin was except through the law. For I would not have known what coveting really was if the law had not said, Do not covet.”(Romans 7:7) "So the law was put in charge to lead us to Christ that we might be justified by faith."(Galatians 3:24).
But what about the Sabbath? When I was young I thought Sunday afternoons were set aside for exercises in boredom. I remember a story about a Scottish Presbyterian pastor, who when he was snowed in and unable to get to the kirk because the road was blocked, took the only option open to him and skated across the loch. After the morning service his Elders called him in and accused him of skating on the Lord's day. He explained that it was his only way or getting there to preach the sermon they had all experienced. They took a moment to confer and then asked him, "Can ye assure us that ye dinnae enjoy it?"
In Colossians 2:16-17, Paul states, “Therefore do not let anyone judge you by what you eat or drink, or with regard to a religious festival, a New Moon celebration or a Sabbath day. These are a shadow of the things that were to come; the reality, however, is found in Christ.” Similarly, Romans 14:5 states, “One man considers one day more sacred than another; another man considers every day alike. Each one should be fully convinced in his own mind.” It is clear that, for the Christian, Sabbath-keeping is a matter of spiritual freedom, not a command from God. We should be convinced in our own mind, but we don't get saved by keeping the Sabbath.
Jesus often performed miracles on the Sabbath; it was almost as though he was goading the Pharisees with their excessive legalism. He said that the Sabbath was made for man; not man for the Sabbath. Various experiments have emphasized our need for regular rest and one day in seven seems about right. We should not confuse the Christian Sunday with the Jewish Sabbath. We spend Sunday in worship, the Jews spent the Sabbath resting.
But the Sabbath does have a special meaning for Christians. The origin of the Sabbath goes back to Creation. After creating the heavens and the earth in six days, God “rested on the seventh day from all His work which He had made” (Genesis 2:2). This doesn’t mean that God was tired and needed a rest. He never tires, and His power is not diminished by the hardest work. It simply means that He ceased from His labors.
God used the example of His resting on the seventh day of Creation to establish the principle of the Sabbath day rest for His people. In Exodus 20:8-11 and Deuteronomy 5:12-15, God gave the Israelites the fourth of His Ten Commandments. They were to “remember” the Sabbath day and “keep it holy.” One day out of every seven, they were to rest from their labors and give the same day of rest to their servants and animals.
With the establishment of the Old Testament Law, the Jews were constantly “laboring” to make themselves acceptable to God. Their labors included trying to obey thousands of do’s and don’ts of the ceremonial law, the Temple law, the civil law, etc. Of course, they couldn’t possibly keep all those laws, so God provided an array of sin offerings and sacrifices so they could come to Him for forgiveness and restore fellowship with Him, but only temporarily.
But the sacrifices had be repeated over and over again until the coming of Christ and "after He had offered one sacrifice for sins forever, sat down on the right of God” (Hebrews 10:12). He also ceased from His labors. He rested. So we can see that the Sabbath points forwards to Jesus as our Sabbath rest.
Hebrews chapter 4 is the definitive passage regarding Jesus as our Sabbath rest. Psalm 95 talks about the disobedient ones who "shall never enter my rest". This is a reference to Deuteronomy 1:35 where the LORD declares that those who came out of Egypt, because of their disobedience, should not, except for Joshua and Caleb, enter the promised land; not even Moses, who struck the rock in his anger, would be allowed to enter in. So is the land of Israel the promised rest? No, rather it is a picture of it. For in Hebrews 4:8 the author of the letter writes, "If Joshua had given them rest, God would not have spoken later about another day" - reference to Psalm 95 written much later and warning the Israelites against disobedience like that of their forefathers.
"There remains, then, a Sabbath-rest for the people of God; for anyone who enters God’s rest also rests from his own work, just as God did from his. Let us, therefore, make every effort to enter that rest, so that no one will fall by following their example of disobedience" (Hebrews 4:9-11) Whereas God rested from the work of creation, the believer ceases his efforts to gain salvation by his own works and rests on the finished work of Christ on the cross.
So the Sabbath points forward to Christ, and like the animal sacrifices that have also ceased because Christ's death has fulfilled them, so the practice of regularly ceasing from work one day in seven has been replaced by the eternal rest that we have in Christ. We do not worship God one day in seven, but like the disciples in Acts 2:46-7, we worship God every day. “Every day they continued to meet together in the temple courts. They broke bread in their homes and ate together with glad and sincere hearts, praising God and enjoying the favor of all the people. And the Lord added to their number daily those who were being saved.”
Thursday, November 26, 2009
OFAR
I have been asked about OFAR (combined oxaliplatin, fludarabine, cytarabine and rituximab) There is one paper at ASH from MDACC on OFAR used as salvage therapy in patients with del 17p. There were no CRs among the 28 patients, but the overall response rate was 39%. The median overall survival was 16 months.
There is a published Phase 1/2 trial of OFAR in JCO, also from MDACC, on the treatment of CLL patients either refractory to fludarabine of with Richter's syndrome (RS). The overall response rates were 50% in RS and 33% in fludarabine-refractory CLL. The median response duration was 10 months.
The dose of oxaliplatin used in OFAR is far less than is used in FOLFOX regimens for colon cancer. At the lower dose the peripheral neuropathy should not be a problem.
There is a published Phase 1/2 trial of OFAR in JCO, also from MDACC, on the treatment of CLL patients either refractory to fludarabine of with Richter's syndrome (RS). The overall response rates were 50% in RS and 33% in fludarabine-refractory CLL. The median response duration was 10 months.
The dose of oxaliplatin used in OFAR is far less than is used in FOLFOX regimens for colon cancer. At the lower dose the peripheral neuropathy should not be a problem.
Xenophobia
The Daily Mail is particularly xenophobic today.
The Chelsea and Westminster Hospital's neonatal ward treats 500 newborns each year from London and the south east. Many of the babies have been born prematurely or have inherited illnesses.
Earlier this year when 243 babies had been admitted to the unit, a survey was taken of the origin of the mothers. 52 were from Africa, 59 from Asia, 64 from Europe, 48 from the Americas and 20 from Australasia. There were only 18 from the UK and nearly as many, 16, from the USA. In all 72 nations were involved.
This facility deals with ailments such as sickle cell anaemia (which is prevalent in African and Mediterranean communities, while almost unknown among those of northern European heritage), HIV passed on from the mother, as well as deafness, blindness and devastating neurological problems common among ethnic communities in which marriages between cousins are the norm.
It seems that it is paid for by the UK taxpayer. One of the things that must be guarded against with Obama-care.
One of the comments in response to the article goes like this:
"We have got plenty of money for everyone - come to Britain we will foot the bill, we are only too happy to cover your costs as well as our own. I don't mind working all the hours God sends so you don't have to. If you are ever passing my house then let yourself in - the key is under the mat and just help yourself to the food in the fridge. If you need to shower then have a nice hot one at my expense, there are plenty of clean towels and feel free to have a nice nap in my bed. Don't worry I will do the laundry after you have gone. I am only too happy to do this for all the foreign nationals because when I am in their country it is all free for me and my family too."
Irony is not dead yet.
The Chelsea and Westminster Hospital's neonatal ward treats 500 newborns each year from London and the south east. Many of the babies have been born prematurely or have inherited illnesses.
Earlier this year when 243 babies had been admitted to the unit, a survey was taken of the origin of the mothers. 52 were from Africa, 59 from Asia, 64 from Europe, 48 from the Americas and 20 from Australasia. There were only 18 from the UK and nearly as many, 16, from the USA. In all 72 nations were involved.
This facility deals with ailments such as sickle cell anaemia (which is prevalent in African and Mediterranean communities, while almost unknown among those of northern European heritage), HIV passed on from the mother, as well as deafness, blindness and devastating neurological problems common among ethnic communities in which marriages between cousins are the norm.
It seems that it is paid for by the UK taxpayer. One of the things that must be guarded against with Obama-care.
One of the comments in response to the article goes like this:
"We have got plenty of money for everyone - come to Britain we will foot the bill, we are only too happy to cover your costs as well as our own. I don't mind working all the hours God sends so you don't have to. If you are ever passing my house then let yourself in - the key is under the mat and just help yourself to the food in the fridge. If you need to shower then have a nice hot one at my expense, there are plenty of clean towels and feel free to have a nice nap in my bed. Don't worry I will do the laundry after you have gone. I am only too happy to do this for all the foreign nationals because when I am in their country it is all free for me and my family too."
Irony is not dead yet.
HE Bates
When I was a teenager I was asked by my headmaster who my favorite author was. I replied, H. E. Bates. My headmaster had never heard of him. Herbert Ernest Bates, CBE (16 May 1905 – 29 January 1974), better known as H. E. Bates, was an English writer and author. He wrote well over a hundred novels and collections of short stories.
His best-known works include Fair stood the Wind for France, Love for Lydia, The Darling Buds of May, and My Uncle Silas.
We have been watching the TV series of The Darling Buds of May, which we missed first time around. It stars David Jason and marked the screen debut of the beautiful Catherine Zeta-Jones (Mrs Michael Douglas). The series is marked by a generosity of spirit that is heart warming. It was first shown during the 1991 recession.
H. E. Bates wrote five books involving the Larkin family, the titles of the first four of which were used as episode titles for the TV series. The first book (much butchered) was made into a movie called The Mating Game, starring Tony Randall and Debbie Reynolds. Pop Larkin was played by David Jason who can also be seen on cable in Only Fools and Horses and Inspector Frost; Ma Larkin, his common law wife, was played by Pam Ferris who was a hit in Roald Dahl's Matilda and can be seen in Rosmary and Thyme on cable, Philip Franks played Cedric Charlton (Charlie) and is currently in Heartbeat as the local copper. He has lost his golden locks and now has short grey hair. As for Miss Zeta Jones, she is as beautiful as ever.
One odd fact about the TV series: Charlie and Marriette have a son, John Blenheim, who is played by a girl, Daisy-May Bates, the great granddaughter of H. E. Bates.
His best-known works include Fair stood the Wind for France, Love for Lydia, The Darling Buds of May, and My Uncle Silas.
We have been watching the TV series of The Darling Buds of May, which we missed first time around. It stars David Jason and marked the screen debut of the beautiful Catherine Zeta-Jones (Mrs Michael Douglas). The series is marked by a generosity of spirit that is heart warming. It was first shown during the 1991 recession.
H. E. Bates wrote five books involving the Larkin family, the titles of the first four of which were used as episode titles for the TV series. The first book (much butchered) was made into a movie called The Mating Game, starring Tony Randall and Debbie Reynolds. Pop Larkin was played by David Jason who can also be seen on cable in Only Fools and Horses and Inspector Frost; Ma Larkin, his common law wife, was played by Pam Ferris who was a hit in Roald Dahl's Matilda and can be seen in Rosmary and Thyme on cable, Philip Franks played Cedric Charlton (Charlie) and is currently in Heartbeat as the local copper. He has lost his golden locks and now has short grey hair. As for Miss Zeta Jones, she is as beautiful as ever.
One odd fact about the TV series: Charlie and Marriette have a son, John Blenheim, who is played by a girl, Daisy-May Bates, the great granddaughter of H. E. Bates.
Wednesday, November 25, 2009
TRU016
TRU-016 is described as “a single chain anti-CD37 Fc fusion molecule that displays pro-apoptotic and Fc-dependent cellular cytotoxicity activities against CLL cells and NHL lines.” CD37 is a tetraspanin transmembrane family protein that is strongly expressed on the surface of mature human B-cells and transformed mature B-cell lymphoma and leukemia cells, including CLL cells. It is expressed minimally or is absent on normal T-cells, natural killer cells, monocytes, and granulocytes.
It must be twenty years since George Stevenson and I first attempted to treat CLL with anti-CD37 monoclonal antibodies. One of the things that we found was that when we produced a univalent chimeric Fab molecule with an Fc attached we enhanced the killing of CLL cells (Mechanisms in removal of tumor by antibody. Stevenson GT et al Cell Biophys. 1994; 24-25:45-50).
There are two papers at ASH on TRU016 and CLL.
It has been previously reported that the chimeric precursor of the fully humanized TRU-016, induced apoptosis in CLL B cells through a novel, caspase-independent pathway. It also showed potent in-vivo activity in a SCID xenograft mouse model. Apart from its direct cytotoxicity, it mediated antibody-dependent cellular cytotoxicity (ADCC) by NK cells both in vitro and in vivo. Recently, in an attempt to enhance the ADCC function, a new variant has been created with a modification of the glycosylation of the Fc portion of the molecule. This has been shown to exhibit enhanced binding to both low- and high-affinity molecular variants of human CD16 (FcRIII) and augmented ADCC potency when compared to its previous formulation. In the study reported at ASH the molecule with the modified glycosolation resulted in 2 to 4 fold increased NK cell mediated ADCC function. This suggests that improved glycosolation will enhance the effect of TRU016
A phase I study with TRU-016 in patients with relapsed and refractory CLL or SLL who had adequate organ function and platelets > 30,000/mm3. Seven doses and two different schedules have been studied. The planned doses range from 0.03 mg/kg to 10 mg/kg IV once a week for 4 doses. The second schedule tests 3, 6 or 10 mg/kg on days 1, 3 and 5 the first week followed by 3 weekly doses.
To date, 32 patients have been treated. In the weekly treatment schedule: 1 patient in each of the first 3 cohorts (0.03, 0.1, and 0.3 mg/kg); 3 patients at 1 mg/kg, 4 patients at 3 mg/kg, 7 patients at 6 mg/kg, and 5 patients at 10 mg/kg. In the TIW loading dose schedule: 8 patients at 3 mg/kg and 2 patients at 6 mg/kg. Genomic data is available for 27 patients and 19 have high risk genomic features [del(17p13.1), n=10, del(11q22.3), n=7, both=2]. The maximum tolerated dose (MTD) has not been reached. 12 serious adverse events have been reported and three may have been related to study drug, including grade 4 neutropenia, Herpes Zoster and ITP. Mild (grade 1-2) infusion toxicity has been observed.
Beginning with the 0.3 mg/kg dose, evidence of biological activity has been observed: one partial response (PR) in a patient with 17p del, two patients with leukemia cutis had partial or complete clearing, and in patients with peripheral lymphocytosis the median reduction was 83% (range 13% to 98%). Improvement in cytopenias has also been observed. Enrollment to cohort 8 and 11 is complete and further up-to-date data will be presented.
Our experiments with anti-CD37, which were hampered by our inability to produce enough of it in the University laboratory, concluded that it was possible to clear cells from the peripheral blood, but we only obtained one PR in the patients that we treated. I remain to be convinced that TRU016 performs better in patients than the native antibody.
It must be twenty years since George Stevenson and I first attempted to treat CLL with anti-CD37 monoclonal antibodies. One of the things that we found was that when we produced a univalent chimeric Fab molecule with an Fc attached we enhanced the killing of CLL cells (Mechanisms in removal of tumor by antibody. Stevenson GT et al Cell Biophys. 1994; 24-25:45-50).
There are two papers at ASH on TRU016 and CLL.
