Tuesday, December 30, 2008
Images from Gaza
Someone has just sent me images from Gaza. Who could fail to be moved by a bleeding child. How callous and horrible must be the people who fire rockets on a foreign town while using children as a human shield just for the propaganda value of a bleeding child. No wonder the Geneva convention calls using civilians in this way a war crime.
Monday, December 29, 2008
Change! Change! Change! Mr Obama
Six bishops in the Church of England have now criticized the government over their being wedded to continuous economic growth. Gordon Brown wants us to start borrowing again. He wants the banks to offer easy credit once more.
As someone who is relatively rich I find it hard to criticize those poor people who want more, but I have to ask the question, "How much is enough?"
Through my letter box today came a magazine offering me such goodies as a telescope that will magnify 60 times for £60. Why would I want one? How about an official Swiss Military chrongraph for £300. It looks awfully like a wrist watch and I have one of those already. How about a car hammock for £25 or a slobber-free 'fetch' toy for dogs at only £9 or a giant electric lint shaver for £15? An instant stick-on shirt button? A solar marker light for paths and drives? Spykee - the first ever wi-fi robot, a snip at £279.95? Rechargeable color-changing flame lights? A natural woven willow hideaway for a wheelie bin?
Is this what is needed to keep the economy running? I sat down this morning wondering whether I should replace my VHS collection with DVDs. Yet I see in this magazine the offer of an old fashioned radiogram so I can play my old 45s or 33s. On my hard-drive recorder I have so many films and TV programmes recorded that I shall never have enough time to watch them. I started watching one tonight - Funny Face with Audry Hepburn and Fred Astair. I've never seen such tosh.
Our society has taken a wrong path. Perhaps bread and circuses are necessary to keep the peasants under control, but if so, what a mess we have made of our lives. Are there no real problems to solve in this world?
Israel declares total war on Hamas. I can see how they have been provoked, but is it likely to solve anything? People have selective memories. A man on talk radio was cursing the Israelis this morning. He complained that Palestinian territory had been annexed in 1967, as if there were no reason for it. As if the six-day war had never taken place.
He was probably too young to remember it - it was 41 years ago. He talked of the Palestinians as if they were not Arabs. Such ignorance! Here was someone who had not been subject to 60 years of brainwashing against Israel. What hope is there for a resolution.
The Old Testament solution would be to wipe out every last Hamas supporter; man woman and child. King Saul was punished even for sparing the King. I doubt that genocide would escape the notice of the world's press, and even George W Bush would be upset with them.
On the other hand, what can the Israelis do when hundreds of rockets rain down on their southern towns? Why do Hamas do it? They inflict very little damage on Israel. Is it to provoke a reaction like this? Do they hope to win a propaganda war? Do they think that Israel cares what the Europeans or the Russians or the Arabs think? Do they imagine America will abandon Israel when a large proportion of the American electorate believes that the return of the Jews to Jerusalem is one of the signs that presage the Second Coming?
Hamas won an election by promising to end corruption, to introduce good schools and a decent free health service. Wouldn't we all vote for motherhood and apple pie. They also promised to wipe Israel from the face of the earth. You probably wouldn't vote for a party that offered free health care, free education, and lower taxes. Your little grey cells would murmur, "It can't be done."
The West Bank and Gaza always was a failed state relying on hand-outs form a guilt-ridden Europe and America who together brought about the state of Israel, in part because of guilt about the Holocaust, in part to assuage Jewish voters and in part because of promises made by our grandfathers. This aid was only forthcoming if two mutually incompatible concepts could be believed at the same time: a free and secure Israel and a peaceful Palestinian homeland. Hamas won't buy into the former so the aid dried up.
The rockets are deliberately fired from densely populated areas. Hamas intends for civilians to be killed. How else can they mobilize the Western Press? Israel doesn't care. They know the Press will hammer them and they don't care. They might care if Obama withdrew American aid, but I bet he won't.
Result: stalemate. The war will continue - cold or hot.
Zadie Smith, the novelist, was guest editor on Radio 4 today. She sent a reporter to Liberia. Remember Liberia? That refuge for freed slaves from America? They elected a female President promising to end corruption. A renewed aid program began with her election. Hasn't it made a difference! Actually no. The aid has flowed into the hands of corrupt rulers; the poor have nothing.
Want to make a difference in this world? Plant a tree; write a book; father a child.
Now what's on television tonight?
As someone who is relatively rich I find it hard to criticize those poor people who want more, but I have to ask the question, "How much is enough?"
Through my letter box today came a magazine offering me such goodies as a telescope that will magnify 60 times for £60. Why would I want one? How about an official Swiss Military chrongraph for £300. It looks awfully like a wrist watch and I have one of those already. How about a car hammock for £25 or a slobber-free 'fetch' toy for dogs at only £9 or a giant electric lint shaver for £15? An instant stick-on shirt button? A solar marker light for paths and drives? Spykee - the first ever wi-fi robot, a snip at £279.95? Rechargeable color-changing flame lights? A natural woven willow hideaway for a wheelie bin?
Is this what is needed to keep the economy running? I sat down this morning wondering whether I should replace my VHS collection with DVDs. Yet I see in this magazine the offer of an old fashioned radiogram so I can play my old 45s or 33s. On my hard-drive recorder I have so many films and TV programmes recorded that I shall never have enough time to watch them. I started watching one tonight - Funny Face with Audry Hepburn and Fred Astair. I've never seen such tosh.
Our society has taken a wrong path. Perhaps bread and circuses are necessary to keep the peasants under control, but if so, what a mess we have made of our lives. Are there no real problems to solve in this world?
Israel declares total war on Hamas. I can see how they have been provoked, but is it likely to solve anything? People have selective memories. A man on talk radio was cursing the Israelis this morning. He complained that Palestinian territory had been annexed in 1967, as if there were no reason for it. As if the six-day war had never taken place.
He was probably too young to remember it - it was 41 years ago. He talked of the Palestinians as if they were not Arabs. Such ignorance! Here was someone who had not been subject to 60 years of brainwashing against Israel. What hope is there for a resolution.
The Old Testament solution would be to wipe out every last Hamas supporter; man woman and child. King Saul was punished even for sparing the King. I doubt that genocide would escape the notice of the world's press, and even George W Bush would be upset with them.
On the other hand, what can the Israelis do when hundreds of rockets rain down on their southern towns? Why do Hamas do it? They inflict very little damage on Israel. Is it to provoke a reaction like this? Do they hope to win a propaganda war? Do they think that Israel cares what the Europeans or the Russians or the Arabs think? Do they imagine America will abandon Israel when a large proportion of the American electorate believes that the return of the Jews to Jerusalem is one of the signs that presage the Second Coming?
Hamas won an election by promising to end corruption, to introduce good schools and a decent free health service. Wouldn't we all vote for motherhood and apple pie. They also promised to wipe Israel from the face of the earth. You probably wouldn't vote for a party that offered free health care, free education, and lower taxes. Your little grey cells would murmur, "It can't be done."
The West Bank and Gaza always was a failed state relying on hand-outs form a guilt-ridden Europe and America who together brought about the state of Israel, in part because of guilt about the Holocaust, in part to assuage Jewish voters and in part because of promises made by our grandfathers. This aid was only forthcoming if two mutually incompatible concepts could be believed at the same time: a free and secure Israel and a peaceful Palestinian homeland. Hamas won't buy into the former so the aid dried up.
The rockets are deliberately fired from densely populated areas. Hamas intends for civilians to be killed. How else can they mobilize the Western Press? Israel doesn't care. They know the Press will hammer them and they don't care. They might care if Obama withdrew American aid, but I bet he won't.
Result: stalemate. The war will continue - cold or hot.
Zadie Smith, the novelist, was guest editor on Radio 4 today. She sent a reporter to Liberia. Remember Liberia? That refuge for freed slaves from America? They elected a female President promising to end corruption. A renewed aid program began with her election. Hasn't it made a difference! Actually no. The aid has flowed into the hands of corrupt rulers; the poor have nothing.
Want to make a difference in this world? Plant a tree; write a book; father a child.
Now what's on television tonight?
Hsp90 again
Several people have asked about the status of heat shock protein 90, inhibition of which was thought of as a new way of treating the most aggressive forms of CLL. Unfortunately the two inhibitors that I described before have proved too toxic to the liver to hold out much hope for them to emerge as anti-CLL drugs. There were 32 papers at ASH which mentioned Hsp90, but most of them were irrelevant to CLL patients. Eloisi Caldas Lopes from Memorial Sloane Kettering described a new inhibitor, PUH-71, which is of a different chemical type to those previously described. This new agent was found to inhibit the growth of human diffuse large B-cell lymphomas in mice without liver toxicity. The agent was preferentially retained in the tumor tissue.
Other Hsp90 inhibitors are in the pipeline. Novartis have two, a pan-Histone deacetylase inhibitor, panobinostat, and a specific Hsp90 inhibitor, AUY, were both tested by Wang et al from MCG Cancer Center, Augusta, Georgia, in a system that stressed the mutant JAK2 status of myeloproliferative disease and both inhibited it through Hsp90 inhibition. In another study workers from Tokyo found that AUY when given with nilotinib could overcome the T315I mutant BCR-ABL that has so far produced a form of imatinib resistance in CML that could not otherwise be overcome. Panobinostat, meanwhile may act synergistically with bortezamib in mantle cell lymphoma (data from MCG Cancer Center, Augusta,H Lee Moffitt Cancer Center, Tampa, and Novartis Institute for Biomedical Research, Cambridge, MA. A phase II study of panobinostat in drug resistant myeloma is being carried out with some beneficial effects.
One of the other difficulties in Hsp90 inhibition is that it tends to upregulate Hsp72 which inhibits apoptosis. According to Emma Davenport and colleagues from the Insitute of Cancer Research, UK, this can be prevented by Hsp72 inhibitors such as KNK437 and triptolide.
John Byrd's group at Colombus, Ohio demonstrated that the Hsp90 inhibitor 17-DMAG represents a novel multi-targeted inhibitor of several critical kinases, transcription factors and anti-apoptosis genes relevant to CLL survival, and not just ZAP70, especially NF-kB. Given its oral formulation, which allows administration of 17-DMAG by continuous dosing and uninterrupted inhibition of Hsp90, initiation of phase II clinical trials in CLL that include detailed pharmacodynamic studies monitoring NF-kB target genes are indicated.
Jamie Cavenagh from Barts reported on a Phase I trial of KW-2478, a novel non-ansamycin, non-purine analogue antagonist for Hsp90. KW-2478 showed a potent anti-tumour activity both in vitro and in vivo in xenograft models, including activity in primary patient samples. The agent retained its activity in primary myeloma cells in the presence of BMSCs, suggesting that KW-2478 can overcome the protective effect of the bone marrow microenvironment. In the phase I trial there was no dose-limiting toxicity and the dose escalation continues.
From MDACC comes the small molecule WP1193, a caffeic acid derivative, which induced apoptosis in all types of drug-resistant CML cells. Treatment of the cells with WP1193 reduced levels of HSP90 transcripts, HSP90 protein and its client proteins, which include Bcr-Abl, Jak2 and Akt.
In conclusion, Hsp90 inhibition remains a promising treatment, not just for CLL, but for a range of different hematological tumors. Its effects are much more complicated that simply down-regulation of Zap-70, and care must be taken that a compensatory up-regulation of protective factors does not take place. The older geldanomycin derivatives may be too toxic for clinical use, but newer, perhaps less toxic inhibitors are in development.
Other Hsp90 inhibitors are in the pipeline. Novartis have two, a pan-Histone deacetylase inhibitor, panobinostat, and a specific Hsp90 inhibitor, AUY, were both tested by Wang et al from MCG Cancer Center, Augusta, Georgia, in a system that stressed the mutant JAK2 status of myeloproliferative disease and both inhibited it through Hsp90 inhibition. In another study workers from Tokyo found that AUY when given with nilotinib could overcome the T315I mutant BCR-ABL that has so far produced a form of imatinib resistance in CML that could not otherwise be overcome. Panobinostat, meanwhile may act synergistically with bortezamib in mantle cell lymphoma (data from MCG Cancer Center, Augusta,H Lee Moffitt Cancer Center, Tampa, and Novartis Institute for Biomedical Research, Cambridge, MA. A phase II study of panobinostat in drug resistant myeloma is being carried out with some beneficial effects.
One of the other difficulties in Hsp90 inhibition is that it tends to upregulate Hsp72 which inhibits apoptosis. According to Emma Davenport and colleagues from the Insitute of Cancer Research, UK, this can be prevented by Hsp72 inhibitors such as KNK437 and triptolide.
John Byrd's group at Colombus, Ohio demonstrated that the Hsp90 inhibitor 17-DMAG represents a novel multi-targeted inhibitor of several critical kinases, transcription factors and anti-apoptosis genes relevant to CLL survival, and not just ZAP70, especially NF-kB. Given its oral formulation, which allows administration of 17-DMAG by continuous dosing and uninterrupted inhibition of Hsp90, initiation of phase II clinical trials in CLL that include detailed pharmacodynamic studies monitoring NF-kB target genes are indicated.
Jamie Cavenagh from Barts reported on a Phase I trial of KW-2478, a novel non-ansamycin, non-purine analogue antagonist for Hsp90. KW-2478 showed a potent anti-tumour activity both in vitro and in vivo in xenograft models, including activity in primary patient samples. The agent retained its activity in primary myeloma cells in the presence of BMSCs, suggesting that KW-2478 can overcome the protective effect of the bone marrow microenvironment. In the phase I trial there was no dose-limiting toxicity and the dose escalation continues.
From MDACC comes the small molecule WP1193, a caffeic acid derivative, which induced apoptosis in all types of drug-resistant CML cells. Treatment of the cells with WP1193 reduced levels of HSP90 transcripts, HSP90 protein and its client proteins, which include Bcr-Abl, Jak2 and Akt.
In conclusion, Hsp90 inhibition remains a promising treatment, not just for CLL, but for a range of different hematological tumors. Its effects are much more complicated that simply down-regulation of Zap-70, and care must be taken that a compensatory up-regulation of protective factors does not take place. The older geldanomycin derivatives may be too toxic for clinical use, but newer, perhaps less toxic inhibitors are in development.
Sunday, December 28, 2008
The platelets - preservatives within the blood.
When I was first converted I used to give a talk about the blood based on the text "The blood of Jesus Christ cleanses is from all unrighteousness".
Considering the mess it makes when it is spilled it is hard to think of blood as a cleansing agent. But, of course, the white blood cells are just that. Without them we become infected with the foulest infections but they are there in the blood to seek out every bacterium wherever it is in the body. No nook or cranny exists but a white cell finds a way in and eats the germ.
That's not all blood does. Red cells carry life-giving oxygen. Watch an anemic patient who is given a blood transfusion. Where they were weak and listless, hardly able to raise themselves from their bed, they become invigorated, vibrant and energetic. "The life is in the blood" says the Bible and you can see what it means. The blood of Jesus Christ not only cleanses, it brings new life.
But apart from red cells and white cells there is a third type of cell that is not much spoken of - the platelet. What does a platelet do? It rushes to fill in holes so the blood doesn't seep out. And that is my topic today. What is it that prevents our faith from seeping away?
I Peter 1:4-5 talks about our inheritance that can never perish, spoil or fade - kept in heaven for us, who through faith are shielded by God's power until the salvation that is ready to be revealed at the last time.
The doctrine of the final perseverance of the saints (or preservation if you prefer) is the final 'P' in TULIP, one of the five points of Calvinism that many people abhor. The doctrine is logical; it seeks to give glory to God for everything. We are saved through God's intervention - we cannot save ourselves because we are Totally depraved - not that we are extremely horrible in every part, but that every part of us has been touched by the corruption of sin; even our wills so that we cannot choose for ourselves to believe God whose Unconditional election instead chooses us - He chooses us not because we have any merit, but because He loves us. Our salvation was achieved on the cross, but the atonement although available to all who would choose to be saved is Limited to the elect because only those who are chosen by God are able to choose Him. It is all of grace and none of works, but this grace is Irresistible - despite our sinful hearts we cannot resist Him, and since it is He who saves to the uttermost it is He who Preserves for eternal life would not be eternal if it had an end.
Nevertheless, TULIP does not carry universal approval, for some will say that it is a man-made concoction produced by selecting certain texts and ignoring contradicting ones, and in any case it does not concur with our experience, for it is clear that some do fall away.
So, there are some who doubt the final preservation of the saints, but there are some that distort it. It is not true that one conversion experience in a great tent somewhere sets you up for life. Alec Motyer tells of the time when he, as a curate in London, was given the task of following up those who had 'gone forward' at the Billy Graham Haringey Crusade. It was a soul destroying experience, he said, for every door he knocked at was either closed to him or greeted him with an embarrassed confession that yes, he had gone forward, but it was a thing of the moment. We all know of people who seemed wonderfully saved, but six weeks later were living their lives in exactly the same way they always had.
Jesus in the parable of the sower, tells is that are many kinds of soil on which the seed falls, and although it may spring up, if it has no roots it will wither and die. In Mark 13:13 it is he who stands firm to the end who will be saved. Salvation is not for those who 'make a decision' but for those who repent; those who think again; those who change their way of thinking, not just change their mind to have it changed back again next week.
We need to be a Gospel people, who always keep the cross before us. Some think the Gospel old hat; an old story that needs to be told to children, but when we are mature please explain to us exactly what Leviticus is about; help us to understand Ezekiel; reveal to us what Revelation means; dare to take us through the second half of Daniel. If we don't continue to keep the Gospel before us we will grow cold in our faith, not recognising the love of God.
Don't assume that the 'old man' within you is dead; he is only sleeping. We need to be a people of repentance. Backsliding follows for those who think they don't need to repent. "Give us this day our daily bread" is followed immediately by "Forgive us our trespasses". There is no such thing as sinless perfection this side of the grave.
Jesus' followers were called disciples because they were under discipline, and we, too, must discipline ourselves if we are to follow him. Prayer, bible reading, and the fellowship of other believers all preserve us - they are the means of grace employed by the Holy Spirit.
I know my faults only too well and perseverance isn't one of them. I am easily distracted. I have one of those wood pigeon minds that pecks a bit here, then there, then over the fence in someone else's garden. I would never eat my way through a whole field of wheat - I'd be too attracted by the barley across the way. I think I have four books on the go at the minute and I'm following about seven TV series. How could I be expected to persevere? Only in God's strength. Ephesians 6:10 tells us to be strong in the Lord and in His mighty power. That is the only way it is possible. You see, we are shielded by God's mighty power.
If it doesn't seem true - you've seen too many fall away - then consider whether they were truly saved, and if you think they were then consider whether they are just backsliding and one day will return. Martin Lloyd Jones tells of a man who seemed to have made a shipwreck of his faith and was so distressed that he was on his way to jump off London Bridge. As he passed by Westminster Chapel he remembered that he had promised himself that he would hear MLJ preach one time before he died. He went in, but was barred from the sanctuary because MLJ was praying. He heard his prayer - "We pray for those here who are backsliding". That day he was wonderfully restored to faith. If your friends or relatives seem to have fallen away then pray for them. Even if you do not see them restored in this life, even if they show no evidence of it, who are you to make that judgement? Thank God only God is required to judge one man from another. Shall not the judge of all the earth do right?
What about those texts that suggest that the saved may yet be lost? We must read every text in context but this is an eternal promise: "All that the Father gives me will come to me, and whoever comes to me I will never drive away. For I have come down from heaven not to do my will but to do the will of him who sent me. And this is the will of him who sent me, that I shall lose none of all that he has given me, but raise them up at the last day. For my Father's will is that everyone who looks to the Son and believes in him shall have eternal life, and I will raise him up at the last day."
It is because we have the shield of God's power that we are safe. When you put your hand in the hand of the one who holds the Universe in place, He won't let you go no matter how slippery you are.
Considering the mess it makes when it is spilled it is hard to think of blood as a cleansing agent. But, of course, the white blood cells are just that. Without them we become infected with the foulest infections but they are there in the blood to seek out every bacterium wherever it is in the body. No nook or cranny exists but a white cell finds a way in and eats the germ.
That's not all blood does. Red cells carry life-giving oxygen. Watch an anemic patient who is given a blood transfusion. Where they were weak and listless, hardly able to raise themselves from their bed, they become invigorated, vibrant and energetic. "The life is in the blood" says the Bible and you can see what it means. The blood of Jesus Christ not only cleanses, it brings new life.
But apart from red cells and white cells there is a third type of cell that is not much spoken of - the platelet. What does a platelet do? It rushes to fill in holes so the blood doesn't seep out. And that is my topic today. What is it that prevents our faith from seeping away?
I Peter 1:4-5 talks about our inheritance that can never perish, spoil or fade - kept in heaven for us, who through faith are shielded by God's power until the salvation that is ready to be revealed at the last time.
The doctrine of the final perseverance of the saints (or preservation if you prefer) is the final 'P' in TULIP, one of the five points of Calvinism that many people abhor. The doctrine is logical; it seeks to give glory to God for everything. We are saved through God's intervention - we cannot save ourselves because we are Totally depraved - not that we are extremely horrible in every part, but that every part of us has been touched by the corruption of sin; even our wills so that we cannot choose for ourselves to believe God whose Unconditional election instead chooses us - He chooses us not because we have any merit, but because He loves us. Our salvation was achieved on the cross, but the atonement although available to all who would choose to be saved is Limited to the elect because only those who are chosen by God are able to choose Him. It is all of grace and none of works, but this grace is Irresistible - despite our sinful hearts we cannot resist Him, and since it is He who saves to the uttermost it is He who Preserves for eternal life would not be eternal if it had an end.
Nevertheless, TULIP does not carry universal approval, for some will say that it is a man-made concoction produced by selecting certain texts and ignoring contradicting ones, and in any case it does not concur with our experience, for it is clear that some do fall away.
So, there are some who doubt the final preservation of the saints, but there are some that distort it. It is not true that one conversion experience in a great tent somewhere sets you up for life. Alec Motyer tells of the time when he, as a curate in London, was given the task of following up those who had 'gone forward' at the Billy Graham Haringey Crusade. It was a soul destroying experience, he said, for every door he knocked at was either closed to him or greeted him with an embarrassed confession that yes, he had gone forward, but it was a thing of the moment. We all know of people who seemed wonderfully saved, but six weeks later were living their lives in exactly the same way they always had.
Jesus in the parable of the sower, tells is that are many kinds of soil on which the seed falls, and although it may spring up, if it has no roots it will wither and die. In Mark 13:13 it is he who stands firm to the end who will be saved. Salvation is not for those who 'make a decision' but for those who repent; those who think again; those who change their way of thinking, not just change their mind to have it changed back again next week.
We need to be a Gospel people, who always keep the cross before us. Some think the Gospel old hat; an old story that needs to be told to children, but when we are mature please explain to us exactly what Leviticus is about; help us to understand Ezekiel; reveal to us what Revelation means; dare to take us through the second half of Daniel. If we don't continue to keep the Gospel before us we will grow cold in our faith, not recognising the love of God.
Don't assume that the 'old man' within you is dead; he is only sleeping. We need to be a people of repentance. Backsliding follows for those who think they don't need to repent. "Give us this day our daily bread" is followed immediately by "Forgive us our trespasses". There is no such thing as sinless perfection this side of the grave.
Jesus' followers were called disciples because they were under discipline, and we, too, must discipline ourselves if we are to follow him. Prayer, bible reading, and the fellowship of other believers all preserve us - they are the means of grace employed by the Holy Spirit.
I know my faults only too well and perseverance isn't one of them. I am easily distracted. I have one of those wood pigeon minds that pecks a bit here, then there, then over the fence in someone else's garden. I would never eat my way through a whole field of wheat - I'd be too attracted by the barley across the way. I think I have four books on the go at the minute and I'm following about seven TV series. How could I be expected to persevere? Only in God's strength. Ephesians 6:10 tells us to be strong in the Lord and in His mighty power. That is the only way it is possible. You see, we are shielded by God's mighty power.
If it doesn't seem true - you've seen too many fall away - then consider whether they were truly saved, and if you think they were then consider whether they are just backsliding and one day will return. Martin Lloyd Jones tells of a man who seemed to have made a shipwreck of his faith and was so distressed that he was on his way to jump off London Bridge. As he passed by Westminster Chapel he remembered that he had promised himself that he would hear MLJ preach one time before he died. He went in, but was barred from the sanctuary because MLJ was praying. He heard his prayer - "We pray for those here who are backsliding". That day he was wonderfully restored to faith. If your friends or relatives seem to have fallen away then pray for them. Even if you do not see them restored in this life, even if they show no evidence of it, who are you to make that judgement? Thank God only God is required to judge one man from another. Shall not the judge of all the earth do right?
What about those texts that suggest that the saved may yet be lost? We must read every text in context but this is an eternal promise: "All that the Father gives me will come to me, and whoever comes to me I will never drive away. For I have come down from heaven not to do my will but to do the will of him who sent me. And this is the will of him who sent me, that I shall lose none of all that he has given me, but raise them up at the last day. For my Father's will is that everyone who looks to the Son and believes in him shall have eternal life, and I will raise him up at the last day."
It is because we have the shield of God's power that we are safe. When you put your hand in the hand of the one who holds the Universe in place, He won't let you go no matter how slippery you are.
Thursday, December 25, 2008
Little Dorrit
Everyone knows that what the BBC does best is its period dramas. After last year’s phenomenally successful 'Bleak House' it has just broadcast a new version of 'Little Dorrit' broken up into half hourly episodes. There is an older version starring Alec Guinness which I found unwatchable, but this one is the real goods. It will be broadcast on PBS Masterpiece in the New Year - don't miss it!
The elderly Dorrit, Father of Marshalsea, is played by Tom Courtenay and his daughter Amy (Little Dorrit) by Claire Foy. Matthew Macfadyen plays Arthur Clennam wonderfully well, even if he is too young for the part. The grotesques are glorious. Judy Parfitt as Mrs Clennam, Alun Armstrong as Jeremiah Flintwinch, Sue Johnson as Affery, Amanda Redman as Mrs Merdle, Ruth Jones as Flora Finching, and especially Andy Serkis as Rigaud.
It is well known that Dickens’s own father was committed to a debtor’s prison and he is the model for the elderly Dorrit, just as he was for Mr Micawber in David Copperfield. Despite his fame as a popular novelist and his ability to construct memorable characters, Dickens was principally a satirist and his target in this novel was mainly the debtor’s prison – long since disappeared. Do not think that the satire ends there, there are secondary targets. Government bureaucracy in the form of the Circumlocution Office is wonderfully portrayed. You need to stand in a line waiting to receive a form that you must fill in to ask permission to fill in a second form requesting permission to make a request of the office. It is run by Tite Barnacle (brilliantly portrayed by 82-year old Robert Hardy) and his family, whose aim in life is to do nothing and whose time is spent discussing matters of no consequence so as to avoid doing any work – and all for a fat salary and gold plated pension. Twenty years ago ‘Yes Minister’ demonstrated that the Civil Service had not changed and news items this week see it similarly set in stone. Civil Servants are looking for ways to prevent having to put into action a ministerial decree that criminals doing ‘community service’ should wear fluorescent jackets identifying them as such.
Even more relevant was the avaricious affluent society as a target. Mr Merdle, the ‘man of the moment’ into whose bank all Society wished to invest could well have been Bernie Madoff – he was running a similar ‘Ponzi scheme’. Mrs Merdle is referred to in the novel as ‘the bosom’ on which Mr Merdle displayed his jewels. Amanda Redman plays ‘the bosom’ very well indeed. The bankruptcy of Mr Merdle may be seen as just a plot device to bring a reversal of fortune to Arthur Clennam, but Dickens makes it a comment on both his and our society. Here’s what he wrote, “Numbers of men in every profession and trade would be blighted by his insolvency; old people who had been in easy circumstances all their lives would have no place for their repentance for their trust in him but the workhouse; legions of women and children would have their whole future desolated by this mighty scoundrel.”
As we see the fallout of the Madoff swindle we see how perceptive was Dickens. Already one naïve investor has killed himself. In the book it is Merdle himself who commits suicide (typically with a borrowed penknife in a hot bath). But the Dickensian description elevates this tawdry act to something more: "a new constellation to be followed by the wise men bringing gifts until it stopped over a certain carrion at the bottom of a bath and disappeared".
These greedy men who make the acquisition of money their end are the Antichrist, he says.
The elderly Dorrit, Father of Marshalsea, is played by Tom Courtenay and his daughter Amy (Little Dorrit) by Claire Foy. Matthew Macfadyen plays Arthur Clennam wonderfully well, even if he is too young for the part. The grotesques are glorious. Judy Parfitt as Mrs Clennam, Alun Armstrong as Jeremiah Flintwinch, Sue Johnson as Affery, Amanda Redman as Mrs Merdle, Ruth Jones as Flora Finching, and especially Andy Serkis as Rigaud.
It is well known that Dickens’s own father was committed to a debtor’s prison and he is the model for the elderly Dorrit, just as he was for Mr Micawber in David Copperfield. Despite his fame as a popular novelist and his ability to construct memorable characters, Dickens was principally a satirist and his target in this novel was mainly the debtor’s prison – long since disappeared. Do not think that the satire ends there, there are secondary targets. Government bureaucracy in the form of the Circumlocution Office is wonderfully portrayed. You need to stand in a line waiting to receive a form that you must fill in to ask permission to fill in a second form requesting permission to make a request of the office. It is run by Tite Barnacle (brilliantly portrayed by 82-year old Robert Hardy) and his family, whose aim in life is to do nothing and whose time is spent discussing matters of no consequence so as to avoid doing any work – and all for a fat salary and gold plated pension. Twenty years ago ‘Yes Minister’ demonstrated that the Civil Service had not changed and news items this week see it similarly set in stone. Civil Servants are looking for ways to prevent having to put into action a ministerial decree that criminals doing ‘community service’ should wear fluorescent jackets identifying them as such.
Even more relevant was the avaricious affluent society as a target. Mr Merdle, the ‘man of the moment’ into whose bank all Society wished to invest could well have been Bernie Madoff – he was running a similar ‘Ponzi scheme’. Mrs Merdle is referred to in the novel as ‘the bosom’ on which Mr Merdle displayed his jewels. Amanda Redman plays ‘the bosom’ very well indeed. The bankruptcy of Mr Merdle may be seen as just a plot device to bring a reversal of fortune to Arthur Clennam, but Dickens makes it a comment on both his and our society. Here’s what he wrote, “Numbers of men in every profession and trade would be blighted by his insolvency; old people who had been in easy circumstances all their lives would have no place for their repentance for their trust in him but the workhouse; legions of women and children would have their whole future desolated by this mighty scoundrel.”
As we see the fallout of the Madoff swindle we see how perceptive was Dickens. Already one naïve investor has killed himself. In the book it is Merdle himself who commits suicide (typically with a borrowed penknife in a hot bath). But the Dickensian description elevates this tawdry act to something more: "a new constellation to be followed by the wise men bringing gifts until it stopped over a certain carrion at the bottom of a bath and disappeared".
These greedy men who make the acquisition of money their end are the Antichrist, he says.
Sunday, December 21, 2008
ASH 1 - The German CLL8 trial
For CLL patients and doctors alike, the main event at ASH was the German CLL8 trial comparing FC with FCR. We already knew from the Roche website that the trial had shown that FCR was sufficiently better than FC for the trial to be stopped after the first interim analysis, but this was our first opportunity to examine the details.
817 patients from several countries were randomized between FC and FCR in standard dosages. The patients were younger than most with a median age of 61 (though some patients were as old as 80) and they were fit with good kidney function. 61% were Binet stage B and 32% stage C, so it is unlikely that this trial took the easy way out by treating patients that didn't really need treating. The overall incidences of trisomy 12 and abnormalities of 13q, 11q23, and 17p13 detected by FISH were 12%, 57%, 25%, and 8%, respectively, with no statistically significant differences between treatment arms. On average patients managed to get 5 of the recommended 6 courses in.
Analysis was in June 2008, with a median of just over 2 years follow-up. Overall response rate was significantly higher for the FCR arm (95% v 88%; p=0.001). The CR rate (1996 NCI criteria) was significantly higher for the FCR arm (52% v 27%; p<0.0001). Progression-free survival was was 76.6% at 2 years in the FCR arm and 62.3% in the FC arm (p<0.0001). But the difference for overall survival was not significant (91% v 88% at 2 years).
Adding the rituximab resulted in more toxicity. Grade 3 and 4 events occurred in 62% v 47% and severe hematologic toxicity in 55% v 39% (the significant difference was for neutropenia), but there was no significant difference in the incidence of serious infections (18.8% v 14.8%) nor of treatment related mortality (2% v 1.5%).
Minimal residual disease (MRD) was assessed in this trial in both blood and bone marrow by 4-color flow - capable of detecting one residual cell among 10,000 tested (for comparison a CR just means that there are fewer than 30% lymphocytes in the bone marrow). Assessment was after 3 courses of treatment, again one month after finishing treatment and again three months after treatment. Whether tested on blood or bone marrow and at whatever time tested there was significantly less residual disease in the FCR arm than in the FC arm. For example, fewer than one in 10,000 cells were detected in 33.6% vs. 6.4% at the first assessment of blood MRD, 67.6% vs. 36.6% at the second and 66.4% vs. 34.2% at the final assessment (for all comparisons FCR is first and p < 0.0001). The results from the marrow showed slightly less clearance of MRD (eg 47.6% v 66.4% for the final assessment of the FCR arm).
Progression-free survival (PFS) was greater if lower levels of MRD were achieved. Although this was more likely when rituximab was included, if it could be achieved it didn't matter which arm of the trial was involved. If FC can give fewer than 1 cell in 10,000 at the final assessment, progression-free survival will be no longer if rituximab is added.
Incidentally, this trial compared two methods of detecting MRD, the 4 color flow method described above and an RQ-PCR method. The results were virtually identical where more than 1 in 10,000 cells were detectable, but below that level RQ-PCR was more sensitive.
Any residual cells present up to 180 days after the last rituximab infusion lacked CD20 - evidence that persisting antibody continued to modulate the antigen.
The trial also looked at the role of prognostic markers in this trial. The incidences of the most common genomic aberrations were 13q- 56.7%, 13q- single 36.4%, 11q- 24.6%, +12 12.0%, and 17p- 8.2%. IGHV was unmutated in 63.4% and V3-21 was rearranged in 4.9%. AS expected, particularly poor outcomes were observed for 17p- in both arms (FC and FCR): CR (4.5% and 19.0%), CR+PR (45.5% and 71.4%), PFS (at 24 months: 0.0% and 29.6%), and OS (at 24 months: 41.0% and 53.3%). However, even these poor results do not suggest that rituximab is completely inactive in p53 deleted disease. Unmutated IGHV gene status was associated with shorter PFS in both arms combined and individually (all p<.001), shorter overall survival in the FC arm (p=.006), and probably in the FCR arm though follow-up is not long enough for this to be statistically significant (p=.092).
Multivariate analysis was applied to the trial. Regarding PFS, independent prognostic factors were 17p- (Hazard Ratio (HR) 6.76, p<.001), unmutated IGHV(HR 1.97, p<.001), FCR (HR 0.51, p<.001) and +12 (HR 0.58, p=.020). Regarding overall survival, only 17p- (HR 7.47, p<.001) and unmutated IGHV (HR 2.09, p=.018) were identified as significant independent factors, though FCR might be with longer follow-up (HR 0.66, p=.085).
In conclusion, genetic parameters remain powerful prognostic markers after 1st line FC and FCR treatment. The overall improvements by FCR result from specific treatment effects in distinct genetic subgroups. It seems particularly important that patients with 11q- appears to benefit most from the addition of rituximab. However, 17p- and unmutated IGHV status remain predictors for shorter PFS and OS independently of the overall improvement by FCR.
817 patients from several countries were randomized between FC and FCR in standard dosages. The patients were younger than most with a median age of 61 (though some patients were as old as 80) and they were fit with good kidney function. 61% were Binet stage B and 32% stage C, so it is unlikely that this trial took the easy way out by treating patients that didn't really need treating. The overall incidences of trisomy 12 and abnormalities of 13q, 11q23, and 17p13 detected by FISH were 12%, 57%, 25%, and 8%, respectively, with no statistically significant differences between treatment arms. On average patients managed to get 5 of the recommended 6 courses in.
Analysis was in June 2008, with a median of just over 2 years follow-up. Overall response rate was significantly higher for the FCR arm (95% v 88%; p=0.001). The CR rate (1996 NCI criteria) was significantly higher for the FCR arm (52% v 27%; p<0.0001). Progression-free survival was was 76.6% at 2 years in the FCR arm and 62.3% in the FC arm (p<0.0001). But the difference for overall survival was not significant (91% v 88% at 2 years).
Adding the rituximab resulted in more toxicity. Grade 3 and 4 events occurred in 62% v 47% and severe hematologic toxicity in 55% v 39% (the significant difference was for neutropenia), but there was no significant difference in the incidence of serious infections (18.8% v 14.8%) nor of treatment related mortality (2% v 1.5%).