It has been previously reported that the chimeric precursor of the fully humanized TRU-016, induced apoptosis in CLL B cells through a novel, caspase-independent pathway. It also showed potent in-vivo activity in a SCID xenograft mouse model. Apart from its direct cytotoxicity, it mediated antibody-dependent cellular cytotoxicity (ADCC) by NK cells both in vitro and in vivo. Recently, in an attempt to enhance the ADCC function, a new variant has been created with a modification of the glycosylation of the Fc portion of the molecule. This has been shown to exhibit enhanced binding to both low- and high-affinity molecular variants of human CD16 (FcRIII) and augmented ADCC potency when compared to its previous formulation. In the study reported at ASH the molecule with the modified glycosolation resulted in 2 to 4 fold increased NK cell mediated ADCC function. This suggests that improved glycosolation will enhance the effect of TRU016
A phase I study with TRU-016 in patients with relapsed and refractory CLL or SLL who had adequate organ function and platelets > 30,000/mm3. Seven doses and two different schedules have been studied. The planned doses range from 0.03 mg/kg to 10 mg/kg IV once a week for 4 doses. The second schedule tests 3, 6 or 10 mg/kg on days 1, 3 and 5 the first week followed by 3 weekly doses.
To date, 32 patients have been treated. In the weekly treatment schedule: 1 patient in each of the first 3 cohorts (0.03, 0.1, and 0.3 mg/kg); 3 patients at 1 mg/kg, 4 patients at 3 mg/kg, 7 patients at 6 mg/kg, and 5 patients at 10 mg/kg. In the TIW loading dose schedule: 8 patients at 3 mg/kg and 2 patients at 6 mg/kg. Genomic data is available for 27 patients and 19 have high risk genomic features [del(17p13.1), n=10, del(11q22.3), n=7, both=2]. The maximum tolerated dose (MTD) has not been reached. 12 serious adverse events have been reported and three may have been related to study drug, including grade 4 neutropenia, Herpes Zoster and ITP. Mild (grade 1-2) infusion toxicity has been observed.
Beginning with the 0.3 mg/kg dose, evidence of biological activity has been observed: one partial response (PR) in a patient with 17p del, two patients with leukemia cutis had partial or complete clearing, and in patients with peripheral lymphocytosis the median reduction was 83% (range 13% to 98%). Improvement in cytopenias has also been observed. Enrollment to cohort 8 and 11 is complete and further up-to-date data will be presented.
Our experiments with anti-CD37, which were hampered by our inability to produce enough of it in the University laboratory, concluded that it was possible to clear cells from the peripheral blood, but we only obtained one PR in the patients that we treated. I remain to be convinced that TRU016 performs better in patients than the native antibody.
Speeding
Today I want to quote at length from a letter to Evangelicals Now that I have just read.
"My Dad is a preacher and I've heard innumerable sermons about the Lordship of Christ... But my Dad breaks the speed limit. He has a device in his car that tells you where speed cameras are... slow drivers cause accidents... speed limits are guidelines not laws... a good driver is safe at 100 mph.
I tried out these arguments on my driving instructor who told me that whoever said that is a liar and a fool.
My school friend's older brother died driving his new car too fast...
A youth leader I have always admired also disregards the speed limit. He is so cool, sporty and God-fearing that I had somehow overlooked this. He told us that he had recently been caught on a speed camera and said that it was his wife driving not him. What about the ten commandments, I asked, what about not telling lies?
He put his arm round my shoulders. He knew I was upset about my friend. True, he should not have been speeding, but it was quite safe and it was a ridiculous limit for that stretch of road. And he put the blame on his wife because otherwise he would lose his driving license (he'd been caught speeding before). If he couldn't drive, he couldn't do his job. It was the lesser of two evils.
I don't go to church anymore."
I thought it was apt after yesterday's post. I take pride in the fact that when I was a lad there were 7000+ deaths on the roads with only about a million vehicles. Today there are just over 2000 with 16 million vehicles. But when you consider a mother's grief at seeing her son's splattered remains in a smashed car it gives you pause. I broke the speed limit yesterday. I may not have been caught speeding for the past 5 years, but that's not the issue is it? Do you take law-breaking seriously?
"My Dad is a preacher and I've heard innumerable sermons about the Lordship of Christ... But my Dad breaks the speed limit. He has a device in his car that tells you where speed cameras are... slow drivers cause accidents... speed limits are guidelines not laws... a good driver is safe at 100 mph.
I tried out these arguments on my driving instructor who told me that whoever said that is a liar and a fool.
My school friend's older brother died driving his new car too fast...
A youth leader I have always admired also disregards the speed limit. He is so cool, sporty and God-fearing that I had somehow overlooked this. He told us that he had recently been caught on a speed camera and said that it was his wife driving not him. What about the ten commandments, I asked, what about not telling lies?
He put his arm round my shoulders. He knew I was upset about my friend. True, he should not have been speeding, but it was quite safe and it was a ridiculous limit for that stretch of road. And he put the blame on his wife because otherwise he would lose his driving license (he'd been caught speeding before). If he couldn't drive, he couldn't do his job. It was the lesser of two evils.
I don't go to church anymore."
I thought it was apt after yesterday's post. I take pride in the fact that when I was a lad there were 7000+ deaths on the roads with only about a million vehicles. Today there are just over 2000 with 16 million vehicles. But when you consider a mother's grief at seeing her son's splattered remains in a smashed car it gives you pause. I broke the speed limit yesterday. I may not have been caught speeding for the past 5 years, but that's not the issue is it? Do you take law-breaking seriously?
Tuesday, November 24, 2009
I submit - 1 Peter 2:18-20
Polls have suggested that Winston Churchill was the greatest Englishman, surpassing William Shakespeare, Isaac Newton, Oliver Cromwell, Michael Faraday, Isambard Kingdom Brunel, William Turner and (my favorite) Edward Jenner. But which Englishman was the greatest villain? We might nominate Richard the Third, or Lord North who lost the American colonies, or Winston Churchill because of Gallipoli, or Jack the Ripper, or even Tony Blair. But spare a thought for Constantine, the Roman Emperor. He was not English by birth, even if you can call it England before the Angles arrived, but then neither was Cliff Richard or Colin Cowdrey. His birthplace was in what is now Bulgaria, but under Diocletian he fled with his father to York and you can’t get more English than that. It was in England that he established his power base and from there that he took control of the Roman Empire.
Some hail Constantine as a hero for turning the Roman Empire Christian. Others regard this as an act of villainy; rather than turning the Roman Empire Christian, he imbued Christianity with the ethos of the Roman Empire. Christian sources record that he experienced a dramatic event in 312 AD at the Battle of Milvian Bridge, after which he would claim the emperorship in the West. According to these sources, Constantine looked up to the sun before the battle and saw a cross of light above it, and with it the Greek words "Εν Τουτω Νικα" ("by this, conquer!", often rendered in the Latin "in hoc signo vinces"); he commanded his troops to adorn their shields with a Christian symbol (the Chi-Rho, the first two Greek letters in Christ), and thereafter they were victorious. You might say that he turned the Christian cross upside down so that it became a sword.
From this harsh beginning stems the whole idea that people might be converted by compulsion, the Crusades and the Inquisition. Another strand of history stemming from Constantine is the holding of religious Councils starting with Nicea in 325 AD. From this comes the dissection of the minute details of what you believe, with the threat of punishment for heresy if you stray from the precise definition of the Trinity or the Mass decreed by the church. The Bible tells us that “If you confess with your mouth, “Jesus is Lord” and believe in your heart that God raised him from the dead, you will be saved. For it is with your heart that you believe and are justified.
There is nothing in that statement that says your doctrine has to be right in every detail. Of course, we want to be obedient to Christ (that comes with Jesus being Lord) but Christians are allowed to vary in their beliefs on non-essentials. The schism between the Western and Eastern Church rested on a single word – did the Holy Spirit proceed from God the Father alone or from the Father and Son together.
But while Constantine was keen to stamp out heresy and get his doctrine right, there was no reformation of his actions. He had already had his brother-in law and his nephew executed by the time of the Council of Nicea, and the following year he had his wife and oldest son murdered – not exactly the actions of a submissive Christian. For it is submission that Peter demands in our passage for today: 1 Peter 2:18-20
Slaves, submit yourselves to your masters with all respect, not only to those who are good and considerate, but also to those who are harsh. For it is commendable if a man bears up under the pain of unjust suffering because he is conscious of God. But how is it to your credit if you receive a beating for doing wrong and endure it? But if you suffer for doing good and you endure it, this is commendable before God.
This is of course a contentious passage. People either say, "Haven't we abolished slavery? Is this any longer relevant?" or they say, "There you are! The Bible condones slavery."
It is clear that despite slavery being abolished in the Western democracies it has by no means been abolished in the world as a whole. According to studies done by anti-slavery groups, there are currently more slaves today than at any time in history! Three quarters are female and over half are children. It is believed that there are around 27 million people in slavery right now. Furthermore, this number does not include people who are not technically slaves but are in a form of servitude tantamount to slavery. This is sometimes called “unfree labor”. The average slave today costs around $90.
Enslavement continues in parts of Africa, the Middle East, and South Asia. It is endemic in Sudan. The Chinese government recently freed those enslaved by brick manufacturers in Shanxi and Henan. In 2008, the Nepalese government abolished the Haliya system of forced labor, freeing about 20,000 people. An estimated 40 million people in India are bonded workers, many working to pay off debts that were incurred generations ago. In Mauritania alone, it is estimated that up to 600,000 men, women and children, or 20% of the population, are enslaved with many used as bonded labor. In Niger, slavery is also a current phenomenon. A Nigerian study has found that more than 800,000 people are enslaved, almost 8% of the population. Pygmies, the people of Central Africa's rain forest, live in servitude to the Bantus. Some tribal sheiks in Iraq still keep blacks, called Abd, which means servant or slave in Arabic, as slaves. Child slavery has commonly been used in the production of cash crops and mining. According to the U.S. Department of State, more than 109,000 children were working on cocoa farms alone in Côte d'Ivoire (Ivory Coast) in "the worst forms of child labor" in 2002. The ruling junta in Burma is under threat of prosecution for crimes against humanity over the continuous forced labor of 800,000 of its citizens.
But does the Bible condone slavery? We have to be careful in imposing 21st Century norms on things happening 2000 years ago. The Bible was written at a time when slavery was not only widespread, but considered perfectly normal and moral. Slaves at the time were also generally treated much better than the slaves of modern times, and would usually end up being made free after a number of years’ servitude. There is a passage in 1 Timothy 1:9-10 translated in the NIV as "We also know that law is made not for the righteous but for lawbreakers and rebels, the ungodly and sinful, the unholy and irreligious; for those who kill their fathers or mothers, for murderers, for adulterers and perverts, for slave traders and liars and perjurers—and for whatever else is contrary to the sound doctrine." The word translated 'slave-traders' is 'andrapodistes' which combines the words for man and foot. It apparently means to put someone under one's foot - to control a person completely. In other versions it is translated 'kidnappers'. I think it refers to the practice of pressing people into slavery. Such people are grouped with adulterers, murderers and perverts.
Although the Bible does not specifically condemn slavery, the New Testament contains the principles that ultimately uprooted it. It was evangelical Christians like Wilberforce, who wore themselves out in changing not only the law, but the whole ethos. Nevertheless, if you have no visible means of support except that you go to work every day at a job you dislike for a wage that allows no luxuries are you very different from a slave? Peter’s instruction to slaves can be applied to wage slaves too.
We don’t like submitting. When I was young I used to watch professional wrestling on television on a Saturday afternoon. The commentator was Kent Walton and I suspect that whole bout was choreographed. One particular move that I remember was the Boston Crab when one wrestler would put his whole weight into bending the back of the other wrestler the wrong way. Once in this position, the wrestler underneath would immediately cry, “Submit!” for fear of being left paraplegic. Submission tends to mean something that is forced upon us and we may feel resentful that it has happened.
But Peter instructs us to submit ourselves. Not because we have been forced into it but ‘for the Lord’s sake.’ This is a voluntary submission that we do because we are obedient to Christ. While we may not think much of Barak Obama or Gordon Brown, we submit because we love the Lord. We may smolder with resentment at being asked to acquiesce to a liberal abortion law, or send our children to a school that does not allow prayers or wear a crash helmet on a motor bike or a law that insists that everyone carries health insurance. When these things are the law of the land we must obey the law. There may be things about the law that we don’t like – in a democracy we are allowed to campaign to change the law – but in the meantime we must obey the law. It’s as though your sweetheart comes up and says, “I know you don’t like it, but do it for my sake.”
If you are punished for breaking the speed limit – good! That’s how it should be. If you are executed for murdering an abortionist – good! That is law in action. How is it to your credit if you receive a beating for doing wrong and you endure it?
But there may come a time when they put you in prison for preaching the Gospel; when they torture you for proclaiming yourself a Christian; when they take away your wife and children; when they pull down your churches; when they deny you employment – it is happening now in certain countries. If you suffer for doing good and you endure it this is commendable before God.
However, you are treated by your neighbors, do good. Constantine never got it right; he continued to do evil things. He had a ‘head’ Christianity not a ‘heart’ Christianity. Good works are not the cause of our salvation, but they are the effect. Repay cruelty with kindness and anger with generosity.
Some hail Constantine as a hero for turning the Roman Empire Christian. Others regard this as an act of villainy; rather than turning the Roman Empire Christian, he imbued Christianity with the ethos of the Roman Empire. Christian sources record that he experienced a dramatic event in 312 AD at the Battle of Milvian Bridge, after which he would claim the emperorship in the West. According to these sources, Constantine looked up to the sun before the battle and saw a cross of light above it, and with it the Greek words "Εν Τουτω Νικα" ("by this, conquer!", often rendered in the Latin "in hoc signo vinces"); he commanded his troops to adorn their shields with a Christian symbol (the Chi-Rho, the first two Greek letters in Christ), and thereafter they were victorious. You might say that he turned the Christian cross upside down so that it became a sword.
From this harsh beginning stems the whole idea that people might be converted by compulsion, the Crusades and the Inquisition. Another strand of history stemming from Constantine is the holding of religious Councils starting with Nicea in 325 AD. From this comes the dissection of the minute details of what you believe, with the threat of punishment for heresy if you stray from the precise definition of the Trinity or the Mass decreed by the church. The Bible tells us that “If you confess with your mouth, “Jesus is Lord” and believe in your heart that God raised him from the dead, you will be saved. For it is with your heart that you believe and are justified.
There is nothing in that statement that says your doctrine has to be right in every detail. Of course, we want to be obedient to Christ (that comes with Jesus being Lord) but Christians are allowed to vary in their beliefs on non-essentials. The schism between the Western and Eastern Church rested on a single word – did the Holy Spirit proceed from God the Father alone or from the Father and Son together.
But while Constantine was keen to stamp out heresy and get his doctrine right, there was no reformation of his actions. He had already had his brother-in law and his nephew executed by the time of the Council of Nicea, and the following year he had his wife and oldest son murdered – not exactly the actions of a submissive Christian. For it is submission that Peter demands in our passage for today: 1 Peter 2:18-20
Slaves, submit yourselves to your masters with all respect, not only to those who are good and considerate, but also to those who are harsh. For it is commendable if a man bears up under the pain of unjust suffering because he is conscious of God. But how is it to your credit if you receive a beating for doing wrong and endure it? But if you suffer for doing good and you endure it, this is commendable before God.
This is of course a contentious passage. People either say, "Haven't we abolished slavery? Is this any longer relevant?" or they say, "There you are! The Bible condones slavery."
It is clear that despite slavery being abolished in the Western democracies it has by no means been abolished in the world as a whole. According to studies done by anti-slavery groups, there are currently more slaves today than at any time in history! Three quarters are female and over half are children. It is believed that there are around 27 million people in slavery right now. Furthermore, this number does not include people who are not technically slaves but are in a form of servitude tantamount to slavery. This is sometimes called “unfree labor”. The average slave today costs around $90.
Enslavement continues in parts of Africa, the Middle East, and South Asia. It is endemic in Sudan. The Chinese government recently freed those enslaved by brick manufacturers in Shanxi and Henan. In 2008, the Nepalese government abolished the Haliya system of forced labor, freeing about 20,000 people. An estimated 40 million people in India are bonded workers, many working to pay off debts that were incurred generations ago. In Mauritania alone, it is estimated that up to 600,000 men, women and children, or 20% of the population, are enslaved with many used as bonded labor. In Niger, slavery is also a current phenomenon. A Nigerian study has found that more than 800,000 people are enslaved, almost 8% of the population. Pygmies, the people of Central Africa's rain forest, live in servitude to the Bantus. Some tribal sheiks in Iraq still keep blacks, called Abd, which means servant or slave in Arabic, as slaves. Child slavery has commonly been used in the production of cash crops and mining. According to the U.S. Department of State, more than 109,000 children were working on cocoa farms alone in Côte d'Ivoire (Ivory Coast) in "the worst forms of child labor" in 2002. The ruling junta in Burma is under threat of prosecution for crimes against humanity over the continuous forced labor of 800,000 of its citizens.
But does the Bible condone slavery? We have to be careful in imposing 21st Century norms on things happening 2000 years ago. The Bible was written at a time when slavery was not only widespread, but considered perfectly normal and moral. Slaves at the time were also generally treated much better than the slaves of modern times, and would usually end up being made free after a number of years’ servitude. There is a passage in 1 Timothy 1:9-10 translated in the NIV as "We also know that law is made not for the righteous but for lawbreakers and rebels, the ungodly and sinful, the unholy and irreligious; for those who kill their fathers or mothers, for murderers, for adulterers and perverts, for slave traders and liars and perjurers—and for whatever else is contrary to the sound doctrine." The word translated 'slave-traders' is 'andrapodistes' which combines the words for man and foot. It apparently means to put someone under one's foot - to control a person completely. In other versions it is translated 'kidnappers'. I think it refers to the practice of pressing people into slavery. Such people are grouped with adulterers, murderers and perverts.
Although the Bible does not specifically condemn slavery, the New Testament contains the principles that ultimately uprooted it. It was evangelical Christians like Wilberforce, who wore themselves out in changing not only the law, but the whole ethos. Nevertheless, if you have no visible means of support except that you go to work every day at a job you dislike for a wage that allows no luxuries are you very different from a slave? Peter’s instruction to slaves can be applied to wage slaves too.
We don’t like submitting. When I was young I used to watch professional wrestling on television on a Saturday afternoon. The commentator was Kent Walton and I suspect that whole bout was choreographed. One particular move that I remember was the Boston Crab when one wrestler would put his whole weight into bending the back of the other wrestler the wrong way. Once in this position, the wrestler underneath would immediately cry, “Submit!” for fear of being left paraplegic. Submission tends to mean something that is forced upon us and we may feel resentful that it has happened.
But Peter instructs us to submit ourselves. Not because we have been forced into it but ‘for the Lord’s sake.’ This is a voluntary submission that we do because we are obedient to Christ. While we may not think much of Barak Obama or Gordon Brown, we submit because we love the Lord. We may smolder with resentment at being asked to acquiesce to a liberal abortion law, or send our children to a school that does not allow prayers or wear a crash helmet on a motor bike or a law that insists that everyone carries health insurance. When these things are the law of the land we must obey the law. There may be things about the law that we don’t like – in a democracy we are allowed to campaign to change the law – but in the meantime we must obey the law. It’s as though your sweetheart comes up and says, “I know you don’t like it, but do it for my sake.”
If you are punished for breaking the speed limit – good! That’s how it should be. If you are executed for murdering an abortionist – good! That is law in action. How is it to your credit if you receive a beating for doing wrong and you endure it?
But there may come a time when they put you in prison for preaching the Gospel; when they torture you for proclaiming yourself a Christian; when they take away your wife and children; when they pull down your churches; when they deny you employment – it is happening now in certain countries. If you suffer for doing good and you endure it this is commendable before God.
However, you are treated by your neighbors, do good. Constantine never got it right; he continued to do evil things. He had a ‘head’ Christianity not a ‘heart’ Christianity. Good works are not the cause of our salvation, but they are the effect. Repay cruelty with kindness and anger with generosity.
Monday, November 23, 2009
Global warming e-mails
The debate about global warming has been enlivened by the release of e-mails to an from the University of East Anglia. This was an involuntary release - someone hacked into their computer.
The issue is whether or not global temperatures have been rising because mankind in all his activities is producing increasing amounts of carbon dioxide, which acts as a greenhouse gas. If this hypothesis is true (and only 41% of the UK population believes it) then the Copenhagen conference which aims to reduce carbon dioxide production is more important than even the current financial crisis. There is an alternative hypothesis which states that fluctuation in global temperature is a natural phenomenon and that it has happened in the past and may well happen in the future. Warming sceptics like Steve McIntyre at Climate Audit have held that the data being presented by various authorities (including NASA) have been doctored to produce graphs that support the warming hypothesis (the famous 'hockey-stick' graph).
The facts that the Thames froze over in the seventeenth century and that grapes were grown in northern England in Romans times are not reflected in the hockey stick graph. I have not read many of the e-mails and I don't intend to - it is outside my field of expertise - but those I have read are alarming. They seem to suggest that there has been a conspiracy to massage the data to eliminate the cold spell in the seventeenth century and make it appear that temperatures were stable until recently. There has certainly been a conspiracy to circumvent the Freedon of Information Act. Now this might have been that they genuinely did not want the data to be in the hands of someone like McIntyre for fear that he would cherry-pick from it, but from the tone of the e-mails that I have seen it appears that it was the climate scientists at East Anglia who were manipulating the data. There are a huge number of emails, so there may be more to come.
My own position on anthropogenic global warming is one of mild scepticism. Scientists are human and I have seen enough scientific fraud to believe that no-one is above manipulating data. When all the climate journals are controlled by people of the same opinion, a little healthy scepticism is not out of place. Carbon dioxide is released from solution by warming that solution - take a bottle of soda pop from a fridge and you will see what I mean. The graphs seem to me to show that CO2 levels rise after a rise in temperature, not before. This would be what one expects if there were a lot of CO2 dissolved in the sea. CO2 is also a growth factor for plant life. There are a lot of blue-green algy in the Pacific. So vast are the oceans of the earth that I would have thought that they had ample buffering capacity to deal with the small amount of CO2 produced by mankind, which is only 7% of the total production.
But then, I am not an expert in this field, just a bit scepticical about what scientists tell me.
The issue is whether or not global temperatures have been rising because mankind in all his activities is producing increasing amounts of carbon dioxide, which acts as a greenhouse gas. If this hypothesis is true (and only 41% of the UK population believes it) then the Copenhagen conference which aims to reduce carbon dioxide production is more important than even the current financial crisis. There is an alternative hypothesis which states that fluctuation in global temperature is a natural phenomenon and that it has happened in the past and may well happen in the future. Warming sceptics like Steve McIntyre at Climate Audit have held that the data being presented by various authorities (including NASA) have been doctored to produce graphs that support the warming hypothesis (the famous 'hockey-stick' graph).
The facts that the Thames froze over in the seventeenth century and that grapes were grown in northern England in Romans times are not reflected in the hockey stick graph. I have not read many of the e-mails and I don't intend to - it is outside my field of expertise - but those I have read are alarming. They seem to suggest that there has been a conspiracy to massage the data to eliminate the cold spell in the seventeenth century and make it appear that temperatures were stable until recently. There has certainly been a conspiracy to circumvent the Freedon of Information Act. Now this might have been that they genuinely did not want the data to be in the hands of someone like McIntyre for fear that he would cherry-pick from it, but from the tone of the e-mails that I have seen it appears that it was the climate scientists at East Anglia who were manipulating the data. There are a huge number of emails, so there may be more to come.
My own position on anthropogenic global warming is one of mild scepticism. Scientists are human and I have seen enough scientific fraud to believe that no-one is above manipulating data. When all the climate journals are controlled by people of the same opinion, a little healthy scepticism is not out of place. Carbon dioxide is released from solution by warming that solution - take a bottle of soda pop from a fridge and you will see what I mean. The graphs seem to me to show that CO2 levels rise after a rise in temperature, not before. This would be what one expects if there were a lot of CO2 dissolved in the sea. CO2 is also a growth factor for plant life. There are a lot of blue-green algy in the Pacific. So vast are the oceans of the earth that I would have thought that they had ample buffering capacity to deal with the small amount of CO2 produced by mankind, which is only 7% of the total production.
But then, I am not an expert in this field, just a bit scepticical about what scientists tell me.
Sunday, November 22, 2009
Intelligent Design
I have been asked to post this letter on my blog. It was a response to an article by Andrew Copson in the Guardian on Intelligent Design. I was happy to add my signature to it.
Copson’s Ignorance of Intelligent Design
Andrew Copson ('A Birthday Present for Darwin', 9th November) describes the proposal to teach evolution in primary schools as an ‘important defence against the ignorance of intelligent design’. Apart from the clear insult to the British people, a majority of whom, when polled, think that intelligent design should be explored in schools, we are concerned about Andrew Copson’s own ignorance of intelligent design.
Like others who adopt his position, he appears to confuse intelligent design with religious belief. While creationism primarily draws its conclusions from religious sources, intelligent design argues from the data available in the natural world. The origin of life, the integrated complexity of biological systems and the vast information content of DNA are not matters which have been near-adequately explained by purely materialistic or neo-Darwinian processes.
Copson advocates accepting the evidence, and that is precisely what intelligent design theorists do. In an area like the origin and development of life, where we cannot observe what happened directly, a proper scientific approach is to make an inference to the best explanation. In the case of the functional information embedded in biological systems, the best explanation, based on the observation everywhere else that such information only arises from intelligence, is that it too has an intelligent source. If Andrew Copson is sceptical of the scientific respectability of this approach, we urge him to read Dr Steven Meyer’s recent book, ‘Signature in the Cell’.
Intelligent design is, therefore, a minimal commitment to intelligent causation. If you insist, by definition, that this kind of explanation is to be excluded in the study of origins, then, of course, you can argue that intelligent design is not a valid scientific position. But if you do that, you have adopted a philosophical, not a scientific, stance and created a circular argument. It is also a category error to imagine that evolution is the opposite of intelligent design.
Clearly, a design paradigm can embrace evolutionary processes. In addition, the evidence for evolution is treated as if all aspects of it are uniformly convincing, failing to distinguish between what is directly observable, such as change and adaptation through natural selection, and the more speculative elements, like the descent of all living things from a single ancestor. The evidence for both is not of equal force.
If evolution is to be taught in schools, it should be done properly, recognising the tentative nature of scientific conclusions and not excluding legitimate scientific propositions which challenge the reigning paradigm.
And on a further point, Andrew Copson overstates his case. Current Government guidance does not specifically ‘prohibit’ the teaching of intelligent design in science lessons. It concludes, wrongly in our view, that intelligent design is not a scientific position, but recommends that if it is raised by pupils in science lessons it be dealt with appropriately. That’s a somewhat different position.
Dr Alastair Noble, Educational Consultant, Eaglesham, Scotland
Copson’s Ignorance of Intelligent Design
Andrew Copson ('A Birthday Present for Darwin', 9th November) describes the proposal to teach evolution in primary schools as an ‘important defence against the ignorance of intelligent design’. Apart from the clear insult to the British people, a majority of whom, when polled, think that intelligent design should be explored in schools, we are concerned about Andrew Copson’s own ignorance of intelligent design.
Like others who adopt his position, he appears to confuse intelligent design with religious belief. While creationism primarily draws its conclusions from religious sources, intelligent design argues from the data available in the natural world. The origin of life, the integrated complexity of biological systems and the vast information content of DNA are not matters which have been near-adequately explained by purely materialistic or neo-Darwinian processes.
Copson advocates accepting the evidence, and that is precisely what intelligent design theorists do. In an area like the origin and development of life, where we cannot observe what happened directly, a proper scientific approach is to make an inference to the best explanation. In the case of the functional information embedded in biological systems, the best explanation, based on the observation everywhere else that such information only arises from intelligence, is that it too has an intelligent source. If Andrew Copson is sceptical of the scientific respectability of this approach, we urge him to read Dr Steven Meyer’s recent book, ‘Signature in the Cell’.
Intelligent design is, therefore, a minimal commitment to intelligent causation. If you insist, by definition, that this kind of explanation is to be excluded in the study of origins, then, of course, you can argue that intelligent design is not a valid scientific position. But if you do that, you have adopted a philosophical, not a scientific, stance and created a circular argument. It is also a category error to imagine that evolution is the opposite of intelligent design.
Clearly, a design paradigm can embrace evolutionary processes. In addition, the evidence for evolution is treated as if all aspects of it are uniformly convincing, failing to distinguish between what is directly observable, such as change and adaptation through natural selection, and the more speculative elements, like the descent of all living things from a single ancestor. The evidence for both is not of equal force.
If evolution is to be taught in schools, it should be done properly, recognising the tentative nature of scientific conclusions and not excluding legitimate scientific propositions which challenge the reigning paradigm.
And on a further point, Andrew Copson overstates his case. Current Government guidance does not specifically ‘prohibit’ the teaching of intelligent design in science lessons. It concludes, wrongly in our view, that intelligent design is not a scientific position, but recommends that if it is raised by pupils in science lessons it be dealt with appropriately. That’s a somewhat different position.
Dr Alastair Noble, Educational Consultant, Eaglesham, Scotland
Saturday, November 21, 2009
Heath once more.
Here is an update on my health.
I have been to the gym three times in the past 2 weeks. A few minutes on the exercise bike at level 11/20 gets my pulse rate up to 140, which is quite high enough for now. 30 exercises for upper body strength lifting 25kg, then 20 crunches for abdominals. Then some stretching. I have achy pectorals and painful knees, but nothing like I used to have before I was ill and exercising at full tilt.
I still feel boated after meals, though this is less than it was. I am taking 'live' yoghurts. I cannot detect any ascites, but this is hard to do on self examination. The peripheral neuropathy is better than it was, but finger tips are still quite numb. My BP remains at below 120/80.