Minimal residual disease (MRD) was assessed in this trial in both blood and bone marrow by 4-color flow - capable of detecting one residual cell among 10,000 tested (for comparison a CR just means that there are fewer than 30% lymphocytes in the bone marrow). Assessment was after 3 courses of treatment, again one month after finishing treatment and again three months after treatment. Whether tested on blood or bone marrow and at whatever time tested there was significantly less residual disease in the FCR arm than in the FC arm. For example, fewer than one in 10,000 cells were detected in 33.6% vs. 6.4% at the first assessment of blood MRD, 67.6% vs. 36.6% at the second and 66.4% vs. 34.2% at the final assessment (for all comparisons FCR is first and p < 0.0001). The results from the marrow showed slightly less clearance of MRD (eg 47.6% v 66.4% for the final assessment of the FCR arm).
Progression-free survival (PFS) was greater if lower levels of MRD were achieved. Although this was more likely when rituximab was included, if it could be achieved it didn't matter which arm of the trial was involved. If FC can give fewer than 1 cell in 10,000 at the final assessment, progression-free survival will be no longer if rituximab is added.
Incidentally, this trial compared two methods of detecting MRD, the 4 color flow method described above and an RQ-PCR method. The results were virtually identical where more than 1 in 10,000 cells were detectable, but below that level RQ-PCR was more sensitive.
Any residual cells present up to 180 days after the last rituximab infusion lacked CD20 - evidence that persisting antibody continued to modulate the antigen.
The trial also looked at the role of prognostic markers in this trial. The incidences of the most common genomic aberrations were 13q- 56.7%, 13q- single 36.4%, 11q- 24.6%, +12 12.0%, and 17p- 8.2%. IGHV was unmutated in 63.4% and V3-21 was rearranged in 4.9%. AS expected, particularly poor outcomes were observed for 17p- in both arms (FC and FCR): CR (4.5% and 19.0%), CR+PR (45.5% and 71.4%), PFS (at 24 months: 0.0% and 29.6%), and OS (at 24 months: 41.0% and 53.3%). However, even these poor results do not suggest that rituximab is completely inactive in p53 deleted disease. Unmutated IGHV gene status was associated with shorter PFS in both arms combined and individually (all p<.001), shorter overall survival in the FC arm (p=.006), and probably in the FCR arm though follow-up is not long enough for this to be statistically significant (p=.092).
Multivariate analysis was applied to the trial. Regarding PFS, independent prognostic factors were 17p- (Hazard Ratio (HR) 6.76, p<.001), unmutated IGHV(HR 1.97, p<.001), FCR (HR 0.51, p<.001) and +12 (HR 0.58, p=.020). Regarding overall survival, only 17p- (HR 7.47, p<.001) and unmutated IGHV (HR 2.09, p=.018) were identified as significant independent factors, though FCR might be with longer follow-up (HR 0.66, p=.085).
In conclusion, genetic parameters remain powerful prognostic markers after 1st line FC and FCR treatment. The overall improvements by FCR result from specific treatment effects in distinct genetic subgroups. It seems particularly important that patients with 11q- appears to benefit most from the addition of rituximab. However, 17p- and unmutated IGHV status remain predictors for shorter PFS and OS independently of the overall improvement by FCR.
No blogging
I have not been blogging much recently. I had the beginnings of a virus in San Francisco and this developed into a heavy cold - what most people have been calling 'flu, but certainly isn't. I have had 'flu three times in my life and it is a much worse illness than this. A severe headache, a high fever, pains in the joints, shivering attacks and a complete listlessness; it is completely impossible to get out of bed. This has been characterized by tiredness, joint pains, sneezing, a sore throat and more recently a stuffy nose and a tickly cough. However, I have certainly not felt like working and have spent my time doing SUDOKU puzzles and watching old episodes of Poirot.
What I am beginning to do is to write my impressions of ASH which I will next blog about.
What I am beginning to do is to write my impressions of ASH which I will next blog about.
Wednesday, December 17, 2008
Judgement at Nuremberg
I was 18 when Judgement at Nuremberg was released, but I first watched it a couple of nights ago. It is a serious film about the second world war. For my generation this was the greatest event in our lives. It casts its shadow over the whole of the twentieth century. Just think of what it signified: the wholesale slaughter of six million Jews, the dawn of the nuclear age, aerial bombing on a vast scale, the subjection of millions to communism, the emergence of America as the greatest power the world has ever seen, the jet engine, rockets, penicillin, the emergence of democracy in Japan, the end of the British and French Empires, the discrediting of Eugenics.
The film is a major production that was nominated for 12 Oscars and awarded two. It starred Spencer Tracy, Burt Lancaster, Richard Widmark, Marlene Dietrich, Maximillian Schell, Montgomery Clift, Judy Garland and even a very young William Shattner. It explores the question of human responsibility. It is a very Calvinist film.
Briefly, a retired circuit judge (Tracy) from Maine is called on to chair a tribunal examining the responsibility of German Judges for the implementation of Nazi laws that required the sterilization and later the extermination of Jews, the mentally handicapped and other 'socially undesirables'. Burt Lancaster plays the chief defendant, a senior and respected German jurist who helped frame the Wiemar Constitution and had written many books on jurisprudence. His role has very few lines apart from one central and long speech accepting culpability. Richard Widmark is the prosecuting counsel, and American army colonel who led the group that first entered Dachau. He is wild eyed and determined for revenge. He likes to show the film of what was discovered at Dachau and by British troops at Belsen at every trial. Maximillian Schell plays a German advocate who is defending counsel. Darkly handsome with a winning smile, he was a wise choice for the Oscar that year. He seeks to exculpate the judges by declaring that they were simply being patriotic; upholding the laws of their country. They had no responsibility for framing the laws, but had to do their duty in enforcing them. His shock of black hair means that he has some resemblance to Adolf Hitler, and he adopts some of Hitler's verbal tricks, so that as you feels yourself warming to him you also begin to realise how so many Germans fell for Hitler.
In order to justify the judges actions he is forced to re-examine two old cases. The first concerns the forced sterilisation of a common laborer for familial mental retardation. Montgomery Clift plays the part of the victim. Although he conveys the anguish of his situation, he is unbelievable as a half-wit. As a result we see it as an injustice as an ordinary working man is sterilised, but had he appeared less intelligent would he not have got the audience asking - well, perhaps he should be sterilized? For Schell demonstrates that the idea of Eugenics was not a German one. He could well have quoted from Francis Galton, but in fact goes to Oliver Wendall Holmes and the Virginian Constitutional amendments. I still hear people bemoaning the fact that the intelligentsia have too few babies and the less clever working class too many.
The second case involved a young Aryan girl who had supposedly been seduced by an old Jew, who had been executed for his crime. The girl was played by Judy Garland in a performance that finally unstrung her from the rainbow. Schell harries her to admit that she really was the old Jews mistress, but she continues to deny it - he was an old family friend. Strictly speaking Garland is too old for the role, but it is still a great performance and it is her anguish that prompts the Burt Lancaster character to make a statement that admits his guilt.
The film is set in 1948, the year that Czechoslovakia was taken over by the communists and the year of the Berlin airlift. The Americans were under pressure to establish West Germany as a friendly power and a bulwark against communism. Pressure is put on the old judge to be nice to the Germans - as a senior officer puts it the call of patriotism is more important than legal niceties. But this is exactly what the trial is about, what the film is about and why it is so relevant for today.
Some sections of society ask our judges to be merciful. That is wrong. Our judges must first and foremost be just. Convicting the guilty is as important as clearing the innocent. In the IG Farber case, running at the same time, the defendants were sometimes acquitted but even is convicted received token sentences.
The judge convicts the judges and hands out life sentences. Sentencing is part of the verdict. A token sentence says you are guilty but not very. There is a place for mercy, but that is in the hands of the Sovereign. Only he or she can dispense it.
Schell seeks to lessen the crime of the judges by saying we are all guilty. The Vatican in signing the Concordat in 1933, the Russians in signing the non-aggression pact, the American industrialists who traded with Germany, those who stood by as Germany invaded the Saar, Austria and the Sudetenland, and even Winston Churchill who wrote to the Times saying that in order to resist the German aggression, Britain needed a leader with the determination and leadership qualities of an Adolf Hitler.
As the Spencer Tracy character seeks to understand the German people he talks to servants and aristocrats, all of whom knew nothing of what was happening in the 'camps'. He doesn't believe a word of it. He accepts that there is a measure of guilt everywhere, but that doesn't lessen the guilt of the judges.
In a final confrontation with the Burt Lancaster character, the convicted judge pleads that he did not realise how it would end up, with so many millions dying. Tracy replies that it ended up like this the moment you sent an innocent man for execution.
Calvinist? Because it insists that everyone is guilty, and each is responsible for his own guilt. The pass mark is not lowered just because the standard is so low.
The film is a major production that was nominated for 12 Oscars and awarded two. It starred Spencer Tracy, Burt Lancaster, Richard Widmark, Marlene Dietrich, Maximillian Schell, Montgomery Clift, Judy Garland and even a very young William Shattner. It explores the question of human responsibility. It is a very Calvinist film.
Briefly, a retired circuit judge (Tracy) from Maine is called on to chair a tribunal examining the responsibility of German Judges for the implementation of Nazi laws that required the sterilization and later the extermination of Jews, the mentally handicapped and other 'socially undesirables'. Burt Lancaster plays the chief defendant, a senior and respected German jurist who helped frame the Wiemar Constitution and had written many books on jurisprudence. His role has very few lines apart from one central and long speech accepting culpability. Richard Widmark is the prosecuting counsel, and American army colonel who led the group that first entered Dachau. He is wild eyed and determined for revenge. He likes to show the film of what was discovered at Dachau and by British troops at Belsen at every trial. Maximillian Schell plays a German advocate who is defending counsel. Darkly handsome with a winning smile, he was a wise choice for the Oscar that year. He seeks to exculpate the judges by declaring that they were simply being patriotic; upholding the laws of their country. They had no responsibility for framing the laws, but had to do their duty in enforcing them. His shock of black hair means that he has some resemblance to Adolf Hitler, and he adopts some of Hitler's verbal tricks, so that as you feels yourself warming to him you also begin to realise how so many Germans fell for Hitler.
In order to justify the judges actions he is forced to re-examine two old cases. The first concerns the forced sterilisation of a common laborer for familial mental retardation. Montgomery Clift plays the part of the victim. Although he conveys the anguish of his situation, he is unbelievable as a half-wit. As a result we see it as an injustice as an ordinary working man is sterilised, but had he appeared less intelligent would he not have got the audience asking - well, perhaps he should be sterilized? For Schell demonstrates that the idea of Eugenics was not a German one. He could well have quoted from Francis Galton, but in fact goes to Oliver Wendall Holmes and the Virginian Constitutional amendments. I still hear people bemoaning the fact that the intelligentsia have too few babies and the less clever working class too many.
The second case involved a young Aryan girl who had supposedly been seduced by an old Jew, who had been executed for his crime. The girl was played by Judy Garland in a performance that finally unstrung her from the rainbow. Schell harries her to admit that she really was the old Jews mistress, but she continues to deny it - he was an old family friend. Strictly speaking Garland is too old for the role, but it is still a great performance and it is her anguish that prompts the Burt Lancaster character to make a statement that admits his guilt.
The film is set in 1948, the year that Czechoslovakia was taken over by the communists and the year of the Berlin airlift. The Americans were under pressure to establish West Germany as a friendly power and a bulwark against communism. Pressure is put on the old judge to be nice to the Germans - as a senior officer puts it the call of patriotism is more important than legal niceties. But this is exactly what the trial is about, what the film is about and why it is so relevant for today.
Some sections of society ask our judges to be merciful. That is wrong. Our judges must first and foremost be just. Convicting the guilty is as important as clearing the innocent. In the IG Farber case, running at the same time, the defendants were sometimes acquitted but even is convicted received token sentences.
The judge convicts the judges and hands out life sentences. Sentencing is part of the verdict. A token sentence says you are guilty but not very. There is a place for mercy, but that is in the hands of the Sovereign. Only he or she can dispense it.
Schell seeks to lessen the crime of the judges by saying we are all guilty. The Vatican in signing the Concordat in 1933, the Russians in signing the non-aggression pact, the American industrialists who traded with Germany, those who stood by as Germany invaded the Saar, Austria and the Sudetenland, and even Winston Churchill who wrote to the Times saying that in order to resist the German aggression, Britain needed a leader with the determination and leadership qualities of an Adolf Hitler.
As the Spencer Tracy character seeks to understand the German people he talks to servants and aristocrats, all of whom knew nothing of what was happening in the 'camps'. He doesn't believe a word of it. He accepts that there is a measure of guilt everywhere, but that doesn't lessen the guilt of the judges.
In a final confrontation with the Burt Lancaster character, the convicted judge pleads that he did not realise how it would end up, with so many millions dying. Tracy replies that it ended up like this the moment you sent an innocent man for execution.
Calvinist? Because it insists that everyone is guilty, and each is responsible for his own guilt. The pass mark is not lowered just because the standard is so low.
Sunday, December 14, 2008
A certain hope. I Peter chapter 1
On our return from San Francisco we found a flood. A water tank in the loft had overflowed. My daughter's bedroom ceiling was saturated, her carpet ruined, the underlay soaked and the floorboards wet. Perhaps worst was the fact that all her references for her PhD were turned to papier mache. Fortunately, we had taken out house and contents insurance a couple of weeks ago and the response from the insurers was great. (Take a bow, Swintons) The leak was repaired within an hour and next Wednesday a drying out company is coming. The carpet had to come up anyway for the electrician after Christmas. Most of the references have been retrievable from the internet, and the others should be obtainable for a couple of hundred dollars.
Then the washing machine broke. With a week's dirty washing this was very trying. I found a company I had never heard of in the Yellow Pages and a couple of hours later a technician called and replaced the brushes on our 5-year old Bosch and now it works well.
In I Peter 1:6-7 it says: In this you greatly rejoice, though now for a little while you may have had to suffer grief in all kinds of trials. These have come so that your faith—of greater worth than gold, which perishes even though refined by fire—may be proved genuine and may result in praise, glory and honor when Jesus Christ is revealed.
My first reaction was to say that many people have it worse than we had it. Christians throughout the world are suffering imprisonment, persecution, torture and beatings for their faith. Others have lost their homes jobs and livelihood. Some are orphaned, bereaved and killed. But that is not enough. It is little comfort for those who are suffering to say that there are some who have it worse. There may come a time when there is no-one worse off. No far better to realise that we have a living hope (verse 3). Whatever happens to us now, better things are coming.
As I look at the cricket score in India I might well say that I hope England win. India are being asked to score an unlikely total on the final day of the Test match and the odds are that England will attain a fine victory. But it by no means certain. Indian batsmen might score well and quickly; in Sachin Tendulka they have probably the finest batsmen in the world. Rain may intervene and force a draw or England's bowling might be innocuous and by blocking and defending India might hang on for a draw. The 'hope' referred to by Peter is not like that. It is more like the opposite of hopelessness. I could never expect to win an Olympic medal at clay pigeon shooting, however much I might hope to do so. I'm hopeless at that sort of thing. But if I open my front door after church and smell the meat in the oven, I not only hope for a fine dinner, I expect it. It is a certain hope.
Our certain hope does not depend on us but on the resurrection of the Lord Jesus (v3). If it depended on me I could well make a mess of it. I've been known to miss open goals in the past. But our salvation depends on Christ. He has already paid the price of our sins and in raising him from the dead, God has signaled that the sacrifice is sufficient. It is an inheritance that cannot perish, spoil or fade. Treasures that we lay up on earth perish. Have you ever disinterred an old dress or tie or suit that has been handing in the loft and found moth holes in it? The stitching has frayed or the colors have faded. Even metal objects will have tarnished. When I was young the pound was worth 2.84 dollars, now it is barely half that, and the dollar itself is pretty worthless. We talked about going into the Euro zone at 2 Euros to the pound, now it is close to parity. We invested in our house. Safe as houses, goes the saying. Our house has become a money pit. There is one inheritance that never fades, perishes or spoils; the salvation of our souls (v9).
This inheritance is kept in heaven for us (v4). It is not heaven itself. The Bible promises a new heaven and a new earth (Revelation Ch 21). Then, there will be no more death or mourning or crying or pain. Then, he will wipe every tear from our eyes. But if we die before the Lord returns we have a resting place with him in heaven (as he said to the dying thief - this day you will be with me in paradise) and when he returns those who die in Christ will rise first with new incorruptible bodies.
For Christ is our inheritance: to be with him, to hear him and see him and touch him. For all the beauty of San Francisco bay, it was worth much more to be able to share it with my wife. However beautiful heaven might be it would not be heaven without Jesus. It is to be with him that makes it heaven. A new heaven and earth that was just like the old one with the slate wiped clean would soon become corrupted again. The new heaven and earth will lack something that characterizes this one - sin.
There is a hope that stands the test of time,
That lifts my eye beyond the beckoning grave,
To see the matchless beauty of a day divine
When I behold his face!
When sufferings cease and sorrows die,
And every longing satisfied.
Then joy unspeakable will flood my soul,
For I am truly home.
Stuart Townend and Mark Edwards.
Then the washing machine broke. With a week's dirty washing this was very trying. I found a company I had never heard of in the Yellow Pages and a couple of hours later a technician called and replaced the brushes on our 5-year old Bosch and now it works well.
In I Peter 1:6-7 it says: In this you greatly rejoice, though now for a little while you may have had to suffer grief in all kinds of trials. These have come so that your faith—of greater worth than gold, which perishes even though refined by fire—may be proved genuine and may result in praise, glory and honor when Jesus Christ is revealed.
My first reaction was to say that many people have it worse than we had it. Christians throughout the world are suffering imprisonment, persecution, torture and beatings for their faith. Others have lost their homes jobs and livelihood. Some are orphaned, bereaved and killed. But that is not enough. It is little comfort for those who are suffering to say that there are some who have it worse. There may come a time when there is no-one worse off. No far better to realise that we have a living hope (verse 3). Whatever happens to us now, better things are coming.
As I look at the cricket score in India I might well say that I hope England win. India are being asked to score an unlikely total on the final day of the Test match and the odds are that England will attain a fine victory. But it by no means certain. Indian batsmen might score well and quickly; in Sachin Tendulka they have probably the finest batsmen in the world. Rain may intervene and force a draw or England's bowling might be innocuous and by blocking and defending India might hang on for a draw. The 'hope' referred to by Peter is not like that. It is more like the opposite of hopelessness. I could never expect to win an Olympic medal at clay pigeon shooting, however much I might hope to do so. I'm hopeless at that sort of thing. But if I open my front door after church and smell the meat in the oven, I not only hope for a fine dinner, I expect it. It is a certain hope.