I have noticed a problem with my hearing. It's not that I cannot hear the sounds, but I have difficulty in deciphering them. Unless I see a person's lips move, I cannot be sure I have heard words correctly. I take several minutes trying to assemble the sounds into a sentence that makes sense and by the time I have got it the conversation has moved on. I don't have very much patience, I am afraid. Young people, especially, fail to sound their terminal consonants and I tend to switch off. Is this just old age? Or is it a chemotherapy side effect?
I am still waiting for my November scan.
I have been to the gym three times in the past 2 weeks. A few minutes on the exercise bike at level 11/20 gets my pulse rate up to 140, which is quite high enough for now. 30 exercises for upper body strength lifting 25kg, then 20 crunches for abdominals. Then some stretching. I have achy pectorals and painful knees, but nothing like I used to have before I was ill and exercising at full tilt.
I still feel boated after meals, though this is less than it was. I am taking 'live' yoghurts. I cannot detect any ascites, but this is hard to do on self examination. The peripheral neuropathy is better than it was, but finger tips are still quite numb. My BP remains at below 120/80.
I have noticed a problem with my hearing. It's not that I cannot hear the sounds, but I have difficulty in deciphering them. Unless I see a person's lips move, I cannot be sure I have heard words correctly. I take several minutes trying to assemble the sounds into a sentence that makes sense and by the time I have got it the conversation has moved on. I don't have very much patience, I am afraid. Young people, especially, fail to sound their terminal consonants and I tend to switch off. Is this just old age? Or is it a chemotherapy side effect?
I am still waiting for my November scan.
Friday, November 20, 2009
Medical ethics
Have you ever heard of Martin Hurson? How about Raymond McCreesh? I must admit that these names meant nothing to me even though in 1981 I used to read the newspapers avidly. Of course, if you had said Bobby Sands, I would have known instantly what you were talking about; the hunger strike by the provisional IRA members in the Maze prison. I think it was about their wanting to be recognized as prisoners of war while the British government saw them as simply criminals.
Depending on how you viewed the Irish cause, you either saw them as martyrs or murderers. I don't want to debate the rights or wrongs of Ireland, but to consider how we ought to deal with hunger strikes. This has been prompted by an article in today's Lancet .
The article has been prompted by the current situation in Guantanamo, and of course, The Lancet, as a left-wing journal, wants to hold Obama to his promises to end torture in the USA. As the author says, hunger strikes are extremely difficult for prison officials and physicians to deal with, especially if they are done in groups, as they are in Guantánamo where about 30 prisoners are currently on hunger strike. Hunger strikers are not suicidal in that their goal is to change a policy or the conditions of their confinement, not to die. The primary issue the continuing hunger strikes at Guantanamo raise with the medical profession and human rights groups is the use of military physicians to break the hunger striker's will by force-feeding in eight-point restraint chairs.
Apparently army doctors have been taking part in the forced feeding of inmates against the rules and regulations of the World Medical Association.
A hunger strike is a non-violent protest that aims to provoke feelings of guilt in others in order to change a policy. It has a long history, particularly in India and Ireland. In both countries those who felt that they had been swindled would camp on the perpetrators doorstep and starve themselves.
In modern days the most prominent instance was by the suffragettes on both Britain and America. Marion Dunlop was the first in 1909. Because the authorities did not want her to become a martyr, she was released. Other suffragettes were subjected to force-feeding, which the suffragettes categorized as a form of torture. Several of them died as a result of force-feeding. In 1913 the Prisoner's Temporary Discharge of Ill Health Act changed policy. Hunger strikers were tolerated but when they became sick the prisoners were released, only to be rearrested to finish their sentences when they had recovered.
In the end what won women the vote was their willingness to act as substitute men in factories and farms during the Great War.
Irish republicans first used the hunger strike as a weapon in 1917. It was countered by the British with force-feeding, which culminated in 1917 in the death of Thomas Ashe in Mountjoy Prison. In October 1920, the Lord Mayor of Cork, Terence MacSwiney, died on hunger strike in Brixton prison. Three other IRA men, Joe Murphy, Conor McElvaney and Michael Fitzgerald, also died on hunger strike in this protest. John and Peter Crowley, Thomas Donovan, Michael Burke, Michael O'Reilly, Christopher Upton, John Power, Joseph Kenny and Seán Hennessy at the prison of Cork had their hunger strike called off by the Sinn Fein leadership after the deaths of MacSwiney, Murphy and Fitzgerald. Some of the strikers had fasted for 94 days – such a long period makes it likely that they were surreptitiously taking food.
Although there was a natural sympathy for the underdog, there was little agreement with some of the views of the Sinn Fein leadership. They defended anti-semitic rioters in Limerick, denounced socialists and pacifists as conscious tools of the British Empire, and successively praised Tsarist Russia and Wilhelm II as morally superior to Great Britain.
Eventually, there was an agreement between Britain and Ireland which established the Irish Free State, though it was impossible to incorporate the Protestant North within the Catholic South without a blood bath.
Oppression of Catholics in the North by the Protestant government reignited the troubles in Ireland in the 1960s. Again, the hunger strike was used as a weapon. Bobby Sands was the first of ten Irish republican paramilitary prisoners to die during the hunger strike in 1981. There was support for the hunger strikers from Irish republicans and the broader nationalist community on both sides of the Irish border. After the deaths of the men and severe public disorder, the British government granted partial concessions to the prisoners, and the strike was called off. The hunger strikes gave a huge propaganda boost to a severely demoralized Provisional IRA. Bobby Sands, who was elected to the UK Parliament is still remembered but few but ardent republicans remember the names of the others. In the end, the IRA agreed a deal with the British. It was a deal that they could have had at almost any time during the troubles. It was brokered by John Major and Tony Blair. It is probable that the hunger strikes prolonged the conflict rather than shortened it. The IRA was always going to be defeated militarily and Londoners, who had survived the Blitz, were not going to be cowed by the Irish bombers. The real enemy of the IRA was the Protestant North which would never come to an agreement with the IRA while the South was in their view, priest-ridden.
British animal-rights activist Barry Horne died on November 5, 2001 after a series of four hunger strikes, the longest of which lasted 68 days leaving him partially blind and with kidney damage. Almost nobody sympathized with his views. Sine the same group resorted to kidnapping the dead body of a farmer’s mother, who would sympathize with them.
On the 15th of August 1987 at the Nallur Murugan Temple Thileepan began his fast. His main objective was to bring awareness and action to a list of public demands made by himself and the Tamil Tigers. The Tamils live mainly in the north of Sri Lanka and are Hindus and probably of Indian origin, whereas the majority of Sinhalese are Buddhist. Although several groups requested him to stop the fast, Thileepan died on the 26th of September 1987. There was widespread grief in Tamil areas. Thousands of people from the North and East flooded Jaffna in northern Sri Lanka as news of his death spread. His death created an anti-Indian mood in Jaffna, which had been pro-India till then.
From the above, it can be seen that hunger strikes are a double edged weapon. If the authorities call the bluff of the striker then he or she dies. The authorities are caught is a vice; let the striker die and they are accused of callousness, force feed him and they are accused of torture. If the striker dies then it does not guarantee martyrdom; if the cause is unpopular then the public are likely to cry, “Good riddance.” No-one would weep if the Yorkshire Ripper or the Southam pedophile starved themselves to death.
The inmates of Guantánamo are the basis of the current Lancet article. In 2006 the New York Times reported that hunger strikers in Guantánamo were being strapped into restraining chairs for hours a day for force-feeding. The number of strikers peaked at 131 around the fourth anniversary of 9/11. There was concern over the international impact if a striker were to die. Prisoners’ lawyers called the methods brutal and inhumane, and said other coercive methods were used, such as being placed in cold air-conditioned isolation cells. The assistant secretary of defense for health affairs said it was a moral question: allow suicide, or take steps to preserve life.
Article 6 of the 1975 World Medical Association Tokyo Declaration states that doctors can undertake force-feeding under certain very restricted rules and only where a second, independent physician is consulted and agrees that the prisoner is not rational. "Where a prisoner refuses nourishment and is considered by the physician as capable of forming an unimpaired and rational judgment concerning the consequences of such a voluntary refusal of nourishment, he or she shall not be fed artificially. The decision as to the capacity of the prisoner to form such a judgment should be confirmed by at least one other independent physician. The consequences of the refusal of nourishment shall be explained by the physician to the prisoner."
The World Medical Association recently revised and updated its Declaration of Malta on Hunger Strikers. Among many changes, it unambiguously states that force feeding is a form of inhuman and degrading treatment in its Article 21. The American Medical Association is a member of the World Medical Association, but the AMA's members are not bound by the WMA's decisions, and neither organization has formal legal powers.
The British government under Maggie Thatcher took the decision not to force-feed the Irish terrorists, a decision that was probably correct. Probably the Americans should do the same. It comes hard for a physician to stand by and watch a person commit suicide, but medicine can only be offered with consent.
Depending on how you viewed the Irish cause, you either saw them as martyrs or murderers. I don't want to debate the rights or wrongs of Ireland, but to consider how we ought to deal with hunger strikes. This has been prompted by an article in today's Lancet .
The article has been prompted by the current situation in Guantanamo, and of course, The Lancet, as a left-wing journal, wants to hold Obama to his promises to end torture in the USA. As the author says, hunger strikes are extremely difficult for prison officials and physicians to deal with, especially if they are done in groups, as they are in Guantánamo where about 30 prisoners are currently on hunger strike. Hunger strikers are not suicidal in that their goal is to change a policy or the conditions of their confinement, not to die. The primary issue the continuing hunger strikes at Guantanamo raise with the medical profession and human rights groups is the use of military physicians to break the hunger striker's will by force-feeding in eight-point restraint chairs.
Apparently army doctors have been taking part in the forced feeding of inmates against the rules and regulations of the World Medical Association.
A hunger strike is a non-violent protest that aims to provoke feelings of guilt in others in order to change a policy. It has a long history, particularly in India and Ireland. In both countries those who felt that they had been swindled would camp on the perpetrators doorstep and starve themselves.
In modern days the most prominent instance was by the suffragettes on both Britain and America. Marion Dunlop was the first in 1909. Because the authorities did not want her to become a martyr, she was released. Other suffragettes were subjected to force-feeding, which the suffragettes categorized as a form of torture. Several of them died as a result of force-feeding. In 1913 the Prisoner's Temporary Discharge of Ill Health Act changed policy. Hunger strikers were tolerated but when they became sick the prisoners were released, only to be rearrested to finish their sentences when they had recovered.
In the end what won women the vote was their willingness to act as substitute men in factories and farms during the Great War.
Irish republicans first used the hunger strike as a weapon in 1917. It was countered by the British with force-feeding, which culminated in 1917 in the death of Thomas Ashe in Mountjoy Prison. In October 1920, the Lord Mayor of Cork, Terence MacSwiney, died on hunger strike in Brixton prison. Three other IRA men, Joe Murphy, Conor McElvaney and Michael Fitzgerald, also died on hunger strike in this protest. John and Peter Crowley, Thomas Donovan, Michael Burke, Michael O'Reilly, Christopher Upton, John Power, Joseph Kenny and Seán Hennessy at the prison of Cork had their hunger strike called off by the Sinn Fein leadership after the deaths of MacSwiney, Murphy and Fitzgerald. Some of the strikers had fasted for 94 days – such a long period makes it likely that they were surreptitiously taking food.
Although there was a natural sympathy for the underdog, there was little agreement with some of the views of the Sinn Fein leadership. They defended anti-semitic rioters in Limerick, denounced socialists and pacifists as conscious tools of the British Empire, and successively praised Tsarist Russia and Wilhelm II as morally superior to Great Britain.
Eventually, there was an agreement between Britain and Ireland which established the Irish Free State, though it was impossible to incorporate the Protestant North within the Catholic South without a blood bath.
Oppression of Catholics in the North by the Protestant government reignited the troubles in Ireland in the 1960s. Again, the hunger strike was used as a weapon. Bobby Sands was the first of ten Irish republican paramilitary prisoners to die during the hunger strike in 1981. There was support for the hunger strikers from Irish republicans and the broader nationalist community on both sides of the Irish border. After the deaths of the men and severe public disorder, the British government granted partial concessions to the prisoners, and the strike was called off. The hunger strikes gave a huge propaganda boost to a severely demoralized Provisional IRA. Bobby Sands, who was elected to the UK Parliament is still remembered but few but ardent republicans remember the names of the others. In the end, the IRA agreed a deal with the British. It was a deal that they could have had at almost any time during the troubles. It was brokered by John Major and Tony Blair. It is probable that the hunger strikes prolonged the conflict rather than shortened it. The IRA was always going to be defeated militarily and Londoners, who had survived the Blitz, were not going to be cowed by the Irish bombers. The real enemy of the IRA was the Protestant North which would never come to an agreement with the IRA while the South was in their view, priest-ridden.
British animal-rights activist Barry Horne died on November 5, 2001 after a series of four hunger strikes, the longest of which lasted 68 days leaving him partially blind and with kidney damage. Almost nobody sympathized with his views. Sine the same group resorted to kidnapping the dead body of a farmer’s mother, who would sympathize with them.
On the 15th of August 1987 at the Nallur Murugan Temple Thileepan began his fast. His main objective was to bring awareness and action to a list of public demands made by himself and the Tamil Tigers. The Tamils live mainly in the north of Sri Lanka and are Hindus and probably of Indian origin, whereas the majority of Sinhalese are Buddhist. Although several groups requested him to stop the fast, Thileepan died on the 26th of September 1987. There was widespread grief in Tamil areas. Thousands of people from the North and East flooded Jaffna in northern Sri Lanka as news of his death spread. His death created an anti-Indian mood in Jaffna, which had been pro-India till then.
From the above, it can be seen that hunger strikes are a double edged weapon. If the authorities call the bluff of the striker then he or she dies. The authorities are caught is a vice; let the striker die and they are accused of callousness, force feed him and they are accused of torture. If the striker dies then it does not guarantee martyrdom; if the cause is unpopular then the public are likely to cry, “Good riddance.” No-one would weep if the Yorkshire Ripper or the Southam pedophile starved themselves to death.
The inmates of Guantánamo are the basis of the current Lancet article. In 2006 the New York Times reported that hunger strikers in Guantánamo were being strapped into restraining chairs for hours a day for force-feeding. The number of strikers peaked at 131 around the fourth anniversary of 9/11. There was concern over the international impact if a striker were to die. Prisoners’ lawyers called the methods brutal and inhumane, and said other coercive methods were used, such as being placed in cold air-conditioned isolation cells. The assistant secretary of defense for health affairs said it was a moral question: allow suicide, or take steps to preserve life.
Article 6 of the 1975 World Medical Association Tokyo Declaration states that doctors can undertake force-feeding under certain very restricted rules and only where a second, independent physician is consulted and agrees that the prisoner is not rational. "Where a prisoner refuses nourishment and is considered by the physician as capable of forming an unimpaired and rational judgment concerning the consequences of such a voluntary refusal of nourishment, he or she shall not be fed artificially. The decision as to the capacity of the prisoner to form such a judgment should be confirmed by at least one other independent physician. The consequences of the refusal of nourishment shall be explained by the physician to the prisoner."
The World Medical Association recently revised and updated its Declaration of Malta on Hunger Strikers. Among many changes, it unambiguously states that force feeding is a form of inhuman and degrading treatment in its Article 21. The American Medical Association is a member of the World Medical Association, but the AMA's members are not bound by the WMA's decisions, and neither organization has formal legal powers.
The British government under Maggie Thatcher took the decision not to force-feed the Irish terrorists, a decision that was probably correct. Probably the Americans should do the same. It comes hard for a physician to stand by and watch a person commit suicide, but medicine can only be offered with consent.
Thursday, November 19, 2009
A Maradonna Moment
We used to have a saying when I was young to the effect that cheats never prosper. An incident occurred in last night's soccer match between France and Ireland which questions that premise. A goal by Ireland had cancelled out one by France in the first leg and the match was heading towards a penalty shoot-out. Then late into overtime, France scored the winning goal. It was scored by William Gallas, but he received the ball from Thierry Henry who illegally handled it before hooking it back across the goalmouth to be headed in. The goal should have been disallowed and Henry might well have been dismissed the field of play. After the match Henry admitted the offence but claimed that it was the referee's responsibility to spot it. Indeed, had he drawn the referee's attention to the handball, he would have been denigrated by his own team and the French supporters.
However, that is what an honest man would have done. It is hardly honest to protest about fouls committed by the other side and then turn a blind eye to one's own misdemeanors. Honesty is really tested when you suffer for it.
Sports fans the world over turned on the football star, who enjoys a global profile partly thanks to an advertising campaign by Gillette, the shaving brand, that placed him in the very top tier alongside Tiger Woods, the golfer and first $1 billion athlete, and Roger Federer, the man who has won more grand slam tournaments than any other tennis player. The sponsors expect to inflict no punishment on him; they say that he can't be blamed for the referee's mistake.
Diego Maradonna committed a similar piece of dishonesty in 1986 at the World Cup finals. Maradonna was at time thought of as the finest footballer of his generation. After that match, his reputation sank. He became a cocaine addict; he became obese; and he went on the manage the worst Argentina team for half a century. He was recently banned from anything to do with football after an outburst of bad language against the press. I guess he couldn't live with himself after cheating like that. Thierry Henry had better beware.
However, that is what an honest man would have done. It is hardly honest to protest about fouls committed by the other side and then turn a blind eye to one's own misdemeanors. Honesty is really tested when you suffer for it.
Sports fans the world over turned on the football star, who enjoys a global profile partly thanks to an advertising campaign by Gillette, the shaving brand, that placed him in the very top tier alongside Tiger Woods, the golfer and first $1 billion athlete, and Roger Federer, the man who has won more grand slam tournaments than any other tennis player. The sponsors expect to inflict no punishment on him; they say that he can't be blamed for the referee's mistake.
Diego Maradonna committed a similar piece of dishonesty in 1986 at the World Cup finals. Maradonna was at time thought of as the finest footballer of his generation. After that match, his reputation sank. He became a cocaine addict; he became obese; and he went on the manage the worst Argentina team for half a century. He was recently banned from anything to do with football after an outburst of bad language against the press. I guess he couldn't live with himself after cheating like that. Thierry Henry had better beware.
Progress at NIH
A stem cell allograft is the only way of curing CLL, but how does it work? It seems that there is immune response from the grafted immune system against the leukemia. Now a paper in this week's Blood suggests how this might work. Hitherto, it has been thought that post-transplant immunity against the leukemia was mediated by T cells, but Baskar and colleagues have asked whether it might be mediated by antibody.
They have looked at stored serial blood samples from two patients who remain in molecular remission respectively 6 and 7 years after their transplant. They have looked by flow cytometry to see whether any of the sera from these samples reacted with CLL cells. This is technically difficult because CLL cells already have immunoglobulin on their surface and they have a receptor that binds to immunoglobulin surrounding them in fluid, so both of these have first to be blocked. Nevertheless both cases had detectable anti-CLL cells antibody in their blood, one peaking at 6 months post-transplant and one peaking at 6 months and the other at 10 months post-transplant. Interestingly these coincided with the disappearance of minimal residual disease in each patient.
The next thing was to find the B cells circulating at the time that were circulating at the time that were responsible for the production of these antibodies. To do this a phage library was constructed. This is a complicated procedure in which the total RNA was extracted from the cryopreserved B cells and the RNA coding for the immunoglobulin fragment containing the antibody activity (known as Fab) was amplified by PCR using appropriate primers. This process also inserts appropriate RNA into bacteriophages (a bacteriophage is a virus that infects a bacterium). E.coli bacteria were then infected by the phage (this process makes the Fab stick out from the surface of the e.coli. This can be used to select those bacteriophage that have a code for an anti-CLL cell Fab. The selection process was dominated by one antibody that in all its manifestations could be predicted to react with the same antigen, which was present on nearly all CLL cells and more weakly on normal B cells, but not on other B-cell tumors or tumor cell lines.
The significance of this study is that it may identify an antigen on CLL cells which is extremely susceptible to killing by antibody, so that a new monoclonal that eliminates CLL cells completely may be produced, or if the antigen is fully identified, other small molecules might be derived that kill CLL cells. This paper also provides a method that could be applied to other leukemias that can be cured by stem cell transplantation.
They have looked at stored serial blood samples from two patients who remain in molecular remission respectively 6 and 7 years after their transplant. They have looked by flow cytometry to see whether any of the sera from these samples reacted with CLL cells. This is technically difficult because CLL cells already have immunoglobulin on their surface and they have a receptor that binds to immunoglobulin surrounding them in fluid, so both of these have first to be blocked. Nevertheless both cases had detectable anti-CLL cells antibody in their blood, one peaking at 6 months post-transplant and one peaking at 6 months and the other at 10 months post-transplant. Interestingly these coincided with the disappearance of minimal residual disease in each patient.
The next thing was to find the B cells circulating at the time that were circulating at the time that were responsible for the production of these antibodies. To do this a phage library was constructed. This is a complicated procedure in which the total RNA was extracted from the cryopreserved B cells and the RNA coding for the immunoglobulin fragment containing the antibody activity (known as Fab) was amplified by PCR using appropriate primers. This process also inserts appropriate RNA into bacteriophages (a bacteriophage is a virus that infects a bacterium). E.coli bacteria were then infected by the phage (this process makes the Fab stick out from the surface of the e.coli. This can be used to select those bacteriophage that have a code for an anti-CLL cell Fab. The selection process was dominated by one antibody that in all its manifestations could be predicted to react with the same antigen, which was present on nearly all CLL cells and more weakly on normal B cells, but not on other B-cell tumors or tumor cell lines.
The significance of this study is that it may identify an antigen on CLL cells which is extremely susceptible to killing by antibody, so that a new monoclonal that eliminates CLL cells completely may be produced, or if the antigen is fully identified, other small molecules might be derived that kill CLL cells. This paper also provides a method that could be applied to other leukemias that can be cured by stem cell transplantation.
Wednesday, November 18, 2009
Sydney Opera House
Over the past few weeks I have been reading The Saga if the Sydney Opera House by Peter Murray. The building is one of the modern wonders of the world and one of the few located in the Southern Hemisphere. It has been recognized as a World Heritage Site and is an icon of Australia.
It was designed by the Danish architect, Jorn (that ‘o’ should have a diagonal line through it) Utzon. He was very good at winning architectural competitions but few of his designs ever got built. His design won the competition in 1957.
The remit was to build a large 3000 seater concert hall come opera house with a second smaller hall to seat 1200 for theater productions. It would be rude to say that Utzon’s design was a back of a fag packet affair (fag being a British word for cigarette without the American connotation), but the design was another of those that wins competitions but doesn’t get built. Indeed in 1957 it was doubtful that it could be. The task of building it was given to another Dane, Ove Arup and Partners, consulting engineers.
The book details the difficulties there were in translating, what was obviously a beautiful design into a real three dimensional building that functioned as it should.
Although praised as a masterpiece, the Sydney Opera House has been criticized. Many people say that the acoustics are poor and that the theater doesn't have enough performance or backstage space. Yet the architectural community has been extremely supportive of Utzon and extremely critical of the Australian governmental machine and the Australian press. Most prominent articles on the Internet are supportive too.
Peter Murray is less so. He points out that the Opera House took 14 years to build and cost 14 times the original estimate. Utzon was impossible to work with and seemed astonished that he should get paid according to work done, rather than simply reimbursed what it cost to keep his Sydney office running, even when most of them were working on other projects like the Zurich concert hall. Arups, whose design solutions for the shells had made use of computer design (and remember what computers were like in the 1960s) were his constant supporters, but he even managed to fall out with them and in 1966 he resigned from the project with only the base and the shells completed. His designs for the interior were in his head with virtually nothing on paper. For the first two stages of the project he had relied on Arups to provide working drawings to build from; now he had fallen out with the engineers he had no-one capable of doing it. There were no drawings for the interior when he eventually resigned.
His resignation was really a sort of negotiating position, but David Hughes the minister responsible had had enough of Utzon. For months he had been out of contact, holidaying inn Hawaii and his offices in Sydney didn’t even have a telephone. Hughes called his bluff and assembled a committee to take his place. There were four main criticisms of Utzon: he insisted on the wrong organizational approach; he ignored questions of time; he ignored questions of cost; and he was not a practical man.
Although Utzon may have been a talented artist, he seemed to have no conception of the difficulties that sub-contractors would have in building his designs. His knowledge of acoustics was minimal and he had no idea how large an area was needed to sit in comfortably at a concert. There was no way that his large hall could accommodate both symphony concerts and opera. Eventually opera was moved to the smaller hall, but even so Sydney still has acoustic problems, especially for those 579 in the large hall who sit behind the orchestra. The total seating in the large hall was for 2679 – more than 300 short of the 3000 asked for, though they did have sufficient leg room.
The opera house was opened on October 20th 1973 by the Queen of Australia. The organ, the largest pipe organ in the world, was not completed until 1979. The final cost was 102 million Australian dollars against an original estimate of 7 million.
In 1976 Dame Edna Everage attempted to enter the Royal enclosure at Royal Acsot wearing this hat.
Ofatumumab at ASH
Those expecting a load of new information on Ofatumumab (O) from ASH are likely to be disappointed. Only three papers have been accepted and only one of these is clinically relevant.
A multi centre trial looked at two doses of O (500mg and 1000mg) used in combination with FC in previously untreated patients with CLL. Only 61 patients were involved, so nothing much can be made of the study statistically. The overall response rate was 70% and 73% respectively, but there were more CRs with the higher dose (50% v 32%) but the difference was not statistically significant. The overall response rates were less than historical controls with FCR, but the make up of cases could account for that. For example 20% of those receiving the higher dose had del 17p. I think all that can be said of this study is that O can be given safely with FC and that responses are in the same ball-park as with FCR. There were no unexpected toxicities.
The other two studies were more technical. One looked at the pharmacokinetics (PK) of O. It demonstrated that baseline factors reflecting disease burden significantly influenced ofatumumab PK. Additionally, higher serum concentrations of ofatumumab at Doses 8 and 12 were associated with positive clinical outcomes in univariate analyses. In other words the more disease there is to soak up the antibody, the lower the serum concentration and the higher the serum concentration, the better the response. Not exactly counter-intuitive, is it.
It is known for NHL (but not for CLL) that a polymorphism on the FC receptor affects response to rituximab. The third paper assessed FcgRIIIa affinity and potency to induce ADCC by purified NK cells for ofatumumab and rituximab in a blinded study. Expected differences in affinity for the 158V and 158F allotypes of FcgRIIIa were observed for both ofatumumab and rituximab. These differences correlated with a stronger ADCC by FcgRIIIa 158V/V compared to 158F/F expressing NK cells. Significantly, ofatumumab was able to induce ADCC more potently than rituximab for both Fc receptor allotypes. Ofatumumab binds CD20 stably and at a distinct membrane-proximal epitope compared to rituximab. Our data suggest that these binding characteristics may positively impact ofatumumab’s ability to direct killing of tumor cells via ADCC. Most of this information was already available from experiments in our lab by Martin Glennie.
A multi centre trial looked at two doses of O (500mg and 1000mg) used in combination with FC in previously untreated patients with CLL. Only 61 patients were involved, so nothing much can be made of the study statistically. The overall response rate was 70% and 73% respectively, but there were more CRs with the higher dose (50% v 32%) but the difference was not statistically significant. The overall response rates were less than historical controls with FCR, but the make up of cases could account for that. For example 20% of those receiving the higher dose had del 17p. I think all that can be said of this study is that O can be given safely with FC and that responses are in the same ball-park as with FCR. There were no unexpected toxicities.
The other two studies were more technical. One looked at the pharmacokinetics (PK) of O. It demonstrated that baseline factors reflecting disease burden significantly influenced ofatumumab PK. Additionally, higher serum concentrations of ofatumumab at Doses 8 and 12 were associated with positive clinical outcomes in univariate analyses. In other words the more disease there is to soak up the antibody, the lower the serum concentration and the higher the serum concentration, the better the response. Not exactly counter-intuitive, is it.
It is known for NHL (but not for CLL) that a polymorphism on the FC receptor affects response to rituximab. The third paper assessed FcgRIIIa affinity and potency to induce ADCC by purified NK cells for ofatumumab and rituximab in a blinded study. Expected differences in affinity for the 158V and 158F allotypes of FcgRIIIa were observed for both ofatumumab and rituximab. These differences correlated with a stronger ADCC by FcgRIIIa 158V/V compared to 158F/F expressing NK cells. Significantly, ofatumumab was able to induce ADCC more potently than rituximab for both Fc receptor allotypes. Ofatumumab binds CD20 stably and at a distinct membrane-proximal epitope compared to rituximab. Our data suggest that these binding characteristics may positively impact ofatumumab’s ability to direct killing of tumor cells via ADCC. Most of this information was already available from experiments in our lab by Martin Glennie.
Tuesday, November 17, 2009
Alemtuzumab at ASH
Alemtuzumab is thought to be a superior monoclonal to rituximab for the treatment of CLL. The question ought then to be asked as to whether FCA would be superior to FCR. In fact the ASH abstracts report just such a trial from France and Belgium.
178 previously untreated patients under the age of 65 who did not have del 17p, were randomized between standard FCR and FCA, with the alemtuzumab being given sc in a dose of 30mg for 3 days every 28 days. Although the overall response rate and CR rate were not statistically different, they were both greater for the FCR arm (96% v 85% and 78% v 58%). The trial is too immature to calculate PFS or OS. The trial was terminated because of excess toxicity in the FCA arm. Febrile neutropenia was twice as common in the FCA arm and there were 7 deaths with FCA and none with FCR.