Our certain hope does not depend on us but on the resurrection of the Lord Jesus (v3). If it depended on me I could well make a mess of it. I've been known to miss open goals in the past. But our salvation depends on Christ. He has already paid the price of our sins and in raising him from the dead, God has signaled that the sacrifice is sufficient. It is an inheritance that cannot perish, spoil or fade. Treasures that we lay up on earth perish. Have you ever disinterred an old dress or tie or suit that has been handing in the loft and found moth holes in it? The stitching has frayed or the colors have faded. Even metal objects will have tarnished. When I was young the pound was worth 2.84 dollars, now it is barely half that, and the dollar itself is pretty worthless. We talked about going into the Euro zone at 2 Euros to the pound, now it is close to parity. We invested in our house. Safe as houses, goes the saying. Our house has become a money pit. There is one inheritance that never fades, perishes or spoils; the salvation of our souls (v9).
This inheritance is kept in heaven for us (v4). It is not heaven itself. The Bible promises a new heaven and a new earth (Revelation Ch 21). Then, there will be no more death or mourning or crying or pain. Then, he will wipe every tear from our eyes. But if we die before the Lord returns we have a resting place with him in heaven (as he said to the dying thief - this day you will be with me in paradise) and when he returns those who die in Christ will rise first with new incorruptible bodies.
For Christ is our inheritance: to be with him, to hear him and see him and touch him. For all the beauty of San Francisco bay, it was worth much more to be able to share it with my wife. However beautiful heaven might be it would not be heaven without Jesus. It is to be with him that makes it heaven. A new heaven and earth that was just like the old one with the slate wiped clean would soon become corrupted again. The new heaven and earth will lack something that characterizes this one - sin.
There is a hope that stands the test of time,
That lifts my eye beyond the beckoning grave,
To see the matchless beauty of a day divine
When I behold his face!
When sufferings cease and sorrows die,
And every longing satisfied.
Then joy unspeakable will flood my soul,
For I am truly home.
Stuart Townend and Mark Edwards.
Rona Locke, RIP.
When I first began attending Lansdowne Baptist Church Trevor and Rona Locke were legends. As pioneer missionaries in India they were supported by the church. We sent them about £5000 a year. With that they supported themselves, their young son Justin, and about six other workers. They were translators. Trevor used to visit tribal peoples committing their languages to tape. Rona, the librarian, kept countless records on file cards (no computers in those days) and together they would transliterate the spoken languages and provide a written form so that reading primers and the Scripture could be provided for these native peoples. Together they were in much demand, not just as missionary speakers, but as the greatest experts in indigenous Indian languages.
Their son was a fine young boy. I remember the church bought him a bicycle when he was 13. He had already had a bike, but seeing a local pastor without one, he had given him his. He grew into a fine young man who married and had two children. A few years ago he lost his life while trying to rescue a drowning friend.
When Trevor and Rona returned from the mission field they could not afford to live in Bournemouth, but settled in Sheffield where house prices are cheaper. Here they began an outreach to Moslems. Trevor suffered a heart attack in Sheffield and following that they returned to their sending church here in Bournemouth.
In their latter years they remained active in the church and Trevor continued to visit the local mosque where his gentle and winning manner was accepted as he tried to win Moslems for Christ. Recently, Rona has suffered a series of strokes, which left her frustrated and she began to find it difficult to communicate. She died this morning. Even now she will be welcomed in heaven. Well done, good and faithful servant!
Their son was a fine young boy. I remember the church bought him a bicycle when he was 13. He had already had a bike, but seeing a local pastor without one, he had given him his. He grew into a fine young man who married and had two children. A few years ago he lost his life while trying to rescue a drowning friend.
When Trevor and Rona returned from the mission field they could not afford to live in Bournemouth, but settled in Sheffield where house prices are cheaper. Here they began an outreach to Moslems. Trevor suffered a heart attack in Sheffield and following that they returned to their sending church here in Bournemouth.
In their latter years they remained active in the church and Trevor continued to visit the local mosque where his gentle and winning manner was accepted as he tried to win Moslems for Christ. Recently, Rona has suffered a series of strokes, which left her frustrated and she began to find it difficult to communicate. She died this morning. Even now she will be welcomed in heaven. Well done, good and faithful servant!
Saturday, December 13, 2008
The Ashes of San Francisco.
Back from San Fransisco. This was my second visit, but I can't remember much about the last one except walking on the boardwalk at Pier 39 is warm sunny weather. This time we spent a week there and had more time to explore.
We stayed at Fisherman's Wharf which in winter is a quiet spot lacking the bustle of the Downtown area. The Shearaton was a perfectly acceptable hotel, though it lacks a proper restaurant. The skyscraper hotels in Downtown may have been plusher, but I disliked the crowds and shopping is not one of my pleasures. The weather was mostly fine, though we had one day of rain and overcast skies. Otherwise it was sunny with temperatures in the sixties. Early morning faogs were not really a problem for us.
The main attraction in SF is Alcatraz, which all visitors must see.Set just over a mile from the shore it was first a fort, then a military prison then a Federal one. Famous inmates included Al Capone, 'Machine-gun' Kelly and Robert 'Birdman' Stroud. Trick question: How many birds did Robert Stroud have at Alcatraz? Answer: None; he had them at Leavenworth. He used the birdseed to make alcohol and was refused birds when he did 'bird' on the island.
The cells were very small and 'D' wing where the prisoners were kept in darkness was particularly oppressive, though the cells were larger there. Did Frank Morris and his two colleagues really make good their escape as the Clint Eastwood film suggests? No-one knows, but their bodies were never found.
Muir woods, over the other side of the Golden Gate bridge is a forest of giant redwoods approached by a scary mountain road. The redwoods came in useful for construction during the gold rush, but were very flammable in 1906 when the earthquake set the city alight. With water supplies disrupted by the quake, the only way to control the fire was with a fire break. All the wooden buildings downtown of Van Ness Avenue were demolished. Jack London, the author of 'Call of the Wild'. sought to make money be replanting the forests felled for timber and bought in quick-growing eucalyptus trees from Australia. Unfortunately these are useless as lumber and he lost his money. Nevertheless their progeny abound in the woods and glades around San Francisco.
We took a bus tour round the city seeing Haight-Ashbury, the Victorian houses, the gay district at Castro, Lombard Street - the second crookedest street in America after Wall Street, and looked down on the city from Twin Peaks. We rode two of the trolley cars and took the 'F-train' in tramcars from Milan and Birmingham. The 1989 earthquake severely damaged the double-decker road around the bay, and rather than rebuild it, the city decided to replace it with a light railway and bought in disused tramcars from around the world.
After three days we ran out of things to do. The Science Museum was propaganda for anthropogenic global warming and neo-Darwinism, neither of which I believe to be accurate descriptions of our planet, though the aquarium is worth a visit.
San Francisco is no longer the largest city on the Bay - San Jose has that honor. In fact the size of SF has not changed much since the 1950s when I knew about these things.
In general, I found the Americans in San Francisco extremely pleasant and friendly. The food was difficult; lots of it but pretty tasteless. The eight-hour time difference meant that we couldn't go out in the evening and we started our day in deep darkness.
I think this will be the last time I visit the west coast; the journey takes too long and my metabolism finds it hard to cope with the jet-lag.
I shall write about the ASH meeting when I get over the time-shift and have collected my thoughts.
We stayed at Fisherman's Wharf which in winter is a quiet spot lacking the bustle of the Downtown area. The Shearaton was a perfectly acceptable hotel, though it lacks a proper restaurant. The skyscraper hotels in Downtown may have been plusher, but I disliked the crowds and shopping is not one of my pleasures. The weather was mostly fine, though we had one day of rain and overcast skies. Otherwise it was sunny with temperatures in the sixties. Early morning faogs were not really a problem for us.
The main attraction in SF is Alcatraz, which all visitors must see.Set just over a mile from the shore it was first a fort, then a military prison then a Federal one. Famous inmates included Al Capone, 'Machine-gun' Kelly and Robert 'Birdman' Stroud. Trick question: How many birds did Robert Stroud have at Alcatraz? Answer: None; he had them at Leavenworth. He used the birdseed to make alcohol and was refused birds when he did 'bird' on the island.
The cells were very small and 'D' wing where the prisoners were kept in darkness was particularly oppressive, though the cells were larger there. Did Frank Morris and his two colleagues really make good their escape as the Clint Eastwood film suggests? No-one knows, but their bodies were never found.
Muir woods, over the other side of the Golden Gate bridge is a forest of giant redwoods approached by a scary mountain road. The redwoods came in useful for construction during the gold rush, but were very flammable in 1906 when the earthquake set the city alight. With water supplies disrupted by the quake, the only way to control the fire was with a fire break. All the wooden buildings downtown of Van Ness Avenue were demolished. Jack London, the author of 'Call of the Wild'. sought to make money be replanting the forests felled for timber and bought in quick-growing eucalyptus trees from Australia. Unfortunately these are useless as lumber and he lost his money. Nevertheless their progeny abound in the woods and glades around San Francisco.
We took a bus tour round the city seeing Haight-Ashbury, the Victorian houses, the gay district at Castro, Lombard Street - the second crookedest street in America after Wall Street, and looked down on the city from Twin Peaks. We rode two of the trolley cars and took the 'F-train' in tramcars from Milan and Birmingham. The 1989 earthquake severely damaged the double-decker road around the bay, and rather than rebuild it, the city decided to replace it with a light railway and bought in disused tramcars from around the world.
After three days we ran out of things to do. The Science Museum was propaganda for anthropogenic global warming and neo-Darwinism, neither of which I believe to be accurate descriptions of our planet, though the aquarium is worth a visit.
San Francisco is no longer the largest city on the Bay - San Jose has that honor. In fact the size of SF has not changed much since the 1950s when I knew about these things.
In general, I found the Americans in San Francisco extremely pleasant and friendly. The food was difficult; lots of it but pretty tasteless. The eight-hour time difference meant that we couldn't go out in the evening and we started our day in deep darkness.
I think this will be the last time I visit the west coast; the journey takes too long and my metabolism finds it hard to cope with the jet-lag.
I shall write about the ASH meeting when I get over the time-shift and have collected my thoughts.
Monday, December 01, 2008
Carol Complete
Finally the carol is completed. The tune is O Holy Night.
Still was the night, the silent world was waiting
The time was right and the place was prepared.
Still in its sin and full of hurt and hating
The world was weak, but a rescue was dared.
God sent His Son, a baby frail and humble
In peril’s place, to suffer in our stead.
Oh! Child of hope; we tremble lest he stumble
In dangerous days. Oh! Child, in manger bed,
You hold our hope; Oh! Hope, hope of the world.
Men from the East, a Jewish king pursuing;
Menace increased as King Herod was roused.
Warned in a dream, his vicious plans undoing,
They would not tell where the baby was housed.
In frenzied rage the king began the killing;
The blood of every baby boy was shed.
Oh! Child of hope, in prophesy fulfilling,
To Egypt has fled; Oh! Child, in borrowed bed,
You hold our hope; Oh! Hope, hope of the world.
Still was the night, the garden finds him praying;
The moon was bright, but his friends fell asleep.
Will he escape, his Father disobeying?
His will is firm, the appointment he’ll keep.
Let Satan spit his venom vile and stinging,
Let torture split his body on the tree,
Oh! Child of hope, salvation he is bringing,
He crushes sin’s head; Oh! Child, in victory,
You hold our hope; Oh! Hope, hope of the world.
Still was the night, the silent world was waiting
The time was right and the place was prepared.
Still in its sin and full of hurt and hating
The world was weak, but a rescue was dared.
God sent His Son, a baby frail and humble
In peril’s place, to suffer in our stead.
Oh! Child of hope; we tremble lest he stumble
In dangerous days. Oh! Child, in manger bed,
You hold our hope; Oh! Hope, hope of the world.
Men from the East, a Jewish king pursuing;
Menace increased as King Herod was roused.
Warned in a dream, his vicious plans undoing,
They would not tell where the baby was housed.
In frenzied rage the king began the killing;
The blood of every baby boy was shed.
Oh! Child of hope, in prophesy fulfilling,
To Egypt has fled; Oh! Child, in borrowed bed,
You hold our hope; Oh! Hope, hope of the world.
Still was the night, the garden finds him praying;
The moon was bright, but his friends fell asleep.
Will he escape, his Father disobeying?
His will is firm, the appointment he’ll keep.
Let Satan spit his venom vile and stinging,
Let torture split his body on the tree,
Oh! Child of hope, salvation he is bringing,
He crushes sin’s head; Oh! Child, in victory,
You hold our hope; Oh! Hope, hope of the world.
Friday, November 28, 2008
Churchill 1899
At the age of 25 Winston Churchill wrote this:
"How dreadful are the curses which Mohammedanism lays on its votaries! Besides the fanatical frenzy, which is as dangerous in a man as hydrophobia in a dog, there is this fearful fatalistic apathy. The effects are apparent in many countries. Improvident habits, slovenly systems of agriculture, sluggish methods of commerce, and insecurity of property exist wherever the followers of the Prophet rule or live. A degraded sensualism deprives this life of its grace and refinement; the next of its dignity and sanctity. The fact that in Mohammedan law every woman must belong to some man as his absolute property (either as a child, a wife, or a concubine) must delay the final extinction of slavery until the faith of Islam has ceased to be a great power among men. Individual Moslems may show splendid qualities. Thousands become the brave and loyal soldiers of the Queen; all know how to die; but the influence of the religion paralyses the social development of those who follow it. No stronger retrograde force exists in the world. Far from being moribund, Mohammedanism is a militant and proselytizing faith. It has already spread throughout Central Africa, raising fearless warriors at every step; and were it not that Christianity is sheltered in the strong arms of science (the science against which it had vainly struggled)the civilisation of modern Europe might fall, as fell the civilisation of ancient Rome."
Alas, the science is transferable.
"How dreadful are the curses which Mohammedanism lays on its votaries! Besides the fanatical frenzy, which is as dangerous in a man as hydrophobia in a dog, there is this fearful fatalistic apathy. The effects are apparent in many countries. Improvident habits, slovenly systems of agriculture, sluggish methods of commerce, and insecurity of property exist wherever the followers of the Prophet rule or live. A degraded sensualism deprives this life of its grace and refinement; the next of its dignity and sanctity. The fact that in Mohammedan law every woman must belong to some man as his absolute property (either as a child, a wife, or a concubine) must delay the final extinction of slavery until the faith of Islam has ceased to be a great power among men. Individual Moslems may show splendid qualities. Thousands become the brave and loyal soldiers of the Queen; all know how to die; but the influence of the religion paralyses the social development of those who follow it. No stronger retrograde force exists in the world. Far from being moribund, Mohammedanism is a militant and proselytizing faith. It has already spread throughout Central Africa, raising fearless warriors at every step; and were it not that Christianity is sheltered in the strong arms of science (the science against which it had vainly struggled)the civilisation of modern Europe might fall, as fell the civilisation of ancient Rome."
Alas, the science is transferable.
Living forever
I see that the world's oldest person has died in Indiana. Edna Parker, died on Wednesday in a nursing home in Shelbyville, Indiana. She was 115 years, 220 days old. Coincidentally it was the same nursing home where the world's tallest woman died last year. Maria de Jesus of Portugal, who was born on September 10, 1893, is now the world's oldest living person.
I noticed that at the Cenotaph memorial service in London on November 11th the oldest survivor of the First World War laid a wreath. He was 114.
People are living longer. I saw in a news item that scientist reckon that they will be able to reverse aging. So I thought to myself, 'Would I want to live for ever?' The answer, of course, was, 'Not if I have to put up with this backache.'
When we see these very old people we pity them. Their bodies have become shrunken and feeble. The man at the Cenotaph wanted to lay the wreath himself, but in the end he was unable to rise from his wheelchair. Our bodies betray us. If we escape disease, the wear and tear of normal living destroys the cartilage in our joints, enfeebles our muscles and dims our senses. We accumulate more and more bits of plastic and stainless steel. Teeth, lenses, joints, heart valves; the replacement industry is one to buy shares in.
The Bible tells us that 'there is a time to be born and a time to die'. Yet Christians expect eternal life. I pose the question, "If scientists really did solve the aging question; if they reversed the wear and tear and left us with the bodies we had when we were 25 and our minds continued to work well and accumulate knowledge, would they still want the eternal life the Bible offers or would they want more of this present world, albeit with new super resilient bodies?"
Paul calls the situation of the dead Christian 'better by far'. Why is that? In the first place, we won't be stuck with these mortal bodies. Here is what Paul writes in I Corinthians Ch 15 "We will all be changed." and "We shall bear the likeness of the man from heaven." and "The perishable must clothe itself with the imperishable."
In Romans 8:29 he writes that we are destined to be 'conformed to the likeness of his Son' and in Philippians 3:21, "we eagerly await a Savior from there, the Lord Jesus Christ, who, by the power that enables him to bring everything under his control, will transform our lowly bodies so that they will be like his glorious body."
Second, we will be with Christ. Paul writes in II Corinthians 5:6 that as long as we are at home in the body we are away from the Lord. He would prefer to be away from the body and at home with the Lord. Whenever I go away to a meeting I miss my wife. I am so pleased that this year at ASH we will be going together. We will be able to share the experience of visiting San Francisco. Normally after just a few days away I am longing to be back home. This feeling of longing is multiplied a hundred times for the Christian. To be at home with Christ must be bliss.
Third, it is all about where we will be with Christ. The disciples knew Jesus face to face and that must have been a wonderful experience, but it was detracted from by the fact that they were living under Roman oppression, in a place of poverty and hardship. People around them were crooks and charlatans, pompous and proud, bombastic and overbearing. They encountered disease and sickness every day. There were beggars and blind men on most street corners. Persecution was the way of the world. When we die we go where there is no sin. No more crying then. He will wipe away all tears from our eyes.
So we have no need to cling to this crippled frame. Anything the scientists come up with will be definitely second best - and were we to live 'forever', the world will end someday. He is coming again.
I noticed that at the Cenotaph memorial service in London on November 11th the oldest survivor of the First World War laid a wreath. He was 114.
People are living longer. I saw in a news item that scientist reckon that they will be able to reverse aging. So I thought to myself, 'Would I want to live for ever?' The answer, of course, was, 'Not if I have to put up with this backache.'
When we see these very old people we pity them. Their bodies have become shrunken and feeble. The man at the Cenotaph wanted to lay the wreath himself, but in the end he was unable to rise from his wheelchair. Our bodies betray us. If we escape disease, the wear and tear of normal living destroys the cartilage in our joints, enfeebles our muscles and dims our senses. We accumulate more and more bits of plastic and stainless steel. Teeth, lenses, joints, heart valves; the replacement industry is one to buy shares in.
The Bible tells us that 'there is a time to be born and a time to die'. Yet Christians expect eternal life. I pose the question, "If scientists really did solve the aging question; if they reversed the wear and tear and left us with the bodies we had when we were 25 and our minds continued to work well and accumulate knowledge, would they still want the eternal life the Bible offers or would they want more of this present world, albeit with new super resilient bodies?"
Paul calls the situation of the dead Christian 'better by far'. Why is that? In the first place, we won't be stuck with these mortal bodies. Here is what Paul writes in I Corinthians Ch 15 "We will all be changed." and "We shall bear the likeness of the man from heaven." and "The perishable must clothe itself with the imperishable."
In Romans 8:29 he writes that we are destined to be 'conformed to the likeness of his Son' and in Philippians 3:21, "we eagerly await a Savior from there, the Lord Jesus Christ, who, by the power that enables him to bring everything under his control, will transform our lowly bodies so that they will be like his glorious body."
Second, we will be with Christ. Paul writes in II Corinthians 5:6 that as long as we are at home in the body we are away from the Lord. He would prefer to be away from the body and at home with the Lord. Whenever I go away to a meeting I miss my wife. I am so pleased that this year at ASH we will be going together. We will be able to share the experience of visiting San Francisco. Normally after just a few days away I am longing to be back home. This feeling of longing is multiplied a hundred times for the Christian. To be at home with Christ must be bliss.
Third, it is all about where we will be with Christ. The disciples knew Jesus face to face and that must have been a wonderful experience, but it was detracted from by the fact that they were living under Roman oppression, in a place of poverty and hardship. People around them were crooks and charlatans, pompous and proud, bombastic and overbearing. They encountered disease and sickness every day. There were beggars and blind men on most street corners. Persecution was the way of the world. When we die we go where there is no sin. No more crying then. He will wipe away all tears from our eyes.
So we have no need to cling to this crippled frame. Anything the scientists come up with will be definitely second best - and were we to live 'forever', the world will end someday. He is coming again.
Tuesday, November 25, 2008
Christmas poem 2
I was asked to write a fourth verse to the Christmas poem, so here it is:
I came to you at Christmas but not just for Christmas Day.
All through the year I’ll hunt you and I will not go away.
Though you think you do not need me, that your staying power’s too strong,
The calamities that crush you will be bound to prove you wrong.
If you think you’re irredeemable; you’ve long since burnt your boats;
The die was cast when years ago you sowed your wild oats,
Oh! Hesitate to think so for I’ve rescued worse than you,
My blood can make the foulest clean; I offer life anew.
I came to you at Calvary; to you and all mankind,
To give you peace from God above; none need be left behind.
Don’t let the world distract you, don’t hanker after things,
However they attract you, they always come with strings.
My Christmas present for you is superb beyond compare;
On that Resurrection Morning won’t you meet me in the air?
I came to you at Christmas but not just for Christmas Day.
All through the year I’ll hunt you and I will not go away.
Though you think you do not need me, that your staying power’s too strong,
The calamities that crush you will be bound to prove you wrong.
If you think you’re irredeemable; you’ve long since burnt your boats;
The die was cast when years ago you sowed your wild oats,
Oh! Hesitate to think so for I’ve rescued worse than you,
My blood can make the foulest clean; I offer life anew.
I came to you at Calvary; to you and all mankind,
To give you peace from God above; none need be left behind.
Don’t let the world distract you, don’t hanker after things,
However they attract you, they always come with strings.
My Christmas present for you is superb beyond compare;
On that Resurrection Morning won’t you meet me in the air?
Surgery in CLL patients
CLL mpatients have to have operations just like anybody else. Are they at particular risk? The answer is no, not unless they have reduced platelets or reduced neutrophils. The reduced immunoglobulins or T cell deficiency do not come iinto play. Surgeons always take account of the platelet count and set their own safety levels according to the type of surgery. If the neutrophil count is less than 1 then either G-CSF or prophylactic antibiotics may be necessary.
The particular operations that CLL patients are subject to are, bone marrow biopsy, for which no special precautions are necessary, lymph node biopsy, which is usually safe if superficial, though a deep lymph node may require platelet cover, and splenectomy. If possible I recommend laparoscopic splenectomy as teh blood loss is usually less. An open operation does carry greater risk and in this circumastance particular attention must be paid to platelet and neutrophil counts.
The particular operations that CLL patients are subject to are, bone marrow biopsy, for which no special precautions are necessary, lymph node biopsy, which is usually safe if superficial, though a deep lymph node may require platelet cover, and splenectomy. If possible I recommend laparoscopic splenectomy as teh blood loss is usually less. An open operation does carry greater risk and in this circumastance particular attention must be paid to platelet and neutrophil counts.
Sunday, November 23, 2008
Psalm 62
Last week we were at a family funeral, this morning a visiting preacher told us of one of his elders who was suffering from terminal cancer. On both occasions the sermon was based on Psalm 62. I imagine that at Bible College they tell you that a good topic for sad occasions is Psalm 62. It comes with the instruction pack.
It is supposed that David wrote the psalm when he had been deposed by his son, Absalom, before he regained the throne, but it doesn't really matter; its theme is universal.
Sometimes we find ourselves in a vulnerable condition; a leaning wall, a tottering fence - we are real pushovers for adversity. Where do we turn to for support?
We may turn to others. So we should. Being part of a Christian community not only requires us to help those in need, but also to ask for help when we are in need. But though others may help we cannot rely on them. They will let us down. The middle verse in the whole Bible is "Put not your trust in princes." For as we see here, "Lowborn men are but a breath, the highborn are a lie; if weighed on a balance they are nothing; together they are only a breath." From the highest to the lowest, a man is but a puff of wind; he is ephemeral. Be he ever-so trustworthy he has no control over the future. How many have faltered when their sponsor or mentor is carried off by death or by new circumstances. As a young doctor I had hitched my wagon to a rising star (there's a good mixed metaphor), until one day he told me he was off to Chicago and I was left to fend for myself. Be he ever so important or just a journeyman, a man may promise the earth but he cannot guarantee to deliver. Perhaps this night his life will be required of him.
You might put your trust in riches. In today's climate who would dare? I do not have a job to lose so I won't be affected by my firm going bust, though many will. I don't have a loan so I won't be made bankrupt if the loan is called in, though many will. I don't have a mortgage so I won't be forced to sell my house at a loss, though many will. Nevertheless, the pound has declined against the Euro and the dollar so much of my wealth has disappeared. In order to bail out the banks the government has borrowed billions. Those billions must be paid back and the government can only repay by taxing more. It's like putting your money in a pocket full of holes. I have not set my heart on riches.
Who then can be relied upon? Where then can my soul find rest? In God alone. He alone is my rock and my salvation. He is my fortress, I shall not be shaken.
Over and over again this psalm insists that we are secure in God and nowhere else. One thing God has spoken, two things have I heard. That you, O God are strong.
It is a sign of the times that we have this picture of a weak and watery God. I have just finished reading "Seeing Red" the autobiography of Graham Poll the soccer referee. Poll is famous for his action during the 2006 World Cup. Certainly the top referee in the UK and highly regarded throughout the world, in many quarters he was expected to be chosen to referee the World Cup Final. As it happened it was to be an Italy v Germany Final so he would have been strongly tipped to get the match as the culmination of a long career.
Those who don't know soccer should recognise it as a violent game. In America is is often seen as a game for children and women, but in Europe and South America it is a game for real men who don't wear body armor. In Columbia and Iraq you are likely to be shot if you lose. In certain countries racism is rife. Twenty years ago crowd trouble was very common with pitched battles in the stadia and streets. Supporters were killed. Although some measure of control has been achieved, the fans are still aggressive. They are known for their singing. The songs are often funny, but more usually sexually explicit and abusive. The referee is often the butt of the humor.
The players are frequently foul-mouthed, deceitful and aggressive. They seek to intimidate the referee into favoring their side. The only defence that the referee has is the card system - a yellow for a warning, but a second yellow means a red card and dismissal from the field of play. At least it did until Graham Poll came along. In the Croatia versus Australia match he managed to give a Croatian defender three yellow cards. It was a tragedy for Poll and ensured that he was sent home in disgrace, his lifetime ambition unfulfilled.
A lot of people see God like that - a lot of warnings but no red card. They imagine a God who talks big but doesn't deliver. They mistake patience for tolerance. They think he winks at sin. So many people seem to 'get away with it' that there seems no point in obeying the rules. "They take delight in lies; with their mouths they bless but in their hearts they curse."
At football matches a company called Pro-zone films every incident. Thirty-six video cameras watch the action from every angle. The referee may miss a shirt tug or a sly push, but the cameras collect it. Things missed by the referee may still result in a retrospective red card. Pro-zone may be new to the Premier League, but God has had it for years. He never misses a trick.
What a referee to have on your side! Nothing the opposition can throw at you goes unnoticed. He is a strong supporter.
But why doesn't he act? The thing is, He is concerned about the result. In any game of football there may be setbacks. In the European Cup final a couple of years ago Liverpool were 3-0 down to AC Milan at half time. It would have been easy to give up in the face of such adversity. Liverpool refused to surrender despite the set-back and eventually won on penalties. God is not primarily concerned about our comfort. He is not looking out for our bank balances. He cares about the result. It is our salvation that matters, ours and every one else's. He is strong enough to protect those He loves.
That was the second thing the psalmist heard. God is not only strong, He is loving. That's why he is so patient. It is not His purpose that any should perish, He wants everyone to repent and reform. You may say it's not going to happen, but how do you know? The most unlikely have turned from their wicked ways. Look at the Nixon henchman, Chuck Colsen. Look at that privileged crook Jonathan Aitken. What about you? You changed didn't you? Do you imagine that others like you won't?
It is supposed that David wrote the psalm when he had been deposed by his son, Absalom, before he regained the throne, but it doesn't really matter; its theme is universal.
Sometimes we find ourselves in a vulnerable condition; a leaning wall, a tottering fence - we are real pushovers for adversity. Where do we turn to for support?
We may turn to others. So we should. Being part of a Christian community not only requires us to help those in need, but also to ask for help when we are in need. But though others may help we cannot rely on them. They will let us down. The middle verse in the whole Bible is "Put not your trust in princes." For as we see here, "Lowborn men are but a breath, the highborn are a lie; if weighed on a balance they are nothing; together they are only a breath." From the highest to the lowest, a man is but a puff of wind; he is ephemeral. Be he ever-so trustworthy he has no control over the future. How many have faltered when their sponsor or mentor is carried off by death or by new circumstances. As a young doctor I had hitched my wagon to a rising star (there's a good mixed metaphor), until one day he told me he was off to Chicago and I was left to fend for myself. Be he ever so important or just a journeyman, a man may promise the earth but he cannot guarantee to deliver. Perhaps this night his life will be required of him.
You might put your trust in riches. In today's climate who would dare? I do not have a job to lose so I won't be affected by my firm going bust, though many will. I don't have a loan so I won't be made bankrupt if the loan is called in, though many will. I don't have a mortgage so I won't be forced to sell my house at a loss, though many will. Nevertheless, the pound has declined against the Euro and the dollar so much of my wealth has disappeared. In order to bail out the banks the government has borrowed billions. Those billions must be paid back and the government can only repay by taxing more. It's like putting your money in a pocket full of holes. I have not set my heart on riches.
Who then can be relied upon? Where then can my soul find rest? In God alone. He alone is my rock and my salvation. He is my fortress, I shall not be shaken.
Over and over again this psalm insists that we are secure in God and nowhere else. One thing God has spoken, two things have I heard. That you, O God are strong.
It is a sign of the times that we have this picture of a weak and watery God. I have just finished reading "Seeing Red" the autobiography of Graham Poll the soccer referee. Poll is famous for his action during the 2006 World Cup. Certainly the top referee in the UK and highly regarded throughout the world, in many quarters he was expected to be chosen to referee the World Cup Final. As it happened it was to be an Italy v Germany Final so he would have been strongly tipped to get the match as the culmination of a long career.
Those who don't know soccer should recognise it as a violent game. In America is is often seen as a game for children and women, but in Europe and South America it is a game for real men who don't wear body armor. In Columbia and Iraq you are likely to be shot if you lose. In certain countries racism is rife. Twenty years ago crowd trouble was very common with pitched battles in the stadia and streets. Supporters were killed. Although some measure of control has been achieved, the fans are still aggressive. They are known for their singing. The songs are often funny, but more usually sexually explicit and abusive. The referee is often the butt of the humor.
The players are frequently foul-mouthed, deceitful and aggressive. They seek to intimidate the referee into favoring their side. The only defence that the referee has is the card system - a yellow for a warning, but a second yellow means a red card and dismissal from the field of play. At least it did until Graham Poll came along. In the Croatia versus Australia match he managed to give a Croatian defender three yellow cards. It was a tragedy for Poll and ensured that he was sent home in disgrace, his lifetime ambition unfulfilled.
A lot of people see God like that - a lot of warnings but no red card. They imagine a God who talks big but doesn't deliver. They mistake patience for tolerance. They think he winks at sin. So many people seem to 'get away with it' that there seems no point in obeying the rules. "They take delight in lies; with their mouths they bless but in their hearts they curse."
At football matches a company called Pro-zone films every incident. Thirty-six video cameras watch the action from every angle. The referee may miss a shirt tug or a sly push, but the cameras collect it. Things missed by the referee may still result in a retrospective red card. Pro-zone may be new to the Premier League, but God has had it for years. He never misses a trick.
What a referee to have on your side! Nothing the opposition can throw at you goes unnoticed. He is a strong supporter.
But why doesn't he act? The thing is, He is concerned about the result. In any game of football there may be setbacks. In the European Cup final a couple of years ago Liverpool were 3-0 down to AC Milan at half time. It would have been easy to give up in the face of such adversity. Liverpool refused to surrender despite the set-back and eventually won on penalties. God is not primarily concerned about our comfort. He is not looking out for our bank balances. He cares about the result. It is our salvation that matters, ours and every one else's. He is strong enough to protect those He loves.
That was the second thing the psalmist heard. God is not only strong, He is loving. That's why he is so patient. It is not His purpose that any should perish, He wants everyone to repent and reform. You may say it's not going to happen, but how do you know? The most unlikely have turned from their wicked ways. Look at the Nixon henchman, Chuck Colsen. Look at that privileged crook Jonathan Aitken. What about you? You changed didn't you? Do you imagine that others like you won't?
Saturday, November 22, 2008
Shingles vaccine
It has been standard advice that CLL patients should not receive vaccines containing live attenuated viruses. Thus MMR, oral polio, yellow fever and a few others are forbidden to patients with CLL, even those with mild disease.
The reasons for this are that patients with CLL have a profound immunodeficiency that is hard to measure. The most obvious manifestation is the low level of serum immunoglobulins, but there is also an ill-defined T-cell defect and a difficulty in antigen presentation by antigen presenting cells (APC).
Now all cancers are associated with poor immunity and all tumors of lymphocytes (lymphomas) have particularly poor immunity even among cancers, but CLL is worse than all the other lymphomas, with the possible exception of Hodgkin’s disease. I think it is the APCs that are the main problem. These are necessary for foreign antigens to be processed into a form recognized by T-cells, and T-cells are necessary for B-cells to make antibody. Normally, dendritic cells are the APCs but in CLL the CLL cell can act as an APC – but a very poor one. I think that what is going on is that the CLL cells – being present to a numerically greater extent than dendritic cells – grab the available antigen and hide it from dendritic cells. Like dogs in the manger they can’t do the job very well themselves but they don’t allow the professionals to do the job properly.
The result is that response to vaccines in CLL is very poor. I demonstrated this along time ago (1974) using the bacteriophage phi-X-174. This is a virus that lives in the bacterium e. coli. It is a new antigen for humans, but very immunogenic. Patients with CLL are completely unable to make antibody to it when they see it for the first time, although if you keep injecting it about half will eventually make a smidgeon of a response. The interesting thing was that even stage 0 patients with very low white counts suffered from the same defect. Among our normal controls there was one individual who had a much better response than anyone else. Two years later he developed Hodgkin’s disease – suggesting that even early Hodgkin’s disease does not have the profound immunodeficiency that early CLL does.
Immunity to Herpes viruses is a special case. Most of us are exposed to most of the herpes viruses when we are children and we never get rid of them. The commonest example of this is a cold sore. If you’ve ever had one you’re bound to have another. You know the things that bring them on: another virus infection like a cold, exposure to the sunlight, being run-down by any of life’s troubles, chemotherapy – anything in fact that diminishes our immunity. This is because the herpes simplex virus, once it inside us stays there and is kept under control by the body’s immune system. Herpes simplex II, which causes genital herpes, varicella/zoster, which causes chicken pox and shingles, EB virus, which causes glandular fever and CMV, which causes a variety of illnesses, are all herpes viruses that continue to live within us after an infection. CMV is especially interesting since about 15% of individuals over the age of 60 have never met it. It is a well known fact that untreated patients with CLL have increased numbers of T cells – but this is only true for those who have previously been infected with CMV. It turns out that the excess T cells are programmed to keep the CMV under control. Similarly with EBV; a lot of T cells are keeping the EBV under control.
Varicella/zoster lives in nerve cells and if immunity drops it crawls out along the nerve the area of skin (a dermatome) supplied by that nerve and causes a very painful rash (shingles). This occurs in about a quarter of old people, but it is rather commoner than this in patients with CLL, and in CLL patients who are treated, especially with fludarabine of Campath, or who have a transplant, it is much more common, unless they have aciclovir prophylaxis. In those with the most severe immunodeficiency, the zoster rash will disseminate and become a florid chicken pox. What doesn’t happen is patients with CLL catching shingles (or chicken pox for that matter) from a child with chicken pox. It seems that you can’t get a superinfection with varicella/zoster, even if you are immunodeficient.
What has brought this up is some correspondence that doctor and CLL-sufferer, Brian Koffman, has been having with Dr Rafael Harpaz of the Herpes Virus Team, Division of Viral Diseases, NCIRD/CDC over the advice given by the Advisory Committee on Immunization Practices (ACIP) on vaccination against shingles in patients with CLL.
The statement that he and I both take exception to is “Patients with leukemia, lymphoma, or other malignancies whose disease is in remission and whose chemotherapy has been terminated for at least 3 months can receive live-virus vaccines.”
As far as live viruses generally are concerned, this may well be true for solid tumors and for AML, CML and ALL, and perhaps for diffuse large B-cell lymphoma, but CLL is a special case among secondary immunodeficiencies since treatment makes the immunodeficiency worse, not better. The only treatments that induce complete remissions in any quantity are combinations containing purine analogues like fludarabine or the monoclonal antibody alemtuzumab. Both types of drug suppress CD4+ T-cells to AIDS-like levels and the suppression continues for at least six months in the case of alemtuzumab and in excess of two years in the case of fludarabine. We in the CLL community recommend that prophylaxis against pneumocystis continue for at least a year or until the CD4 count is greater than 200. It would be perverse to allow vaccination with live vaccines at three months into a remission. The blood transfusion authorities insist on irradiated blood transfusions for patients who have received fludarabine or alemtuzumab, because of the risk of transfusion-induced graft versus host disease. I am sure that we should not allow treated CLL patients to receive live-virus vaccines.