The German CLL2 trial looked at the safety profile of FCA in 61 patients aged 36-78, some of whom had been previously treated. Twelve out of 56 patients died within 6 months of completing treatment of which 5 were treatment-related. The fact that 7 died of CLL or concomitant disease suggests that this was a particularly sick group of patients. Serious adverse events included CMV-reactivation (5 patients), herpes-zoster-reactivation (1 patient), pneumonia (5 patients, 2 of which had Aspergillosis-pneumonias), AIHA (1 patient) and fever of unknown origin (12 patients). It was felt that there was more toxicity with this regimen than for FA, which had been tested previously.
If it is not to be used as a substitute for rituximab, how then might it best be used? The CALG conducted a trial of alemtuzumab as consolidation treatment after FR induction. The results were hardly promising. Patients who had stable disease or responsive disease 4 months after the last dose of fludarabine were treated with SC alemtuzumab 3 mg on day 1, 10 mg on day 3, and 30 mg on day 5, and then thrice weekly thereafter for 6 weeks (18 total doses). Fifty-eight pts out of the original 102 received alemtuzumab, and 42 (72%) completed the planned 6 weeks of therapy. OR, CR, and PR rates after alemtuzumab were 91%, 66% and 26%, and 50% were MRD negative. Twenty-eight of 45 pts (62%) in PR after FR who received alemtuzumab attained CR. Of 11 pts in CR after FR who received alemtuzumab, 5 were MRD negative prior to consolidation and 3 of the other 6 converted to MRD negative afterwards. Two-year PFS (76% vs 70%, p=0.54) and OS (84% vs 88%, p=0.89) were similar for pts who did and did not receive alemtuzumab. There were no differences in PFS or OS among the 30 pts in CR after FR whether or not they received alemtuzumab, although the numbers were small.
Grade 3-4 neutropenia and thrombocytopenia were observed in 43% and 19% of pts during alemtuzumab therapy. Grade 3-4 non-hematologic toxicity was observed in 41% of pts, including 19% infections and 19% febrile neutropenia, during alemtuzumab therapy. Five pts in CR after FR who received alemtuzumab died from infections (viral meningitis, Listeria meningitis, Legionella pneumonia, CMV and PCP pneumonia), and one pt in PR after FR who received alemtuzumab died of Epstein-Barr (EBV) viremia without evidence of EBV lymphoma. These deaths occurred both during and for up to 7 months after alemtuzumab therapy. Patients had received standard Pneumocystis (PCP) and Varicella zoster virus prophylaxis and were monitored weekly by PCR for Cytomegalovirus (CMV) viremia.
The MDS Anderson has added alemtuzumab to FCR as CFAR; it is given as -30mg iv on days 1, 3 and 5 of each course. Eighty patients with previously treated CLL received CFAR for an intended total of 6 courses. There were 21 CR (27%), 3 NPR (4%) and 29 PR (37%) for an ORR 67%. Median OS and time to treatment failure (TTF) were 16.6 and 10.6 months respectively for all pts. For pts achieving CR, median OS (50+ months) and TTF (28+ months) have not been reached. Grade 3/4 infectious complications included pneumonia (n=7) or sepsis (n=3). Other infections included minor infections (n=32), CMV reactivation (n=13), and other herpes virus infections (n=5). CFAR is an effective therapy in this group of heavily treated pts with CLL. They demonstrated favorable responses in patients younger than 70 years with F-sensitive disease who had 5 or fewer prior therapies. They concluded that CFAR is a good salvage regimen for patients who have received prior FC based regimen.
CFAR has also been used as first line treatment in patients with high risk disease, defined as those with a beta-2-microglobulin greater than 4. Sixty patients under the age of 70 were enrolled. Thirty-five patients couldn't complete the intended 6 courses. The reasons included delayed recovery of counts (18), infection (8), AIHA (4), treatment failure (3) and patient choice (2). The overall response rate was 92% with CRs in 70%, but the median time to progression was only 38 months. Patients with 17p deletion, 11q deletion and unmutated IgVH had significantly shorter times to progression (18 months, 27 months and 33 months respectively.
Eleven (19%) patients have died: 4 with disease progression after achieving CR; 2 who did not respond; 2 with Richter's transformation; 1 who developed AML; 1 due to metastatic lung cancer; and 1 due to severe pneumonia 8 months after achieving CR. Grade 3/4 neutropenia and thrombocytopenia occurred in 31% and 13% courses respectively. Major infections, including pneumonia and sepsis, were reported for 10(17%) pts. Minor infectious such as bronchitis, urinary tract infections and herpes zoster were reported for 15(25%) pts. These figures are similar to figures obtained for FCR at MDACC. CMV reactivation occurred in 7 (12%) patients, but many of the patients who were spared this were on valgancyclovir prophylaxis. There was one death due to CMV pneumonia. CFAR does not seem to be much of an improvement over FCR.
Alemtuzumab is licensed for first line use in CLL. The ASH papers do not support the idea that it should be used in this way whether as FCA or CFAR. FCR remains the best first line treatment. The use of alemtuzumab as consolidation treatment can be seen to be hazardous on the basis of the CALGB trial and indeed on the basis of an earlier German trial. Early evidence from a British trial not reported at ASH, suggests that these hazards can be overcome. The place of alemtuzumab in fludarabine refractory disease awaits determination. It may also have a place in stem cell transplantation, but I will report on this on another day.
178 previously untreated patients under the age of 65 who did not have del 17p, were randomized between standard FCR and FCA, with the alemtuzumab being given sc in a dose of 30mg for 3 days every 28 days. Although the overall response rate and CR rate were not statistically different, they were both greater for the FCR arm (96% v 85% and 78% v 58%). The trial is too immature to calculate PFS or OS. The trial was terminated because of excess toxicity in the FCA arm. Febrile neutropenia was twice as common in the FCA arm and there were 7 deaths with FCA and none with FCR.
The German CLL2 trial looked at the safety profile of FCA in 61 patients aged 36-78, some of whom had been previously treated. Twelve out of 56 patients died within 6 months of completing treatment of which 5 were treatment-related. The fact that 7 died of CLL or concomitant disease suggests that this was a particularly sick group of patients. Serious adverse events included CMV-reactivation (5 patients), herpes-zoster-reactivation (1 patient), pneumonia (5 patients, 2 of which had Aspergillosis-pneumonias), AIHA (1 patient) and fever of unknown origin (12 patients). It was felt that there was more toxicity with this regimen than for FA, which had been tested previously.
If it is not to be used as a substitute for rituximab, how then might it best be used? The CALG conducted a trial of alemtuzumab as consolidation treatment after FR induction. The results were hardly promising. Patients who had stable disease or responsive disease 4 months after the last dose of fludarabine were treated with SC alemtuzumab 3 mg on day 1, 10 mg on day 3, and 30 mg on day 5, and then thrice weekly thereafter for 6 weeks (18 total doses). Fifty-eight pts out of the original 102 received alemtuzumab, and 42 (72%) completed the planned 6 weeks of therapy. OR, CR, and PR rates after alemtuzumab were 91%, 66% and 26%, and 50% were MRD negative. Twenty-eight of 45 pts (62%) in PR after FR who received alemtuzumab attained CR. Of 11 pts in CR after FR who received alemtuzumab, 5 were MRD negative prior to consolidation and 3 of the other 6 converted to MRD negative afterwards. Two-year PFS (76% vs 70%, p=0.54) and OS (84% vs 88%, p=0.89) were similar for pts who did and did not receive alemtuzumab. There were no differences in PFS or OS among the 30 pts in CR after FR whether or not they received alemtuzumab, although the numbers were small.
Grade 3-4 neutropenia and thrombocytopenia were observed in 43% and 19% of pts during alemtuzumab therapy. Grade 3-4 non-hematologic toxicity was observed in 41% of pts, including 19% infections and 19% febrile neutropenia, during alemtuzumab therapy. Five pts in CR after FR who received alemtuzumab died from infections (viral meningitis, Listeria meningitis, Legionella pneumonia, CMV and PCP pneumonia), and one pt in PR after FR who received alemtuzumab died of Epstein-Barr (EBV) viremia without evidence of EBV lymphoma. These deaths occurred both during and for up to 7 months after alemtuzumab therapy. Patients had received standard Pneumocystis (PCP) and Varicella zoster virus prophylaxis and were monitored weekly by PCR for Cytomegalovirus (CMV) viremia.
The MDS Anderson has added alemtuzumab to FCR as CFAR; it is given as -30mg iv on days 1, 3 and 5 of each course. Eighty patients with previously treated CLL received CFAR for an intended total of 6 courses. There were 21 CR (27%), 3 NPR (4%) and 29 PR (37%) for an ORR 67%. Median OS and time to treatment failure (TTF) were 16.6 and 10.6 months respectively for all pts. For pts achieving CR, median OS (50+ months) and TTF (28+ months) have not been reached. Grade 3/4 infectious complications included pneumonia (n=7) or sepsis (n=3). Other infections included minor infections (n=32), CMV reactivation (n=13), and other herpes virus infections (n=5). CFAR is an effective therapy in this group of heavily treated pts with CLL. They demonstrated favorable responses in patients younger than 70 years with F-sensitive disease who had 5 or fewer prior therapies. They concluded that CFAR is a good salvage regimen for patients who have received prior FC based regimen.
CFAR has also been used as first line treatment in patients with high risk disease, defined as those with a beta-2-microglobulin greater than 4. Sixty patients under the age of 70 were enrolled. Thirty-five patients couldn't complete the intended 6 courses. The reasons included delayed recovery of counts (18), infection (8), AIHA (4), treatment failure (3) and patient choice (2). The overall response rate was 92% with CRs in 70%, but the median time to progression was only 38 months. Patients with 17p deletion, 11q deletion and unmutated IgVH had significantly shorter times to progression (18 months, 27 months and 33 months respectively.
Eleven (19%) patients have died: 4 with disease progression after achieving CR; 2 who did not respond; 2 with Richter's transformation; 1 who developed AML; 1 due to metastatic lung cancer; and 1 due to severe pneumonia 8 months after achieving CR. Grade 3/4 neutropenia and thrombocytopenia occurred in 31% and 13% courses respectively. Major infections, including pneumonia and sepsis, were reported for 10(17%) pts. Minor infectious such as bronchitis, urinary tract infections and herpes zoster were reported for 15(25%) pts. These figures are similar to figures obtained for FCR at MDACC. CMV reactivation occurred in 7 (12%) patients, but many of the patients who were spared this were on valgancyclovir prophylaxis. There was one death due to CMV pneumonia. CFAR does not seem to be much of an improvement over FCR.
Alemtuzumab is licensed for first line use in CLL. The ASH papers do not support the idea that it should be used in this way whether as FCA or CFAR. FCR remains the best first line treatment. The use of alemtuzumab as consolidation treatment can be seen to be hazardous on the basis of the CALGB trial and indeed on the basis of an earlier German trial. Early evidence from a British trial not reported at ASH, suggests that these hazards can be overcome. The place of alemtuzumab in fludarabine refractory disease awaits determination. It may also have a place in stem cell transplantation, but I will report on this on another day.
Monday, November 16, 2009
Is free speech an absolute right?
Is free speech an absolute freedom that should not be countermanded? The recent appearance of the leader of the British National Party on the flagship public debate program on the BBC was defended on the grounds of free speech. Today on BBC radio there was a campaign to stop cyber bullying. Cyber bullying is the use of social networking sites like Facebook to write cruel and unpleasant things about an individual. Recently, a young woman killed herself after being the victim of cyber bullying.
Political correctness has been developed in order to limit the offence cause to others by the way that we speak. It is a lost cause. Whatever you say, someone is bound to be offended. Some local authorities have stopped saying Merry Christmas for fear of offending non-Christians. In doing so they have offended Christians. Attempts at limiting offence to Muslims have offended homosexuals. Attempts at limiting offence to homosexuals have offended Muslims. Some politically correct language has offended pedants like me who want to preserve the English language in all its glory.
I do not think free speech is an absolute. Whether you have free speech depends on the context. If you live on a mountain in Montana you can just about say what you want, principally because nobody likely to be offended is going to hear you. As with so many things, context is vital. You do not have freedom to yell, "Fire!" in a crowded concert hall.
There is no law that prevents you from saying something offensive, just the convention of good manners. As I have said before, a secular book I read on the great virtues puts politeness at the head of the list since, since society is impossible without it.
The Wire was reckoned to be the best TV program to come out of America in years. However, the dialogue was replete with offensive words. One sequence showing two detectives tracing the path of a bullet was free of dialogue apart from the dozens of 'F**ks' uttered. African Americans generally referred to each other as 'N*gg*r', but, of course, no 'Honky' would be allowed to do so. Oh! Am I allowed to use that word? When the program was broadcast in the UK, the BBC gave clear warnings of what some viewers would find offensive. There is such a thing as an 'off' switch.
We have a grading system for movies and videos. We have parental PINS to prevent our children getting access to some Internet sites. When my wife was a librarian some books were kept 'under the counter' because they were thought unsuitable for minors. In some newsagents the 'Girlie' magazines are kept on the top shelf, out of the way of the prying eyes of young children. Over the years there has been a liberalising approach to anything concerned with sex. We find it hard to believe that our forebears put skirts on table legs. Some years ago an editor was sent to prison for publishing a blasphemous libel; a homoerotic poem about Jesus. It is very unlikely that the same thing would happen now.
Yet Britain is the libel capital of the world; the offended sue here to get bigger payouts. We limit free speech by law if it seeks to defame with an untruth. The question that concerns libertarians is whether the state wishes to extend the powers it has to censor what people say. Minority groups are worried that legislation that, no doubt, with good intent wants to enshrine good manners in law, might restrict legitimate comment. The trouble with free speech legislation is that it goes too far. Homosexuals want to be protected from bullying and free to express their sexuality in public in the same way that heterosexuals do. But if it is granted to homosexuals under the heading of free speech, what is to stop pedophiles or those who like sex with animals claiming the same? I am not equating all these practices, but there is no disguising the fact that homosexuality disgusts a sizable section of the population. There are not enough prisons to punish Disgusted of Tunbridge Wells.
The liberalising tendency is winning at the moment, but it will not always be so. A backlash is developing against unfettered immigration. In 1979 the unrestrained power of the Unions left the dead unburied and rats running loose in the streets as garbage went uncollected. As a result, Mrs Thatcher's government cut off the Unions at the knees. Privatisation sapped the power of organized labor. Restrictive legislation (unrepealed by Tony Blair) enfeebled the strike threat. Right wing governments have not gone for ever.
What is the Christian perspective on free speech? It centers mainly on the freedom to preach the gospel. In many countries this is restricted, but not yet in the UK. Christians generally prefer to live in an ordered society and not to question the right of the government to govern; render unto Caesar... even if he is a tyrant. However, rendering unto God comes first and if there is a conflict they are willing to suffer the punishment the state decrees. Not that this means that they will not campaign against perceived wrongs. Men like Wilberforce campaigned against the slave trade when most of society thought slavery in Jamaica preferable to wage-slavery in Lancashire. Is free speech something that they should campaign for? Remember what was said about those who lead children astray. Something about millstones and deep sea diving, as I recall. If children are to be protected there is already an exception. Freedom of expression is a lot more complicated and blanket laws are not helpful.
Should Christians be offended? I think we have a responsibility not to seek out offence. I would never go to a Gay-Pride parade. I would not watch late-night TV programs meant to titillate. I would not buy Girlie magazines. But I might protest if I thought that bad language was commonplace in all television programs, or same-sex-snogging became a part of children's TV. Everything must be seen in context. I believe there are absolutes when it comes to right and wrong. Not everything that is sinful is unlawful. Jesus's take on murder was having hateful thoughts about another person. How do you legislate for that. There are far more adulterers than homosexuals in our churches, and far more gossips than both. We should start putting our own house in order before we insist on reform in unbelievers. While sexual sins are important, they are not more important than the many other sins listed in Scripture - including gossip, neglect of parents and mean-spiritedness.
So, no I do not think free speech is an absolute. I do believe in politeness and in only giving offence when you may legitimately intend to.
Political correctness has been developed in order to limit the offence cause to others by the way that we speak. It is a lost cause. Whatever you say, someone is bound to be offended. Some local authorities have stopped saying Merry Christmas for fear of offending non-Christians. In doing so they have offended Christians. Attempts at limiting offence to Muslims have offended homosexuals. Attempts at limiting offence to homosexuals have offended Muslims. Some politically correct language has offended pedants like me who want to preserve the English language in all its glory.
I do not think free speech is an absolute. Whether you have free speech depends on the context. If you live on a mountain in Montana you can just about say what you want, principally because nobody likely to be offended is going to hear you. As with so many things, context is vital. You do not have freedom to yell, "Fire!" in a crowded concert hall.
There is no law that prevents you from saying something offensive, just the convention of good manners. As I have said before, a secular book I read on the great virtues puts politeness at the head of the list since, since society is impossible without it.
The Wire was reckoned to be the best TV program to come out of America in years. However, the dialogue was replete with offensive words. One sequence showing two detectives tracing the path of a bullet was free of dialogue apart from the dozens of 'F**ks' uttered. African Americans generally referred to each other as 'N*gg*r', but, of course, no 'Honky' would be allowed to do so. Oh! Am I allowed to use that word? When the program was broadcast in the UK, the BBC gave clear warnings of what some viewers would find offensive. There is such a thing as an 'off' switch.
We have a grading system for movies and videos. We have parental PINS to prevent our children getting access to some Internet sites. When my wife was a librarian some books were kept 'under the counter' because they were thought unsuitable for minors. In some newsagents the 'Girlie' magazines are kept on the top shelf, out of the way of the prying eyes of young children. Over the years there has been a liberalising approach to anything concerned with sex. We find it hard to believe that our forebears put skirts on table legs. Some years ago an editor was sent to prison for publishing a blasphemous libel; a homoerotic poem about Jesus. It is very unlikely that the same thing would happen now.
Yet Britain is the libel capital of the world; the offended sue here to get bigger payouts. We limit free speech by law if it seeks to defame with an untruth. The question that concerns libertarians is whether the state wishes to extend the powers it has to censor what people say. Minority groups are worried that legislation that, no doubt, with good intent wants to enshrine good manners in law, might restrict legitimate comment. The trouble with free speech legislation is that it goes too far. Homosexuals want to be protected from bullying and free to express their sexuality in public in the same way that heterosexuals do. But if it is granted to homosexuals under the heading of free speech, what is to stop pedophiles or those who like sex with animals claiming the same? I am not equating all these practices, but there is no disguising the fact that homosexuality disgusts a sizable section of the population. There are not enough prisons to punish Disgusted of Tunbridge Wells.
The liberalising tendency is winning at the moment, but it will not always be so. A backlash is developing against unfettered immigration. In 1979 the unrestrained power of the Unions left the dead unburied and rats running loose in the streets as garbage went uncollected. As a result, Mrs Thatcher's government cut off the Unions at the knees. Privatisation sapped the power of organized labor. Restrictive legislation (unrepealed by Tony Blair) enfeebled the strike threat. Right wing governments have not gone for ever.
What is the Christian perspective on free speech? It centers mainly on the freedom to preach the gospel. In many countries this is restricted, but not yet in the UK. Christians generally prefer to live in an ordered society and not to question the right of the government to govern; render unto Caesar... even if he is a tyrant. However, rendering unto God comes first and if there is a conflict they are willing to suffer the punishment the state decrees. Not that this means that they will not campaign against perceived wrongs. Men like Wilberforce campaigned against the slave trade when most of society thought slavery in Jamaica preferable to wage-slavery in Lancashire. Is free speech something that they should campaign for? Remember what was said about those who lead children astray. Something about millstones and deep sea diving, as I recall. If children are to be protected there is already an exception. Freedom of expression is a lot more complicated and blanket laws are not helpful.
Should Christians be offended? I think we have a responsibility not to seek out offence. I would never go to a Gay-Pride parade. I would not watch late-night TV programs meant to titillate. I would not buy Girlie magazines. But I might protest if I thought that bad language was commonplace in all television programs, or same-sex-snogging became a part of children's TV. Everything must be seen in context. I believe there are absolutes when it comes to right and wrong. Not everything that is sinful is unlawful. Jesus's take on murder was having hateful thoughts about another person. How do you legislate for that. There are far more adulterers than homosexuals in our churches, and far more gossips than both. We should start putting our own house in order before we insist on reform in unbelievers. While sexual sins are important, they are not more important than the many other sins listed in Scripture - including gossip, neglect of parents and mean-spiritedness.
So, no I do not think free speech is an absolute. I do believe in politeness and in only giving offence when you may legitimately intend to.
Saturday, November 14, 2009
Forgiveness
A couple of days ago a 16-year old was jailed for raping a five-year-old boy. The offence took place just days after he had been spared a custodial sentence for a previous attack. The young man, who is said to have Asperger's syndrome, abducted and repeatedly abused the child only eight days after being shown leniency for the rape of a seven-year-old boy. The first victim's family were committed Christians and the court had heard that they forgave him and called for a "corrective" rather than punitive sentence.
During this week I have been watching a TV mini-series called Collision. A multi-car pile-up was being investigated by a cop who had lost his own wife in a car crash the previous year. His daughter had been paralysed in the same crash and was now in a wheelchair. During the course of the program, the drunken driver responsible for his wife's death was released from prison. He sought out the cop and explained that during his time in prison he had become a Christian and now felt that he ought to go to the cop and beg for forgiveness. The cop beat him up. As the story proceeded, exploring the lives of those involved in the crash, it was clear that each of them had done something reprehensible. What was noticeable was how wives forgave errant husbands so as to keep their families together. The cop's crippled daughter even suggested that he forgive the drunken driver. She had, after all, forgiven her father for his affair with a policewoman. She emphasized that without forgiveness he would never be able to move on.
So the question is posed, "Should we forgive?" Even more pertinent, should Christians forgive.
I think there are several points to make. You cannot forgive on behalf of someone else. Even the parents of the abused child cannot forgive on his behalf. They were themselves offended by the abuser's act and they can forgive that, but not really the harm done to the child.
Forgiveness may well be undesired. When the Christian in the play asked forgiveness of the cop, the cop pushed him away. The Christian then said, "I forgive you for pushing me." This raised the level of anger in the cop so that he almost killed him. The cop didn't want forgiving.
Forgiveness does take away responsibility. God's forgiveness may save us from Hell, but it doesn't save us from prison. The judge shouldn't have spared the rapist from jail after the first offence. The thief on the cross was forgiven by Jesus, but he still had to complete his sentence - he had to die.
In a recent episode of House, a young doctor murdered an African tyrant under his care and got away with it. However, it weighed on his Catholic conscience and he went to confession. The priest, quite rightly, says, "You can't be absolved by saying a few Hail Marys; you must go to the police."
Finally, forgiveness is ineffectual without repentance. And repentance means more than saying you're sorry. It means a whole change around in your life.
But isn't God's forgiveness unconditional? Doesn't the Bible say, "While we were still sinners, Christ died for us."?
The offer of forgiveness is unconditional. God made the first move without asking us to do anything first. We are not offered forgiveness because we have made amends, done some community service, given to the poor or spent years as a missionary. God describes all such attempts at atonement as 'dirty rags'. Forgiveness is free; the price has already been paid.
However, we are given the free will to reject the offer. Just like the cop in the mini-series we can give the person doing the offering a punch on the nose. Forgiveness is not forced upon us. As the cop's daughter implied, forgiveness is a great healer. It can induce repentance, but without repentance it is ineffectual.
What difference did it make to the young rapist that he had been forgiven by his victim's parents? None at all. There was no repentance (perhaps because of the diagnosis attached to him he was unable to repent. Perhaps he was like the soldiers at the foot of the cross - they know not what they do.) Whatever the answer he had to be locked up. A beast in a zoo does not know what it is doing when it attacks the visitors; it still needs locking up.
If your brother/son/mother were blown up by a suicide bomber, you would have a hard time forgiving the perpetrator; perhaps in forgiving Islam and everyone associated with it. So would I. A Christian must learn to forgive. "Forgive us our sins as we forgive those who sin against us." That does not mean that the man who planned the atrocity and those who funded and facilitated it are free from blame. They broke the law and must face the punishment that the law decrees. We do not operate under Shariah law, where the payment of blood money can absolve the crime. Our law demands a penalty (in different places, imprisonment or execution). Our ability to forgive doesn't come into it and should not influence the judge when passing sentence.
But being able to forgive unburdens the victim.
During this week I have been watching a TV mini-series called Collision. A multi-car pile-up was being investigated by a cop who had lost his own wife in a car crash the previous year. His daughter had been paralysed in the same crash and was now in a wheelchair. During the course of the program, the drunken driver responsible for his wife's death was released from prison. He sought out the cop and explained that during his time in prison he had become a Christian and now felt that he ought to go to the cop and beg for forgiveness. The cop beat him up. As the story proceeded, exploring the lives of those involved in the crash, it was clear that each of them had done something reprehensible. What was noticeable was how wives forgave errant husbands so as to keep their families together. The cop's crippled daughter even suggested that he forgive the drunken driver. She had, after all, forgiven her father for his affair with a policewoman. She emphasized that without forgiveness he would never be able to move on.
So the question is posed, "Should we forgive?" Even more pertinent, should Christians forgive.
I think there are several points to make. You cannot forgive on behalf of someone else. Even the parents of the abused child cannot forgive on his behalf. They were themselves offended by the abuser's act and they can forgive that, but not really the harm done to the child.
Forgiveness may well be undesired. When the Christian in the play asked forgiveness of the cop, the cop pushed him away. The Christian then said, "I forgive you for pushing me." This raised the level of anger in the cop so that he almost killed him. The cop didn't want forgiving.
Forgiveness does take away responsibility. God's forgiveness may save us from Hell, but it doesn't save us from prison. The judge shouldn't have spared the rapist from jail after the first offence. The thief on the cross was forgiven by Jesus, but he still had to complete his sentence - he had to die.
In a recent episode of House, a young doctor murdered an African tyrant under his care and got away with it. However, it weighed on his Catholic conscience and he went to confession. The priest, quite rightly, says, "You can't be absolved by saying a few Hail Marys; you must go to the police."
Finally, forgiveness is ineffectual without repentance. And repentance means more than saying you're sorry. It means a whole change around in your life.
But isn't God's forgiveness unconditional? Doesn't the Bible say, "While we were still sinners, Christ died for us."?
The offer of forgiveness is unconditional. God made the first move without asking us to do anything first. We are not offered forgiveness because we have made amends, done some community service, given to the poor or spent years as a missionary. God describes all such attempts at atonement as 'dirty rags'. Forgiveness is free; the price has already been paid.
However, we are given the free will to reject the offer. Just like the cop in the mini-series we can give the person doing the offering a punch on the nose. Forgiveness is not forced upon us. As the cop's daughter implied, forgiveness is a great healer. It can induce repentance, but without repentance it is ineffectual.
What difference did it make to the young rapist that he had been forgiven by his victim's parents? None at all. There was no repentance (perhaps because of the diagnosis attached to him he was unable to repent. Perhaps he was like the soldiers at the foot of the cross - they know not what they do.) Whatever the answer he had to be locked up. A beast in a zoo does not know what it is doing when it attacks the visitors; it still needs locking up.
If your brother/son/mother were blown up by a suicide bomber, you would have a hard time forgiving the perpetrator; perhaps in forgiving Islam and everyone associated with it. So would I. A Christian must learn to forgive. "Forgive us our sins as we forgive those who sin against us." That does not mean that the man who planned the atrocity and those who funded and facilitated it are free from blame. They broke the law and must face the punishment that the law decrees. We do not operate under Shariah law, where the payment of blood money can absolve the crime. Our law demands a penalty (in different places, imprisonment or execution). Our ability to forgive doesn't come into it and should not influence the judge when passing sentence.
But being able to forgive unburdens the victim.
Friday, November 13, 2009
ASH 2009
It is now possible to view the ASH abstracts for 2009. Although I have already broken the news that for the first time a first line treatment has been shown to improve overall survival, we can now view the details here.
We owe a great deal to Michael Hallek and his team for doing this trial, and we ought to ought to complain to the drug company for not doing the trial at an earlier stage. Their perfidy has deprived many people of what is the best available treatment for CLL.
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 indication for treatment, perhaps a higher threshold for starting treatment should be adopted.
However in another study from the German group the better efficacy of the FCR regimen in terms of response rates and progression-free survival does not yet result in an improved quality of life.
We owe a great deal to Michael Hallek and his team for doing this trial, and we ought to ought to complain to the drug company for not doing the trial at an earlier stage. Their perfidy has deprived many people of what is the best available treatment for CLL.
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 indication for treatment, perhaps a higher threshold for starting treatment should be adopted.
However in another study from the German group the better efficacy of the FCR regimen in terms of response rates and progression-free survival does not yet result in an improved quality of life.
Thursday, November 12, 2009
Scientists rule. OK?
Would you trust a scientist? Quite apart from whether he is honest or not; is his opinion worth anything? I suppose, in this day and age when actors, pop-singers and sports stars are supposed to have the last word on everything, you might think that a scientist is a bit of an improvement.
The correct answer is, "If he knows what he's talking about." And for the purpose of this article so I don't have to keep writing his/her, let's assume that the male embraces the female.
I have always prided myself on reading widely and picking up scraps of information from many different places. However, if you got me on astrophysics then my opinion would be worth no more than that of Tiger Woods. On CLL though, I could wipe the floor with Stephen Hawking.
Even on CLL it is possible to disagree. Michael Keating and I, though agreeing on many things, had a fierce debate on one aspect of CLL on which we disagreed.
The best committee that I ever sat on was chaired by a non-specialist who had no detailed knowledge of the subject under consideration. He allowed debate to flow.
Scientists as a group dig very deep and narrow holes. They often know an awful lot about very little. Politicians, on the other hand, skim the surface from a large area. They can't be expected to know a subject deeply, but, if they are honest, they will look at a topic fairly and seek expert help over detail.