In 30 years experience of treating CLL I have never known patients to recover their immunity, no matter what treatment has been given. Complete remissions in CLL are unsatisfactory, allowing the marrow to retain 30% lymphocytes. Newer standards of response involving elimination of minimal residual disease (MRD) have not been evaluated for any return of immunity, but suppression of B-lymphocytes to this degree usually involves equivalent suppression of T-cells.
However, perhaps the zoster vaccine is a special case. This is how the ACIP argument runs:
“*Virtually all adults aged 60 and over are at risk of HZ (i.e., are infected with latent varicella zoster virus, or VZV). In contrast to other live vaccines, HZV does not protect by preventing infection but by preventing reactivation of this latent infection, which is much more likely in immunocompromised persons. A strategy of vaccinating household contacts would not protect a person with CLL (in contrast, say, to vaccinating household contacts with varicella vaccine to protect a child with leukemia).
* People receiving HZV have pre-existing immunity to VZV. While second episodes of chickenpox occasionally occur, second VZV infections remain uncommon even among the most profoundly immunocompromised persons and those rare episodes that do occur are not severe. Immunity to VZV in such patients appears to be adequate to protect against disseminated infection from the wild-type, natural VZV virus, and the risk of adverse effects from live-attenuated VZV contained in HZV should be correspondingly lower.
* In fact, there is empiric evidence to support the safety of HZV in immunocompromised persons. In early trials, the live-attenuated VZV used in varicella vaccine as well as HZV was administered to hundreds of profoundly immunocompromised children with leukemia in remission and *without* preexisting immunity to VZV, and the vaccine was well tolerated. These children tolerated subsequent second doses of the vaccine even better. Live attenuated VZV has since been safely and effectively used in many more children with other immunocompromising conditions such as transplant recipients and HIV infection. Live attenuated VZV is now recommended in HIV-infected persons without prior immunity to VZV. Finally, live attenuated VZV has also been used in HIV-infected children with prior varicella infection and immunity. As would be expected, the children tolerated the vaccination very well.
* General guidance on use of live attenuated vaccines by persons with leukemia has been evaluated by ACIP and published in their General Recommendations on Immunization published Dec. 2006. The document states that "Patients with leukemia, lymphoma, or other malignancies whose disease is in remission and whose chemotherapy has been terminated for at least 3 months can receive live-virus vaccines."
Given the potential severe, life threatening HZ in persons with CLL in remission, and the considerations regarding the safety of this vaccine, the ACIP recommends that the vaccine should be used in such circumstances.”
Their argument is not without merit. It could well be that the presence of the HZV virus under control signifies that there is sufficient protection against reinfection with new HZV and that an attenuated HZV virus vaccine would be without danger. I certainly hope so. But it would be foolhardy to accept this without an appropriate clinical trial. Experience in ALL in remission and among children with HIV infection before they become profoundly CD4+ T-lymphocytopenic is not relevant to what would happen in CLL.
A clinical trial is feasible, since it would be possible to vaccinate patients with antivirals standing by in case a serious infection ensues. I think that such a trial should be conducted, but it won’t be as long as Merck is bolstered by the advice from ACIP.
The reasons for this are that patients with CLL have a profound immunodeficiency that is hard to measure. The most obvious manifestation is the low level of serum immunoglobulins, but there is also an ill-defined T-cell defect and a difficulty in antigen presentation by antigen presenting cells (APC).
Now all cancers are associated with poor immunity and all tumors of lymphocytes (lymphomas) have particularly poor immunity even among cancers, but CLL is worse than all the other lymphomas, with the possible exception of Hodgkin’s disease. I think it is the APCs that are the main problem. These are necessary for foreign antigens to be processed into a form recognized by T-cells, and T-cells are necessary for B-cells to make antibody. Normally, dendritic cells are the APCs but in CLL the CLL cell can act as an APC – but a very poor one. I think that what is going on is that the CLL cells – being present to a numerically greater extent than dendritic cells – grab the available antigen and hide it from dendritic cells. Like dogs in the manger they can’t do the job very well themselves but they don’t allow the professionals to do the job properly.
The result is that response to vaccines in CLL is very poor. I demonstrated this along time ago (1974) using the bacteriophage phi-X-174. This is a virus that lives in the bacterium e. coli. It is a new antigen for humans, but very immunogenic. Patients with CLL are completely unable to make antibody to it when they see it for the first time, although if you keep injecting it about half will eventually make a smidgeon of a response. The interesting thing was that even stage 0 patients with very low white counts suffered from the same defect. Among our normal controls there was one individual who had a much better response than anyone else. Two years later he developed Hodgkin’s disease – suggesting that even early Hodgkin’s disease does not have the profound immunodeficiency that early CLL does.
Immunity to Herpes viruses is a special case. Most of us are exposed to most of the herpes viruses when we are children and we never get rid of them. The commonest example of this is a cold sore. If you’ve ever had one you’re bound to have another. You know the things that bring them on: another virus infection like a cold, exposure to the sunlight, being run-down by any of life’s troubles, chemotherapy – anything in fact that diminishes our immunity. This is because the herpes simplex virus, once it inside us stays there and is kept under control by the body’s immune system. Herpes simplex II, which causes genital herpes, varicella/zoster, which causes chicken pox and shingles, EB virus, which causes glandular fever and CMV, which causes a variety of illnesses, are all herpes viruses that continue to live within us after an infection. CMV is especially interesting since about 15% of individuals over the age of 60 have never met it. It is a well known fact that untreated patients with CLL have increased numbers of T cells – but this is only true for those who have previously been infected with CMV. It turns out that the excess T cells are programmed to keep the CMV under control. Similarly with EBV; a lot of T cells are keeping the EBV under control.
Varicella/zoster lives in nerve cells and if immunity drops it crawls out along the nerve the area of skin (a dermatome) supplied by that nerve and causes a very painful rash (shingles). This occurs in about a quarter of old people, but it is rather commoner than this in patients with CLL, and in CLL patients who are treated, especially with fludarabine of Campath, or who have a transplant, it is much more common, unless they have aciclovir prophylaxis. In those with the most severe immunodeficiency, the zoster rash will disseminate and become a florid chicken pox. What doesn’t happen is patients with CLL catching shingles (or chicken pox for that matter) from a child with chicken pox. It seems that you can’t get a superinfection with varicella/zoster, even if you are immunodeficient.
What has brought this up is some correspondence that doctor and CLL-sufferer, Brian Koffman, has been having with Dr Rafael Harpaz of the Herpes Virus Team, Division of Viral Diseases, NCIRD/CDC over the advice given by the Advisory Committee on Immunization Practices (ACIP) on vaccination against shingles in patients with CLL.
The statement that he and I both take exception to is “Patients with leukemia, lymphoma, or other malignancies whose disease is in remission and whose chemotherapy has been terminated for at least 3 months can receive live-virus vaccines.”
As far as live viruses generally are concerned, this may well be true for solid tumors and for AML, CML and ALL, and perhaps for diffuse large B-cell lymphoma, but CLL is a special case among secondary immunodeficiencies since treatment makes the immunodeficiency worse, not better. The only treatments that induce complete remissions in any quantity are combinations containing purine analogues like fludarabine or the monoclonal antibody alemtuzumab. Both types of drug suppress CD4+ T-cells to AIDS-like levels and the suppression continues for at least six months in the case of alemtuzumab and in excess of two years in the case of fludarabine. We in the CLL community recommend that prophylaxis against pneumocystis continue for at least a year or until the CD4 count is greater than 200. It would be perverse to allow vaccination with live vaccines at three months into a remission. The blood transfusion authorities insist on irradiated blood transfusions for patients who have received fludarabine or alemtuzumab, because of the risk of transfusion-induced graft versus host disease. I am sure that we should not allow treated CLL patients to receive live-virus vaccines.
In 30 years experience of treating CLL I have never known patients to recover their immunity, no matter what treatment has been given. Complete remissions in CLL are unsatisfactory, allowing the marrow to retain 30% lymphocytes. Newer standards of response involving elimination of minimal residual disease (MRD) have not been evaluated for any return of immunity, but suppression of B-lymphocytes to this degree usually involves equivalent suppression of T-cells.
However, perhaps the zoster vaccine is a special case. This is how the ACIP argument runs:
“*Virtually all adults aged 60 and over are at risk of HZ (i.e., are infected with latent varicella zoster virus, or VZV). In contrast to other live vaccines, HZV does not protect by preventing infection but by preventing reactivation of this latent infection, which is much more likely in immunocompromised persons. A strategy of vaccinating household contacts would not protect a person with CLL (in contrast, say, to vaccinating household contacts with varicella vaccine to protect a child with leukemia).
* People receiving HZV have pre-existing immunity to VZV. While second episodes of chickenpox occasionally occur, second VZV infections remain uncommon even among the most profoundly immunocompromised persons and those rare episodes that do occur are not severe. Immunity to VZV in such patients appears to be adequate to protect against disseminated infection from the wild-type, natural VZV virus, and the risk of adverse effects from live-attenuated VZV contained in HZV should be correspondingly lower.
* In fact, there is empiric evidence to support the safety of HZV in immunocompromised persons. In early trials, the live-attenuated VZV used in varicella vaccine as well as HZV was administered to hundreds of profoundly immunocompromised children with leukemia in remission and *without* preexisting immunity to VZV, and the vaccine was well tolerated. These children tolerated subsequent second doses of the vaccine even better. Live attenuated VZV has since been safely and effectively used in many more children with other immunocompromising conditions such as transplant recipients and HIV infection. Live attenuated VZV is now recommended in HIV-infected persons without prior immunity to VZV. Finally, live attenuated VZV has also been used in HIV-infected children with prior varicella infection and immunity. As would be expected, the children tolerated the vaccination very well.
* General guidance on use of live attenuated vaccines by persons with leukemia has been evaluated by ACIP and published in their General Recommendations on Immunization published Dec. 2006. The document states that "Patients with leukemia, lymphoma, or other malignancies whose disease is in remission and whose chemotherapy has been terminated for at least 3 months can receive live-virus vaccines."
Given the potential severe, life threatening HZ in persons with CLL in remission, and the considerations regarding the safety of this vaccine, the ACIP recommends that the vaccine should be used in such circumstances.”
Their argument is not without merit. It could well be that the presence of the HZV virus under control signifies that there is sufficient protection against reinfection with new HZV and that an attenuated HZV virus vaccine would be without danger. I certainly hope so. But it would be foolhardy to accept this without an appropriate clinical trial. Experience in ALL in remission and among children with HIV infection before they become profoundly CD4+ T-lymphocytopenic is not relevant to what would happen in CLL.
A clinical trial is feasible, since it would be possible to vaccinate patients with antivirals standing by in case a serious infection ensues. I think that such a trial should be conducted, but it won’t be as long as Merck is bolstered by the advice from ACIP.
Sunday, November 16, 2008
Idiotype vaccines - an update
The idea that the B cell receptor might be used as a target for immunotherapy belongs to George and Freda Stevenson who published a paper in Nature in 1975. They called this target idiotype because it was the same for every tumor cell but different for every other normal B lymphocyte. The following year they made an antibody which I used to treat a patient with CLL. Subsequently Ron Levy at Stanford made monoclonal antibodies against idiotype and successfully treated patients with non-Hodgkin's lymphoma with them. In 1981 Ron Levy and George Stevenson were jointly awarded the first Armand Hammer Prize for Cancer Research for this work.
It soon became apparent that the labor involved in making made to measure anti-idiotypic monoclonal antibodies for lymphoma patients was so great, that it was never seriously feasible - even in America, and certainly not in the NHS. The focus turned from monoclonal antibodies to idiotype vaccines. Work in mice showed that it was possible to produce immune responses against idiotype that were therapeutically active. Ron Levy managed to produce vaccines from the patients' tumors and carried out a trial in lymphoma patients. In a paper published in 1997 in Blood he showed that if an antibody response was generated by a patient against the idiotype vaccine, then such patients lived for significantly longer than patients who were unable to generate an antibody response. This looked like good news, but an alternative explanation, other than that the vaccination was doing the patients good, was that this was a way of separating good risk patients from bad risk patients - if you were capable of mounting an immune response you were in a better risk bucket than if you couldn't
Nevertheless, this result was so encouraging that no fewer than three randomized clinical trials were undertaken to see if vaccinated patients lived for longer than non-vaccinated patients. AT least two of these trials have now reported (though not yet published). The bottom line is that it is certainly true that if you make antibody against idiotype you live longer than those who can't make antibody, but overall there was no difference in survival between the two arms.
Last week at the Annual LRF lecture, I heard Ron Levy give an update on these trials. The idiotype protein is strapped to a carrier protein called Keyhole Limpet Hemacyanin (KLH) Rather than go to the expense of measuring anti-idiotype (a separate assay for each patient), you can pick out your good responders by measuring the response to KLH. Sure enough the vaccinated patients who made an antibody response to KLH did better than those who did not - so if you want to use it as a screening test choose immune response to KLH rather than immune response to idiotype.
Of course the control patients were given KLH and some made a response to it. The important question is, "Do they get an improved survival over control patients without an immune response to KLH?"
The answer is, they do not. Therefore, if you are capable of generating an immune response, then vaccination against idiotype does improve survival - at least that is the new hypothesis. Because this was a subset analysis, and the original trial was not designed in this way, the statistics are not valid. The results can only be used for hypothesis generating. A new randomized trial restricting the entrants to those capable of making an immune response is about to start.
I emphasize that this is in follicular lymphoma. Although a trial in CLL has been under way, CLL patients have a poor ability to generate an immune response and are therefore not good candidates for such a trial.
Another trial mentioned by Ron Levy concerned the use of CpG - an immune stimulant that stimulates antigen presentation via the Toll-Like Receptor 9 on dendritic cells. It appears that this process can be stimulated by a mixture of monoclonal antibodies - an agonistic anti OX40 antibody and an antagonistic anti-CTLA4 antibody.
It soon became apparent that the labor involved in making made to measure anti-idiotypic monoclonal antibodies for lymphoma patients was so great, that it was never seriously feasible - even in America, and certainly not in the NHS. The focus turned from monoclonal antibodies to idiotype vaccines. Work in mice showed that it was possible to produce immune responses against idiotype that were therapeutically active. Ron Levy managed to produce vaccines from the patients' tumors and carried out a trial in lymphoma patients. In a paper published in 1997 in Blood he showed that if an antibody response was generated by a patient against the idiotype vaccine, then such patients lived for significantly longer than patients who were unable to generate an antibody response. This looked like good news, but an alternative explanation, other than that the vaccination was doing the patients good, was that this was a way of separating good risk patients from bad risk patients - if you were capable of mounting an immune response you were in a better risk bucket than if you couldn't
Nevertheless, this result was so encouraging that no fewer than three randomized clinical trials were undertaken to see if vaccinated patients lived for longer than non-vaccinated patients. AT least two of these trials have now reported (though not yet published). The bottom line is that it is certainly true that if you make antibody against idiotype you live longer than those who can't make antibody, but overall there was no difference in survival between the two arms.
Last week at the Annual LRF lecture, I heard Ron Levy give an update on these trials. The idiotype protein is strapped to a carrier protein called Keyhole Limpet Hemacyanin (KLH) Rather than go to the expense of measuring anti-idiotype (a separate assay for each patient), you can pick out your good responders by measuring the response to KLH. Sure enough the vaccinated patients who made an antibody response to KLH did better than those who did not - so if you want to use it as a screening test choose immune response to KLH rather than immune response to idiotype.
Of course the control patients were given KLH and some made a response to it. The important question is, "Do they get an improved survival over control patients without an immune response to KLH?"
The answer is, they do not. Therefore, if you are capable of generating an immune response, then vaccination against idiotype does improve survival - at least that is the new hypothesis. Because this was a subset analysis, and the original trial was not designed in this way, the statistics are not valid. The results can only be used for hypothesis generating. A new randomized trial restricting the entrants to those capable of making an immune response is about to start.
I emphasize that this is in follicular lymphoma. Although a trial in CLL has been under way, CLL patients have a poor ability to generate an immune response and are therefore not good candidates for such a trial.
Another trial mentioned by Ron Levy concerned the use of CpG - an immune stimulant that stimulates antigen presentation via the Toll-Like Receptor 9 on dendritic cells. It appears that this process can be stimulated by a mixture of monoclonal antibodies - an agonistic anti OX40 antibody and an antagonistic anti-CTLA4 antibody.
Wednesday, November 12, 2008
Christmas poem
I came to you at Christmas when the frost had fixed the grass,
When they decorate department stores with balls of coloured glass,
When the Square is lit with silver shapes and sparkles green and red
And the trees are decked with fairy lights that flicker overhead,
When the shopper-laden buses hustle down Westover Road
And you wonder if that tea set will suffice for Mrs Spode;
When the speakers blare out ‘Jingles Bells’ off-key and very loud
And the bargain hunters muscle through the shoulder-crushing crowd;
When a lady limps and lurches under purchases too large
From a bright and shiny toyshop never known to undercharge,
When you fight for bulbs and batteries and each last-minute task,
For an electronic Christmas that is all that they could ask;
And I caught your eye and thought, for a moment, you might stop;
But the fever was upon you and your only thought was,”Shop!”
I came to you at Christmas down at number thirty-four
Where the reindeer and fat Santa quite irradiate the door,
Where the presents are piled high underneath the plastic tree
And the herald angels hark from a plasma screen TV,
Where there’s whisky overflowing and a Quality Street tin
And heaps of chocolate biscuits and buckets full of gin,
Where the parsnips and potatoes are roasting in the pan
And the turkey has been cooking since before the day began,
Where the cake from Marks and Spencers will be passed off as your own,
Just like the Christmas pudding – last year’s gift from Auntie Joan;
And it’s time to do the vegetables, the peas and beans and sprouts
And the microwavable mince pies at four or thereabouts.
And I caught your eye and thought, for a moment, you might look;
But the fever was upon you and your only thought was, “Cook!”
I came to you at Christmas; but not as a masquerade,
All safely wrapped in swaddling clothes and in a manger laid.
I was not at the rehearsals; I was sorting goats from sheep
For my gaze is universal and you know I never sleep.
In Zimbabwe I was hungry; in Romania I was cold,
In Malawi I was orphaned and in Darfur I was sold;
In other lands imprisoned; in other countries stoned;
The plain facts skated over or by other means condoned.
I was there in Boscombe Crescent sleeping on that slatted seat
I was scrabbling in the rubbish bin for something fresh to eat
I was with the young offenders down at Portland on the coast
Kept away from home and family at a time that matters most.
I was sick in the Macmillan and I almost caught your eye
But the fever was upon me and, of course, I came to die.
When they decorate department stores with balls of coloured glass,
When the Square is lit with silver shapes and sparkles green and red
And the trees are decked with fairy lights that flicker overhead,
When the shopper-laden buses hustle down Westover Road
And you wonder if that tea set will suffice for Mrs Spode;
When the speakers blare out ‘Jingles Bells’ off-key and very loud
And the bargain hunters muscle through the shoulder-crushing crowd;
When a lady limps and lurches under purchases too large
From a bright and shiny toyshop never known to undercharge,
When you fight for bulbs and batteries and each last-minute task,
For an electronic Christmas that is all that they could ask;
And I caught your eye and thought, for a moment, you might stop;
But the fever was upon you and your only thought was,”Shop!”
I came to you at Christmas down at number thirty-four
Where the reindeer and fat Santa quite irradiate the door,
Where the presents are piled high underneath the plastic tree
And the herald angels hark from a plasma screen TV,
Where there’s whisky overflowing and a Quality Street tin
And heaps of chocolate biscuits and buckets full of gin,
Where the parsnips and potatoes are roasting in the pan
And the turkey has been cooking since before the day began,
Where the cake from Marks and Spencers will be passed off as your own,
Just like the Christmas pudding – last year’s gift from Auntie Joan;
And it’s time to do the vegetables, the peas and beans and sprouts
And the microwavable mince pies at four or thereabouts.
And I caught your eye and thought, for a moment, you might look;
But the fever was upon you and your only thought was, “Cook!”
I came to you at Christmas; but not as a masquerade,
All safely wrapped in swaddling clothes and in a manger laid.
I was not at the rehearsals; I was sorting goats from sheep
For my gaze is universal and you know I never sleep.
In Zimbabwe I was hungry; in Romania I was cold,
In Malawi I was orphaned and in Darfur I was sold;
In other lands imprisoned; in other countries stoned;
The plain facts skated over or by other means condoned.
I was there in Boscombe Crescent sleeping on that slatted seat
I was scrabbling in the rubbish bin for something fresh to eat
I was with the young offenders down at Portland on the coast
Kept away from home and family at a time that matters most.
I was sick in the Macmillan and I almost caught your eye
But the fever was upon me and, of course, I came to die.
Sunday, November 09, 2008
Answered prayer.
Most people get better from most things most of the time. You break a leg? Mostly it heals up after a while and you can walk again. You get the 'flu? Generally you're better again after a few days in bed. Measles? Mumps? Chicken pox? Even before vaccines, most people caught them as children and most survived. Even with heart attacks and strokes, although more likely to be lethal, many people make an uneventful recovery.
Do doctors help? Well, they might make sure your leg sets straight, and relieve your suffering with some aspirin, but for most things doctors do as they have done for centuries - comforting words and placebos; a good bedside manner.
That is not the end of it, of course. Over the past 50 years we have got pretty good at treating bacterial infection. Pneumonia was the most important of these. Viral respiratory infection (for which we can do nothing) opens a gate for the common bacteria to get in, and as in most situations where the drainage of fluid is impaired an serious infection ensues. Penicillin and its many successors have saved many lives. Safe surgery has been another boon. Anesthetics that allow it and antiseptic techniques that prevent the germs getting into open wounds have ensured enormous advances that have made fatal cancers curable, and many otherwise dangerous condition like appendicitis trivial.
Many of the other medical advances have been to do with public health. Sir Richard Doll's epidemiological observation that demonstrated that smokers got lung cancer mush more commonly than non-smokers was the beginning of a realization that the way we live inflicts upon us various ailments. There are all sorts of drugs like anti hypertensives and statins that don't make us feel any better, yet they prevent us being struck down by a potentially fatal illness (we hope). Even with some cancers, we detect them when they cause us no problems and apply treatments in the hope that they never will.
It comes as no surprise therefore that people who take precautions about their health - eating well, not smoking, taking plenty of exercise, drinking little alcohol - live longer than those who live a life of riotous hedonism. Not should surprise us that such people are found more commonly in churches than outside of them. We could also say that the sense of community provided by church membership settles the mind and spirit, making mental and psychosomatic illness less likely.
It was Francis Galton, I think, who believed that he had a proof that prayer did not work. 'God save the King' was, he said, the most commonly prayed prayer, yet on average kings lived shorter lives than the rest of the population, and therefore prayer did not work. It is, of course, a facile argument with so many flaws that it is not worth contradicting. However, of recent years a number of other studies have been published suggesting that when Christians pray for, say, patients in coronary care units, those prayed for survive better. In one famous study volunteers prayed for half of the 393 heart attack patients in a San Francisco hospital. Among the group prayed for significantly fewer died, most had a faster recovery, requiring the use of fewer potent drugs and none had to be put on life support. The study was blinded; the patients did not know they were being prayed for. There are some similar studies that show contradictory results. and some observers find methodological flaws in such approaches. I make no comment.
Most Christian doctors I know have never seen an unequivocal authentic miracle. Dr Paul Brand, the famous leprosy surgeon/missionary, spent many decades in practice and never saw one. When people mentioned the success of tele-evangelists, he commented that he must have spent his life in the wrong profession. Why had he spent so much time doing painstaking surgery, when he could have achieved the same or better results in the twinkling of an eye? I remember a patient of mine with chronic myeloid leukemia who had a blastic transformation. In the days before imatanib that was a lethal development. He was a keen Christian and the elders of his church prayed over him and laid hands on him. He went into remission. I was shocked. All I had given him was prednisolone. When I shared this with a CML expert he referred me to a few similar cases that had responded to prednisolone. I remember also a mix up where an old lady with acute lymphoblastic leukemia was inadvertently given chlorambucil. She went into remission, even though that drug is supposed to have no effect. There was no suggestion of any supernatural intervention in this case.
The body has remarkable natural healing powers and although we presume to understand the pathology of leukemia, what we don't know is greater than what we do. Do miracles occur? Of course they do - our whole faith is based on the fact that a dead man came back to life. As Paul said - 'if Christ be not risen we are of all men most miserable'. But at least in Western Civilization where these things can be subjected to scientific scrutiny, I am pretty sure that the sort of miracle that happened in Jesus's time no longer happens now. We don't see blind men made to see when mud is placed on their eyes, or the paralyzed take up their beds and walk, or water turned into wine or 5000 fed with five loaves and two fish or men who have been dead and rotting in the grave for four days brought back to life. Perhaps these things still happen in non-scientific communities where the only proof is what a witness says and there is still scope for disbelief, but it seems to me that God is concerned to ensure to us that the laws of physics and chemistry are a constant and reliable circumstance. Perhaps He also wants to ensure that we don't lapse into a 'benefits' culture. If everything were available by miracle service, why would we ever work for a living.
Imagine a particular faith healer who had a reliable record of curing people. The scientists would be swarming all over him to investigate exactly how he worked the 'trick'. It would be Simon Magus all over again.
There will always be stories of miracles, but they will never be truly testable. A God who could be proved would require no faith. Sceptics will always be able to say 'there was insufficient evidence'. New Testament miracles were signs authenticating Jesus, just as Moses was given a shape-changing staff to prove his representative authority before Pharaoh. We have the Scripture; we have the Holy Spirit; we don't have authenticating miracles.
In the eighteenth century millions died from smallpox. Christians prayed to be free of this terrible scourge. God answered that prayer. He sent them Edward Jenner. He has also sent them thousands of scientists, physicians, nurses, radiographers, physiotherapists and pharmacists. The rate of cot-death has reduced remarkably by the simple expedient of lying the child on its back. Thousands of parents cried out in bafflement, "Why did God take my child?" It wasn't God to blame. We simply did not know better. At the time of the black death in London long-haired prophets saw it as a sign of the coming Apocalypse; yet the remedy was rat poison. Pious Dutch Calvinists saw smoking as a sign of a spiritual Christian; only the rebellious refused to smoke. They accepted their lung cancer and emphysema as God's will for them. God sent them Sir Richard Doll.
Even though I have never seen a healing miracle, I continue to pray for them. I never presume on one. I believe God is sovereign and He will have His way. Even in the years after Jesus' death Paul was well aware that prayer could not command relief from illness; Epaphroditus, Trophemus, Timothy and Paul himself were not miraculously healed despite their proximity to the resurrection. Paul's prayers were for the salvation of souls and their growth in grace. As for illness he was content with, "My grace is sufficient for you."
Do doctors help? Well, they might make sure your leg sets straight, and relieve your suffering with some aspirin, but for most things doctors do as they have done for centuries - comforting words and placebos; a good bedside manner.
That is not the end of it, of course. Over the past 50 years we have got pretty good at treating bacterial infection. Pneumonia was the most important of these. Viral respiratory infection (for which we can do nothing) opens a gate for the common bacteria to get in, and as in most situations where the drainage of fluid is impaired an serious infection ensues. Penicillin and its many successors have saved many lives. Safe surgery has been another boon. Anesthetics that allow it and antiseptic techniques that prevent the germs getting into open wounds have ensured enormous advances that have made fatal cancers curable, and many otherwise dangerous condition like appendicitis trivial.
Many of the other medical advances have been to do with public health. Sir Richard Doll's epidemiological observation that demonstrated that smokers got lung cancer mush more commonly than non-smokers was the beginning of a realization that the way we live inflicts upon us various ailments. There are all sorts of drugs like anti hypertensives and statins that don't make us feel any better, yet they prevent us being struck down by a potentially fatal illness (we hope). Even with some cancers, we detect them when they cause us no problems and apply treatments in the hope that they never will.
It comes as no surprise therefore that people who take precautions about their health - eating well, not smoking, taking plenty of exercise, drinking little alcohol - live longer than those who live a life of riotous hedonism. Not should surprise us that such people are found more commonly in churches than outside of them. We could also say that the sense of community provided by church membership settles the mind and spirit, making mental and psychosomatic illness less likely.
It was Francis Galton, I think, who believed that he had a proof that prayer did not work. 'God save the King' was, he said, the most commonly prayed prayer, yet on average kings lived shorter lives than the rest of the population, and therefore prayer did not work. It is, of course, a facile argument with so many flaws that it is not worth contradicting. However, of recent years a number of other studies have been published suggesting that when Christians pray for, say, patients in coronary care units, those prayed for survive better. In one famous study volunteers prayed for half of the 393 heart attack patients in a San Francisco hospital. Among the group prayed for significantly fewer died, most had a faster recovery, requiring the use of fewer potent drugs and none had to be put on life support. The study was blinded; the patients did not know they were being prayed for. There are some similar studies that show contradictory results. and some observers find methodological flaws in such approaches. I make no comment.
Most Christian doctors I know have never seen an unequivocal authentic miracle. Dr Paul Brand, the famous leprosy surgeon/missionary, spent many decades in practice and never saw one. When people mentioned the success of tele-evangelists, he commented that he must have spent his life in the wrong profession. Why had he spent so much time doing painstaking surgery, when he could have achieved the same or better results in the twinkling of an eye? I remember a patient of mine with chronic myeloid leukemia who had a blastic transformation. In the days before imatanib that was a lethal development. He was a keen Christian and the elders of his church prayed over him and laid hands on him. He went into remission. I was shocked. All I had given him was prednisolone. When I shared this with a CML expert he referred me to a few similar cases that had responded to prednisolone. I remember also a mix up where an old lady with acute lymphoblastic leukemia was inadvertently given chlorambucil. She went into remission, even though that drug is supposed to have no effect. There was no suggestion of any supernatural intervention in this case.
The body has remarkable natural healing powers and although we presume to understand the pathology of leukemia, what we don't know is greater than what we do. Do miracles occur? Of course they do - our whole faith is based on the fact that a dead man came back to life. As Paul said - 'if Christ be not risen we are of all men most miserable'. But at least in Western Civilization where these things can be subjected to scientific scrutiny, I am pretty sure that the sort of miracle that happened in Jesus's time no longer happens now. We don't see blind men made to see when mud is placed on their eyes, or the paralyzed take up their beds and walk, or water turned into wine or 5000 fed with five loaves and two fish or men who have been dead and rotting in the grave for four days brought back to life. Perhaps these things still happen in non-scientific communities where the only proof is what a witness says and there is still scope for disbelief, but it seems to me that God is concerned to ensure to us that the laws of physics and chemistry are a constant and reliable circumstance. Perhaps He also wants to ensure that we don't lapse into a 'benefits' culture. If everything were available by miracle service, why would we ever work for a living.
Imagine a particular faith healer who had a reliable record of curing people. The scientists would be swarming all over him to investigate exactly how he worked the 'trick'. It would be Simon Magus all over again.
There will always be stories of miracles, but they will never be truly testable. A God who could be proved would require no faith. Sceptics will always be able to say 'there was insufficient evidence'. New Testament miracles were signs authenticating Jesus, just as Moses was given a shape-changing staff to prove his representative authority before Pharaoh. We have the Scripture; we have the Holy Spirit; we don't have authenticating miracles.
In the eighteenth century millions died from smallpox. Christians prayed to be free of this terrible scourge. God answered that prayer. He sent them Edward Jenner. He has also sent them thousands of scientists, physicians, nurses, radiographers, physiotherapists and pharmacists. The rate of cot-death has reduced remarkably by the simple expedient of lying the child on its back. Thousands of parents cried out in bafflement, "Why did God take my child?" It wasn't God to blame. We simply did not know better. At the time of the black death in London long-haired prophets saw it as a sign of the coming Apocalypse; yet the remedy was rat poison. Pious Dutch Calvinists saw smoking as a sign of a spiritual Christian; only the rebellious refused to smoke. They accepted their lung cancer and emphysema as God's will for them. God sent them Sir Richard Doll.
Even though I have never seen a healing miracle, I continue to pray for them. I never presume on one. I believe God is sovereign and He will have His way. Even in the years after Jesus' death Paul was well aware that prayer could not command relief from illness; Epaphroditus, Trophemus, Timothy and Paul himself were not miraculously healed despite their proximity to the resurrection. Paul's prayers were for the salvation of souls and their growth in grace. As for illness he was content with, "My grace is sufficient for you."
Saturday, November 08, 2008
Do Statins make Rituximab ineffective?
A few years ago a revolution took place in medical publishing with the introduction of open access journals freely available on line. Of course, someone has to pay for all the work that goes into publishing a journal and if there are no subscribers, it has to be the author who pays. This might seem like vanity publishing – like those slim volumes of dreadful poems, but clearly the journals hope that scientists will include provision for paying for publication in their grant applications. To some extent this already happens since page charges are slapped on everything that is published by journals like Blood. Indeed publishing in Blood is costly and the referees who do the work of assessing the article and making constructive criticisms receive no reimbursement. The American Society for Hematology makes a fine profit from the enterprise.
This is by way of introducing the fact that until now I had not read any of these open access articles, but I have just read an important paper in PLoS Medicine (I think that stands for public library of science. The article by Magdelena Winiarska from Warsaw, Poland tells us that “Statins impair antitumor effects of rituximab by introducing conformational changes of CD20”.
The title alone strikes fear into the heart of patients receiving statins who are also receiving rituximab. So before we jump to any conclusions we ought to read the paper and see if it says what the title implies.
First they demonstrated that incubating Raji cells (an EBV stimulated B-cell line often used for B cell experiments) with a statin for 48 hours reduced rituximab-induced complement dependent cytotoxicity (CDC) and antibody dependent cellular cytotoxicity (ADCC) in a dose dependent manner. Incubation with statins reduces the binding of anti-CD20 antibody to the surface of Raji cells, but it does not reduce the amount of CD20 produced by the cells. It appears that it is the reduction of cholesterol in the cell membrane that is responsible for this effect, which is common to all statins and works for other lymphoblastoid cell lines like Daudi and Ramos and with other anti-CD20 antibodies of both type I and type II. Incubation with cholesterol after the statin treatment restores the CDC and ADCC to normal. Although, binding of rituximab to CD20 translates the antigen into cholesterol-rich lipid rafts, this mechanism is not involved in the reduction of CDC or ADCC. Using something called an “atomic force microscope” and also limited proteolysis with trypsin and chymotrypsin they were able to establish that incubation with statins induces conformational changes in the CD20 antigen that affects the binding of type I and type II anti-CD20 antibodies.
Experiments with lymphoblastoid cell lines are all very well, but does this have any meaning in clinical practice? To address this question they incubated freshly isolated tumor cells from patients with mantle cell lymphomas with MbetaCD (which like statins extracts cholesterol from the cells membrane) and attempted to kill them with rituximab in a CDC assay. Killing was significantly reduced.
They also demonstrated that inpatients who were receiving statins for hypercholesterolemia, the binding of anti-CD20 to normal B cells decreased by 15-20%.
So does this have any meaning for CLL patients who are treated with rituximab?
First, I must draw attention to the fact that the clinical experiment has not been done. No-one has shown a lesser effect for rituximab in patients on statins.
Second, the reduction in killing of fresh lymphoma cells (as opposed to cells from a lymphoblastoid cell line) was after incubation with MbetaCD rather than a statin. I am sure they did the experiments with a statin but did not report it probably because there was no effect.
Third, as well as the incubation experiment with cells from three mantle cell lymphomas they also used cells from a patient with small B cell lymphoma (probably CLL but one can’t be sure). This patient started off with less surface CD20 on his or her cells and although incubation it was lessened significantly, but not by very much.
Fourth, if statins really did make such a difference as is implied, I would expect to see this paper in Blood or JCO or Haematologica or B J Haem – not in PLoS Medicine.
Finally, I should draw attention to a paper in Leukemia from 2003 by Polyak et al from Canada. They demonstrated that the monoclonal antibody FMC7 reacts with an epitope of CD20. As most CLL students know, FMC7 is usually absent from CLL cells. Why is that? It appears that the CD20 molecule undergoes a conformational change that hides the FMC7 epitope under certain circumstances. What circumstance? When the membrane is depleted of cholesterol. It appears that in CLL the cholesterol has already been depleted, which may explain why rituximab is such a poor drug in CLL compared to its activity in other kinds of lymphoma
This is by way of introducing the fact that until now I had not read any of these open access articles, but I have just read an important paper in PLoS Medicine (I think that stands for public library of science. The article by Magdelena Winiarska from Warsaw, Poland tells us that “Statins impair antitumor effects of rituximab by introducing conformational changes of CD20”.
The title alone strikes fear into the heart of patients receiving statins who are also receiving rituximab. So before we jump to any conclusions we ought to read the paper and see if it says what the title implies.
First they demonstrated that incubating Raji cells (an EBV stimulated B-cell line often used for B cell experiments) with a statin for 48 hours reduced rituximab-induced complement dependent cytotoxicity (CDC) and antibody dependent cellular cytotoxicity (ADCC) in a dose dependent manner. Incubation with statins reduces the binding of anti-CD20 antibody to the surface of Raji cells, but it does not reduce the amount of CD20 produced by the cells. It appears that it is the reduction of cholesterol in the cell membrane that is responsible for this effect, which is common to all statins and works for other lymphoblastoid cell lines like Daudi and Ramos and with other anti-CD20 antibodies of both type I and type II. Incubation with cholesterol after the statin treatment restores the CDC and ADCC to normal. Although, binding of rituximab to CD20 translates the antigen into cholesterol-rich lipid rafts, this mechanism is not involved in the reduction of CDC or ADCC. Using something called an “atomic force microscope” and also limited proteolysis with trypsin and chymotrypsin they were able to establish that incubation with statins induces conformational changes in the CD20 antigen that affects the binding of type I and type II anti-CD20 antibodies.