To go back to the topic of drugs. A complete libertarian would say that if someone wants to take a drug that harms his own body the let him; it is his, and only his, responsibility. On the other hand, if he has the same health insurance as I do, why should my premiums go up just because he indulges himself?
However, many drugs cause harm to the community. Alcoholics, apart from raising my insurance premium, beat their wives, cause motor car accidents, vomit in the streets, desert their children, reduce their families to penury and can't work properly. So what? Banning alcohol does not work; we saw how much harm it did during Prohibition. It just leads to an increase in criminal behavior. Look at it another way; legalizing it hasn't worked either. We still have wife-beatings, car accidents and poverty.
Scientists may tell us that cannabis is less harmful than tobacco and alcohol. How do they know? At first glance cigarette smoking seemed an attractive proposition. Actors, singers and sports stars endorsed the product. Even doctors agreed. Given, it did make your clothes stink, but it helped your cough, didn't it? Then in 1951, Richard Doll demonstrated that smoking caused lung cancer. The evidence was convincing enough to make him stop smoking. Nevertheless, it took many years before anybody believed him and many more before everybody believed him. Such convincing evidence is hard to obtain. There are no such studies for cannabis or ecstasy. People lie - either because of guilt of bravado - about their drug taking. How would you isolate the effect of one drug compared to another?
Cannabis apparently induces a degree of intoxication. How long after smoking a joint is it safe to drive? If you were stopped, what test would the policeman use to determine whether you were safe to drive? Supposing you had popped an 'E' and later on smoked some pot. Are you safe to fly your aeroplane tomorrow? A scientist who has opinion on such a thing had better couch it in conditional clauses if he doesn't want to be sued.
If the question is a simpler one such as, "Do cannabis users develop schizophrenia more commonly than non-users?" then the answer is yes, but asked how commonly, a wise scientist will demur. Remember the guy who won the Nobel Prize for inventing the transistor? This was a proper Nobel Prize; not like the Mickey Mouse ones they gave to Gore and Obama. Well, he turned out to espouse the discredited science of Eugenics, and even started a sperm bank for geniuses. Do you want to be ruled by scientists? I don't. There is a quote from the New Testament where Festus, the Roman governor says to the Apostle Paul, "Your great learning is driving you insane!" We would be insane to be ruled by scientists.
The correct answer is, "If he knows what he's talking about." And for the purpose of this article so I don't have to keep writing his/her, let's assume that the male embraces the female.
I have always prided myself on reading widely and picking up scraps of information from many different places. However, if you got me on astrophysics then my opinion would be worth no more than that of Tiger Woods. On CLL though, I could wipe the floor with Stephen Hawking.
Even on CLL it is possible to disagree. Michael Keating and I, though agreeing on many things, had a fierce debate on one aspect of CLL on which we disagreed.
The best committee that I ever sat on was chaired by a non-specialist who had no detailed knowledge of the subject under consideration. He allowed debate to flow.
Scientists as a group dig very deep and narrow holes. They often know an awful lot about very little. Politicians, on the other hand, skim the surface from a large area. They can't be expected to know a subject deeply, but, if they are honest, they will look at a topic fairly and seek expert help over detail.
To go back to the topic of drugs. A complete libertarian would say that if someone wants to take a drug that harms his own body the let him; it is his, and only his, responsibility. On the other hand, if he has the same health insurance as I do, why should my premiums go up just because he indulges himself?
However, many drugs cause harm to the community. Alcoholics, apart from raising my insurance premium, beat their wives, cause motor car accidents, vomit in the streets, desert their children, reduce their families to penury and can't work properly. So what? Banning alcohol does not work; we saw how much harm it did during Prohibition. It just leads to an increase in criminal behavior. Look at it another way; legalizing it hasn't worked either. We still have wife-beatings, car accidents and poverty.
Scientists may tell us that cannabis is less harmful than tobacco and alcohol. How do they know? At first glance cigarette smoking seemed an attractive proposition. Actors, singers and sports stars endorsed the product. Even doctors agreed. Given, it did make your clothes stink, but it helped your cough, didn't it? Then in 1951, Richard Doll demonstrated that smoking caused lung cancer. The evidence was convincing enough to make him stop smoking. Nevertheless, it took many years before anybody believed him and many more before everybody believed him. Such convincing evidence is hard to obtain. There are no such studies for cannabis or ecstasy. People lie - either because of guilt of bravado - about their drug taking. How would you isolate the effect of one drug compared to another?
Cannabis apparently induces a degree of intoxication. How long after smoking a joint is it safe to drive? If you were stopped, what test would the policeman use to determine whether you were safe to drive? Supposing you had popped an 'E' and later on smoked some pot. Are you safe to fly your aeroplane tomorrow? A scientist who has opinion on such a thing had better couch it in conditional clauses if he doesn't want to be sued.
If the question is a simpler one such as, "Do cannabis users develop schizophrenia more commonly than non-users?" then the answer is yes, but asked how commonly, a wise scientist will demur. Remember the guy who won the Nobel Prize for inventing the transistor? This was a proper Nobel Prize; not like the Mickey Mouse ones they gave to Gore and Obama. Well, he turned out to espouse the discredited science of Eugenics, and even started a sperm bank for geniuses. Do you want to be ruled by scientists? I don't. There is a quote from the New Testament where Festus, the Roman governor says to the Apostle Paul, "Your great learning is driving you insane!" We would be insane to be ruled by scientists.
Wednesday, November 11, 2009
How long to train a surgeon?
Concern has been raised about the training of doctors. Gretchen Purcell Jackson and John L Tapley, pediatric surgeons from Nashville, have just published an article in the BMJ which suggests that our surgeons are in danger of being seriously undertrained. Typically, a surgical training takes 5 years to obtain the necessary skills to be come a general surgeon with extra years for research and subspecialty training. Educational psychologists have shown that acquiring an elite level of expertise or performance requires 10 years of intense involvement and 10,000 hours of practice. This would be true for musicians, chess players or Olympic divers. The authors suggest that surgery, which requires both manual dexterity and cognitive understanding, needs twice that amount of training.
In the States surgeons are rejecting the idea that an 80 hour working week is sufficient to train a surgeon while in Europe the working-time directive is insisting on a 48 hour week. Sleep researchers have demonstrated that heavy night call, defined as every fourth or fifth night, compromises attention and vigilance as much as alcohol intoxication. One institution that introduced the 80 hour week found it produced happier trainees with a better quality of life but it also may well have compromised the surgeons' educational experience.
5 years at 80 hours a week does give the necessary 20,000 hours, but only if no more than 2 weeks holiday is taken. How can Denmark train its surgeons with a 37 hour week?
Although, the prime purpose in reducing surgeons' hours has been to enhance patient safety, it seems to have had the opposite effect where it has been tried. at one center preventable and non-preventable complication rates increased significantly after the introduction of an 80 hour week. In New York, where Teaching Hospitals adopted the 80-hour week but non-teaching hospitals did not, there were increases in unintentional punctures and thromboembolic events in those with the hours restrictions. The extra duties have to be done by someone - the answer is often moonlighting or else lying about hours.
When I think back to my own training, in the early days I worked alternate nights and then on a 1 in 4 rota. Hematologists in the UK have to obtain both the MRCP like internal medicine specialists and then the MRCPath like pathologists. They are also expected to publish. I completed my training 6 years after qualifying, but I did take work home. It may well be that surgeons need a longer period of training because of the 'piano practice' required. Musicians don't expect their instruments to start hemorrhaging uncontrollably.
When I was younger there were trainee surgeons in their early forties. Such were the rewards in private practice that they were prepared to put up with this extended training. Nowadays we see consultant surgeons appointed in their early thirties. They do far fewer operations than their forbears, both in range and number. I know one surgeon who never opens an abdomen, but is an expert in taking out lymph nodes and removes spleens through a laparoscope. Perhaps they are all a lot more talented than they used to be.
In the States surgeons are rejecting the idea that an 80 hour working week is sufficient to train a surgeon while in Europe the working-time directive is insisting on a 48 hour week. Sleep researchers have demonstrated that heavy night call, defined as every fourth or fifth night, compromises attention and vigilance as much as alcohol intoxication. One institution that introduced the 80 hour week found it produced happier trainees with a better quality of life but it also may well have compromised the surgeons' educational experience.
5 years at 80 hours a week does give the necessary 20,000 hours, but only if no more than 2 weeks holiday is taken. How can Denmark train its surgeons with a 37 hour week?
Although, the prime purpose in reducing surgeons' hours has been to enhance patient safety, it seems to have had the opposite effect where it has been tried. at one center preventable and non-preventable complication rates increased significantly after the introduction of an 80 hour week. In New York, where Teaching Hospitals adopted the 80-hour week but non-teaching hospitals did not, there were increases in unintentional punctures and thromboembolic events in those with the hours restrictions. The extra duties have to be done by someone - the answer is often moonlighting or else lying about hours.
When I think back to my own training, in the early days I worked alternate nights and then on a 1 in 4 rota. Hematologists in the UK have to obtain both the MRCP like internal medicine specialists and then the MRCPath like pathologists. They are also expected to publish. I completed my training 6 years after qualifying, but I did take work home. It may well be that surgeons need a longer period of training because of the 'piano practice' required. Musicians don't expect their instruments to start hemorrhaging uncontrollably.
When I was younger there were trainee surgeons in their early forties. Such were the rewards in private practice that they were prepared to put up with this extended training. Nowadays we see consultant surgeons appointed in their early thirties. They do far fewer operations than their forbears, both in range and number. I know one surgeon who never opens an abdomen, but is an expert in taking out lymph nodes and removes spleens through a laparoscope. Perhaps they are all a lot more talented than they used to be.
Tuesday, November 10, 2009
Apologies
Never complain; never explain; never apologize. The words are variously attributed to Neville Chamberlain, John Wayne and Benjamin Disraeli. But someone who should perhaps have taken them to heart is our esteemed Prime Minister, Gordon Brown.
We have learnt that Gordon Brown takes it on himself to hand-write a personal letter to the relatives bereaved by a soldier's death in Afghanistan. One mother, who has lost her son, complained loudly (to a tabloid newspaper) that the letter sent by GB was illegible, and spelt both her and her son's name wrong. Mrs Janes was addressed as Mrs James and her son, Jamie, as James, though GB did score through the terminal 'es' and replace it with 'ie'. Later Brown telephoned to apologize, blaming it on his bad writing (it is very bad and he writes in a thick black felt-tip). There are some spelling errors that can be put down to his bad writing - he tends to omit the letter 'e' near the ends of words as they finish in a terminal squiggle, but the excuse seems lame since he called the family 'James' when announcing the death of the son at Prime Minister's Questions in the Commons, and he clearly realized that 'James' should be 'Jamie', but rather than trying to correct it, he should have wasted that piece of paper and started again. It does give the impression that this was a hurried scribble.
Now, he did not need to write a personal letter and no doubt he was in a hurry. A prime minister's job is a hard one and he can't behave like Campbell Bannerman did in 1906 and take a nap in the afternoon. But apologize? PG Wodehouse once wrote, "It is a good rule in life never to apologize. The right sort of people does not want apologies, and the wrong sort of people takes a mean advantage of them.”
This is certainly what happened to GB. The mother, no doubt at the behest of the tabloid newspaper, taped the phone call. She did not accept the apology and easily pointed out the inherent lie in his excuse. She further turned the complaint into what was probably bugging her in the first place. Her son didn't need to die. Had a helicopter been available he might have been evacuated in time, but there weren't enough helicopters.
The transcript of the telephone call was plastered over the tabloids this morning. Although the public reaction is slightly in Gordon Brown's favor, he would have been wise to have kept his head down. People understand that he went the extra mile in writing the letter, but he has appeared maladroit in the way he has handled himself, and who wants a clumsy Prime Minister.
So what are rules about apologizing?
First: don't apologize for something you are not responsible for. It has been unseemly and nauseating to see politicians apologizing for things that happened 200 years ago when standards were different. Even when standards are the same. Young Germans should not apologize for Hitler - he was Austrian anyway. What's done is done. Nothing will change the past. Get over it; that's the way things are. Anyone ever thought of criticizing the Italians because Nero burnt Christians to light his arenas?
Second: if you are responsible for something, apologize in person, face to face to the offended party; but don't make a public spectacle of it. Do it quickly. Don't have it dragged out of you.
Third: don't make excuses. If you are truly sorry it is because it is your fault - not the fault of the weather, your work being too onerous or some other fool putting you off.
Fourth: do better in future.
We have learnt that Gordon Brown takes it on himself to hand-write a personal letter to the relatives bereaved by a soldier's death in Afghanistan. One mother, who has lost her son, complained loudly (to a tabloid newspaper) that the letter sent by GB was illegible, and spelt both her and her son's name wrong. Mrs Janes was addressed as Mrs James and her son, Jamie, as James, though GB did score through the terminal 'es' and replace it with 'ie'. Later Brown telephoned to apologize, blaming it on his bad writing (it is very bad and he writes in a thick black felt-tip). There are some spelling errors that can be put down to his bad writing - he tends to omit the letter 'e' near the ends of words as they finish in a terminal squiggle, but the excuse seems lame since he called the family 'James' when announcing the death of the son at Prime Minister's Questions in the Commons, and he clearly realized that 'James' should be 'Jamie', but rather than trying to correct it, he should have wasted that piece of paper and started again. It does give the impression that this was a hurried scribble.
Now, he did not need to write a personal letter and no doubt he was in a hurry. A prime minister's job is a hard one and he can't behave like Campbell Bannerman did in 1906 and take a nap in the afternoon. But apologize? PG Wodehouse once wrote, "It is a good rule in life never to apologize. The right sort of people does not want apologies, and the wrong sort of people takes a mean advantage of them.”
This is certainly what happened to GB. The mother, no doubt at the behest of the tabloid newspaper, taped the phone call. She did not accept the apology and easily pointed out the inherent lie in his excuse. She further turned the complaint into what was probably bugging her in the first place. Her son didn't need to die. Had a helicopter been available he might have been evacuated in time, but there weren't enough helicopters.
The transcript of the telephone call was plastered over the tabloids this morning. Although the public reaction is slightly in Gordon Brown's favor, he would have been wise to have kept his head down. People understand that he went the extra mile in writing the letter, but he has appeared maladroit in the way he has handled himself, and who wants a clumsy Prime Minister.
So what are rules about apologizing?
First: don't apologize for something you are not responsible for. It has been unseemly and nauseating to see politicians apologizing for things that happened 200 years ago when standards were different. Even when standards are the same. Young Germans should not apologize for Hitler - he was Austrian anyway. What's done is done. Nothing will change the past. Get over it; that's the way things are. Anyone ever thought of criticizing the Italians because Nero burnt Christians to light his arenas?
Second: if you are responsible for something, apologize in person, face to face to the offended party; but don't make a public spectacle of it. Do it quickly. Don't have it dragged out of you.
Third: don't make excuses. If you are truly sorry it is because it is your fault - not the fault of the weather, your work being too onerous or some other fool putting you off.
Fourth: do better in future.
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