Experiments with lymphoblastoid cell lines are all very well, but does this have any meaning in clinical practice? To address this question they incubated freshly isolated tumor cells from patients with mantle cell lymphomas with MbetaCD (which like statins extracts cholesterol from the cells membrane) and attempted to kill them with rituximab in a CDC assay. Killing was significantly reduced.
They also demonstrated that inpatients who were receiving statins for hypercholesterolemia, the binding of anti-CD20 to normal B cells decreased by 15-20%.
So does this have any meaning for CLL patients who are treated with rituximab?
First, I must draw attention to the fact that the clinical experiment has not been done. No-one has shown a lesser effect for rituximab in patients on statins.
Second, the reduction in killing of fresh lymphoma cells (as opposed to cells from a lymphoblastoid cell line) was after incubation with MbetaCD rather than a statin. I am sure they did the experiments with a statin but did not report it probably because there was no effect.
Third, as well as the incubation experiment with cells from three mantle cell lymphomas they also used cells from a patient with small B cell lymphoma (probably CLL but one can’t be sure). This patient started off with less surface CD20 on his or her cells and although incubation it was lessened significantly, but not by very much.
Fourth, if statins really did make such a difference as is implied, I would expect to see this paper in Blood or JCO or Haematologica or B J Haem – not in PLoS Medicine.
Finally, I should draw attention to a paper in Leukemia from 2003 by Polyak et al from Canada. They demonstrated that the monoclonal antibody FMC7 reacts with an epitope of CD20. As most CLL students know, FMC7 is usually absent from CLL cells. Why is that? It appears that the CD20 molecule undergoes a conformational change that hides the FMC7 epitope under certain circumstances. What circumstance? When the membrane is depleted of cholesterol. It appears that in CLL the cholesterol has already been depleted, which may explain why rituximab is such a poor drug in CLL compared to its activity in other kinds of lymphoma
Phrases that upset.
Today's Telegraph has a list of phrases that upset that has been compiled by researchers at Oxford University. The top ten are:
1 - At the end of the day
2 - Fairly unique
3 - I personally
4 - At this moment in time
5 - With all due respect
6 - Absolutely
7 - It's a nightmare
8 - Shouldn't of (instead of shouldn't have)
9 - 24/7
10 - It's not rocket science
What is interesting is that the article to date has attracted 1477 comments. A lot of people are upset.
My own personal hate is 'fulsome praise'. Most people seem to think that it means extravagant praise when it means quite the opposite. 'fulsome' derives not from 'full' but from 'foul'. 'Fulsome praise' means praise contaminated by a sneer. If you like, it is a snide remark that seems at first to be praising but when you think about it has a rotten core.
1 - At the end of the day
2 - Fairly unique
3 - I personally
4 - At this moment in time
5 - With all due respect
6 - Absolutely
7 - It's a nightmare
8 - Shouldn't of (instead of shouldn't have)
9 - 24/7
10 - It's not rocket science
What is interesting is that the article to date has attracted 1477 comments. A lot of people are upset.
My own personal hate is 'fulsome praise'. Most people seem to think that it means extravagant praise when it means quite the opposite. 'fulsome' derives not from 'full' but from 'foul'. 'Fulsome praise' means praise contaminated by a sneer. If you like, it is a snide remark that seems at first to be praising but when you think about it has a rotten core.
Better than a Zimmer
Walking aids just got better. This new device produced by Honda supports those who have difficulty walking any distance or in working in a crouched position. If you have dodgy knees this is for you!
Tuesday, November 04, 2008
November
The weather forecaster yesterday predicted a low cloud cover for the south coast today. He was absolutely right. It is dull and overcast. Quite a grey day in fact. It was a grade A weather forecast.
Sunday, November 02, 2008
Election
No, I am not about to come out for either Obama or McCain. I am tackling the knotty problem at the start of I Peter.
The doctrine of election is anathema to many Christians. They can't bear to think of God choosing some for damnation. But there it is in Scripture, "Peter, an apostle of Jesus Christ to God's elect." This is not an isolated instance. Paul writes to the Ephesians "For he chose us in him before the creation of the world," and John writes "to the chosen lady" and Jude "to those who have been called."
The thing is that not only is it plainly present in Scripture, but it is also absolutely necessary. Jesus died on the cross to purchase everything needed for salvation. Whether you are a little old lady in Bognor Regis or a Napoleon of crime there is nothing you have done to is too dirty to be washed away. Dishonesty, lying, theft, extortion, adultery or any sexual sin, bullying, betrayal, greed, lust, laziness, gluttony, selfishness, brutality, even murder; none of them is so large or so heinous that they cannot be washed clean by Jesus. But here's the rub, whether you are a Napoleon of crime or a little old lady in Bognor Regis, there is no-one so clean as not to need washing. White lies, speeding, failing to declare something small on your tax return or not declaring a foreign purchase to the Customs Officer, lascivious thoughts enjoyed even if left unacted upon, a bus fare unpaid as a child, an apple stolen from a stall, a secret passed on as gossip, perhaps disguised as a prayer, an angry word, rudeness to a call center, cowardly backing down when you should have stood up for what is right, acquiescence at evil, neglect of those in need, a joke told against the helpless or weak or undefended minority; there is nothing so trivial that it doesn't need paying for. The Bible tells us that all have sinned and fallen short of the glory of God.
Sin in English is a technical word from archery. It is used when an arrow falls short of the target. Unless you hit the bullseye every time you are a sinner in need of a savior. Does Tiger Woods get a hole in one every time on every par 3? Does David Beckham score every time with every free-kick from just outside the penalty area? Did every Beatles record go straight to number 1? Is every hit a homer from Alex Rodriguez? Did Mohammad Ali win every fight by a knockout? Even the best professionals aren't perfect; do you expect to be?
So you'd better repent. Isn't that what all Christian preachers demand?
And just how do you think you are going to do that? The Bible says that we were all dead in trespasses and sins. Paul's letter to the Ephesians chapter 2 begins: As for you, you were dead in your transgressions and sins, in which you used to live when you followed the ways of this world and of the ruler of the kingdom of the air, the spirit who is now at work in those who are disobedient. All of us also lived among them at one time, gratifying the cravings of our sinful nature and following its desires and thoughts. Like the rest, we were by nature objects of wrath. But because of his great love for us, God, who is rich in mercy, made us alive with Christ even when we were dead in transgressions—it is by grace you have been saved.
We had no capacity to save ourselves. Even though Jesus had done everything that was necessary to spare us from the consequence of our rebellion against God, we could do nothing to grasp hold of it. Can the dead live? In Christ, God has demonstrated that they can, but only if God makes it so. God, who is rich in mercy made us alive with Christ when we were dead in transgressions. We are alive in Christ because God has chosen to make us alive in Christ; of our own strength we could not have done it.
Certain theologians want to make salvation a joint activity. Christ paid the price on the cross and we did our bit by choosing Christ. How did we do that when we were dead? For it is by grace you have been saved, through faith—and this not from yourselves, it is the gift of God — not by works, so that no one can boast (Ephesians 2:8-9)
How does that square with human responsibility? If we are only saved on God's whim and we can do nothing about it, how can we be blamed for not believing?
Human responsibility is also taught in Scripture. Imagine a ward full of drunks all in liver failure. Who is responsible for their being there? It's my ward, but I never made them drink. Indeed, I and doctors like me have been telling anyone who listens that alcohol is dangerous and can cause cirrhosis. I have been warning that younger and younger people are coming into hospital with damage to their livers. I have been trying to make them stop.
Is the fault of the shops who lower the price of alcohol as a loss leader and thus make it easier for them to drink? I think the shops who do that are irresponsible, but I, like millions of others walk straight by the stack of gin bottles in the supermarket and don't give them a second thought.
Is it the fault of their parents who set them a bad example or ill-treated them when they were young? There are thousands of children who come from bad homes yet turn into model citizens.
Is it the fault of the kind people who give money to beggars and don't consider that the money will go straight into the next bottle of spirits? I think giving money to panhandlers is silly - far better to buy them a sandwich, but even so the donors were only being kind.
Is it the fault of their genes? Some people can drink with impunity. Yes, but many alcoholics are rescued by AA and don't end up on the liver ward.
No, when it comes down to it the person who ends up with alcoholic liver disease, despite all the excuses, can only accept that he or she is personally responsible.
Suppose, now I come along and offer one of the patients a liver transplant. He doesn't have to pay, all he has to do is accept. Will you blame me that I don't offer a transplant to every patient? Will you tell me I am being unfair? Will you say that I have chosen to condemn all the others to a terrible death?
I would be being unfair. If fairness came into it I would leave them all to take the consequences of their drinking. Just as if God chose to save none he would be being fair to all. God's offer of salvation is not about fairness, it is not about justice, it is not even because some deserve mercy. It is all about grace - undeserved mercy. No-one should demand their rights from God -if they got what was due to them they would be excluded from His presence for ever.
Others hold back at the presumption of predestination. Verse 2 of 1 Peter 1 says that the elect are chosen according to the foreknowledge of God the Father. Does that mean that He zipped round to see the ending and then came back in time and chose those who would eventually choose Him? By no means. The word translated 'according to' does not mean 'depending on' but 'in harmony with'. God certainly knows the end from the beginning; from His point of view the future is fixed - but not from ours. There is no future is relying on destiny. We live our lives in the hope of every possibility. Yesterday, Liverpool (top of the league) played Spurs (bottom of the league) Within 3 minutes Liverpool were ahead and thereafter peppered the Spurs goal with monotonous regularity. They seemed destined to win easily. Then, the Liverpool central defender inadvertently scored for the opposition and in the last minute of overtime Spurs scored an improbable goal to win the match. It's never over 'til it's over. Charles Haddon Spurgeon, the great preacher of the nineteenth century was once admonished for spreading pearls before swine. "There is no point in preaching to those who are not elect, sir."
"I agree, " said Spurgeon, "Perhaps you would be so good as to put a chalk mark on the shoulders of those who are elect. Then I will be certain only to preach to them."
Why God chose whom he chose is a mystery. Jesus said, "I praise you, Father, Lord of heaven and earth, because you have hidden these things from the wise and learned, and revealed them to little children. Yes, Father, for this was your good pleasure. (Matthew 25:11,12) All we can say is they are chosen for the Father's good pleasure.
How is it done? How do the dead live? Through the sanctifying work of the Spirit. This is the work of the Holy Spirit
Why was it done? For obedience to Jesus Christ and sprinkling by his blood.
Here is the answer to those who say, "Once saved always saved; therefore I can rest on my laurels." We are saved for obedience and when we stumble as we all do there is still the sprinkling by his blood to cleanse us anew.
The grace of God is a wonderful doctrine. Spurgeon again, "He must have chosen me because, knowing my heart, I should never have chosen Him. And He must have chosen me before I was born, because he certainly would not have chosen me after I was born and started sinning."
"I'm forever grateful" goes the chorus, and from that gratitude comes every good work of the Christian. We don't strive for good works to earn our salvation - how would we ever know if we had done enough. We strive for good works because of our salvation - not to repay the cost, but out of gratitude and praise.
The doctrine of election is anathema to many Christians. They can't bear to think of God choosing some for damnation. But there it is in Scripture, "Peter, an apostle of Jesus Christ to God's elect." This is not an isolated instance. Paul writes to the Ephesians "For he chose us in him before the creation of the world," and John writes "to the chosen lady" and Jude "to those who have been called."
The thing is that not only is it plainly present in Scripture, but it is also absolutely necessary. Jesus died on the cross to purchase everything needed for salvation. Whether you are a little old lady in Bognor Regis or a Napoleon of crime there is nothing you have done to is too dirty to be washed away. Dishonesty, lying, theft, extortion, adultery or any sexual sin, bullying, betrayal, greed, lust, laziness, gluttony, selfishness, brutality, even murder; none of them is so large or so heinous that they cannot be washed clean by Jesus. But here's the rub, whether you are a Napoleon of crime or a little old lady in Bognor Regis, there is no-one so clean as not to need washing. White lies, speeding, failing to declare something small on your tax return or not declaring a foreign purchase to the Customs Officer, lascivious thoughts enjoyed even if left unacted upon, a bus fare unpaid as a child, an apple stolen from a stall, a secret passed on as gossip, perhaps disguised as a prayer, an angry word, rudeness to a call center, cowardly backing down when you should have stood up for what is right, acquiescence at evil, neglect of those in need, a joke told against the helpless or weak or undefended minority; there is nothing so trivial that it doesn't need paying for. The Bible tells us that all have sinned and fallen short of the glory of God.
Sin in English is a technical word from archery. It is used when an arrow falls short of the target. Unless you hit the bullseye every time you are a sinner in need of a savior. Does Tiger Woods get a hole in one every time on every par 3? Does David Beckham score every time with every free-kick from just outside the penalty area? Did every Beatles record go straight to number 1? Is every hit a homer from Alex Rodriguez? Did Mohammad Ali win every fight by a knockout? Even the best professionals aren't perfect; do you expect to be?
So you'd better repent. Isn't that what all Christian preachers demand?
And just how do you think you are going to do that? The Bible says that we were all dead in trespasses and sins. Paul's letter to the Ephesians chapter 2 begins: As for you, you were dead in your transgressions and sins, in which you used to live when you followed the ways of this world and of the ruler of the kingdom of the air, the spirit who is now at work in those who are disobedient. All of us also lived among them at one time, gratifying the cravings of our sinful nature and following its desires and thoughts. Like the rest, we were by nature objects of wrath. But because of his great love for us, God, who is rich in mercy, made us alive with Christ even when we were dead in transgressions—it is by grace you have been saved.
We had no capacity to save ourselves. Even though Jesus had done everything that was necessary to spare us from the consequence of our rebellion against God, we could do nothing to grasp hold of it. Can the dead live? In Christ, God has demonstrated that they can, but only if God makes it so. God, who is rich in mercy made us alive with Christ when we were dead in transgressions. We are alive in Christ because God has chosen to make us alive in Christ; of our own strength we could not have done it.
Certain theologians want to make salvation a joint activity. Christ paid the price on the cross and we did our bit by choosing Christ. How did we do that when we were dead? For it is by grace you have been saved, through faith—and this not from yourselves, it is the gift of God — not by works, so that no one can boast (Ephesians 2:8-9)
How does that square with human responsibility? If we are only saved on God's whim and we can do nothing about it, how can we be blamed for not believing?
Human responsibility is also taught in Scripture. Imagine a ward full of drunks all in liver failure. Who is responsible for their being there? It's my ward, but I never made them drink. Indeed, I and doctors like me have been telling anyone who listens that alcohol is dangerous and can cause cirrhosis. I have been warning that younger and younger people are coming into hospital with damage to their livers. I have been trying to make them stop.
Is the fault of the shops who lower the price of alcohol as a loss leader and thus make it easier for them to drink? I think the shops who do that are irresponsible, but I, like millions of others walk straight by the stack of gin bottles in the supermarket and don't give them a second thought.
Is it the fault of their parents who set them a bad example or ill-treated them when they were young? There are thousands of children who come from bad homes yet turn into model citizens.
Is it the fault of the kind people who give money to beggars and don't consider that the money will go straight into the next bottle of spirits? I think giving money to panhandlers is silly - far better to buy them a sandwich, but even so the donors were only being kind.
Is it the fault of their genes? Some people can drink with impunity. Yes, but many alcoholics are rescued by AA and don't end up on the liver ward.
No, when it comes down to it the person who ends up with alcoholic liver disease, despite all the excuses, can only accept that he or she is personally responsible.
Suppose, now I come along and offer one of the patients a liver transplant. He doesn't have to pay, all he has to do is accept. Will you blame me that I don't offer a transplant to every patient? Will you tell me I am being unfair? Will you say that I have chosen to condemn all the others to a terrible death?
I would be being unfair. If fairness came into it I would leave them all to take the consequences of their drinking. Just as if God chose to save none he would be being fair to all. God's offer of salvation is not about fairness, it is not about justice, it is not even because some deserve mercy. It is all about grace - undeserved mercy. No-one should demand their rights from God -if they got what was due to them they would be excluded from His presence for ever.
Others hold back at the presumption of predestination. Verse 2 of 1 Peter 1 says that the elect are chosen according to the foreknowledge of God the Father. Does that mean that He zipped round to see the ending and then came back in time and chose those who would eventually choose Him? By no means. The word translated 'according to' does not mean 'depending on' but 'in harmony with'. God certainly knows the end from the beginning; from His point of view the future is fixed - but not from ours. There is no future is relying on destiny. We live our lives in the hope of every possibility. Yesterday, Liverpool (top of the league) played Spurs (bottom of the league) Within 3 minutes Liverpool were ahead and thereafter peppered the Spurs goal with monotonous regularity. They seemed destined to win easily. Then, the Liverpool central defender inadvertently scored for the opposition and in the last minute of overtime Spurs scored an improbable goal to win the match. It's never over 'til it's over. Charles Haddon Spurgeon, the great preacher of the nineteenth century was once admonished for spreading pearls before swine. "There is no point in preaching to those who are not elect, sir."
"I agree, " said Spurgeon, "Perhaps you would be so good as to put a chalk mark on the shoulders of those who are elect. Then I will be certain only to preach to them."
Why God chose whom he chose is a mystery. Jesus said, "I praise you, Father, Lord of heaven and earth, because you have hidden these things from the wise and learned, and revealed them to little children. Yes, Father, for this was your good pleasure. (Matthew 25:11,12) All we can say is they are chosen for the Father's good pleasure.
How is it done? How do the dead live? Through the sanctifying work of the Spirit. This is the work of the Holy Spirit
Why was it done? For obedience to Jesus Christ and sprinkling by his blood.
Here is the answer to those who say, "Once saved always saved; therefore I can rest on my laurels." We are saved for obedience and when we stumble as we all do there is still the sprinkling by his blood to cleanse us anew.
The grace of God is a wonderful doctrine. Spurgeon again, "He must have chosen me because, knowing my heart, I should never have chosen Him. And He must have chosen me before I was born, because he certainly would not have chosen me after I was born and started sinning."
"I'm forever grateful" goes the chorus, and from that gratitude comes every good work of the Christian. We don't strive for good works to earn our salvation - how would we ever know if we had done enough. We strive for good works because of our salvation - not to repay the cost, but out of gratitude and praise.