Most people are agreed that FCR is the best first line therapy if you are fit enough. CAL-101 and PCI32765 both look promising as disease modifying agents that act a bit like Gleevec for CLL, though the jury is still out on long-term effects. What about second-line in patients who have responded well to FCR?
It seems that repeating FCR in patients who have had a 2-year remission and not suffered major problems with it first time around is probably the right idea. However, few people will be able to get six course in a second time and the older patient and one with co-morbidities might be better advise not to try.
Is there a place for bedamustine plus rituximab as second line in patients declared unfit for a second FCR? An Italian atudy has addressed this issue. They evaluated bendamustine plus or minus rituximab in a group of heavily pretreated patients.
109 patients of median age 66 (39-85) were included. There were 80 males. 20 had B symptoms. Median prior therapies was 3 (1-8). 38% had received previous fludarabine and 39% had had previous rituximab. 62 were resistant to their last treatment. 22 received bendamustine alone and 87 the combination of bendamustine + rituximab. There was no attempt to randomize between them and I can't really see the point of lumping the together. This was the B J Haem. In Leukemia Research we would have been a bit more stringent about how the trial was reported. In fact it wasn't a trial at all, but a retropective look back at how bendamustine had been used in 24 Italian centers. I am afraid I would have rejected the paper for Leukemia Research.
105 patients were evaluable for response. 30 obtained CR, 43 a PR and 32 obtained no response. The CR rate for B+R was 32.5% and only 13.6% for B alone. Responsive patients had a better response (84.8%) than resistant patients (57.6%) (p=0.004). The median duration of response was 13 months.
Only 36% of patients received the intended 6 courses. 7% received 5 courses, 21% 4 courses and 34% 1-3 courses. Four patients were stopped early because of toxicity (1 herpetic encephalitis, 1 relapse of a melanoma, 1 myocardial infarction and 1 grade 4 neutropenia. 16.5% had grade 4 neutropenia and 17.5% thrombocytopenia, 15.5% anemia and 4.5% infection. Three of the 34 deaths were thought to be treatment-related.
What to make of this study? In view of my previous posting, not much. This was not a trial with an independent review panel. Responses were assessed by the patients' individual doctors and bias easily creeps in. The median duration of response was just over a year - not very long. All we can say is that Bendamustine is a drug that has some response in previously treated patients. A year later roughly a third of those treated were dead. I'm not sure what was gained by publishing this report. I am not impressed.
Monday, May 16, 2011
Public heath issues
Libertarians will not be pleased with the New Scottish government since their first declared act will be to introduce a minimum price for alcohol of 50p per unit. Of all places in the world, Scotland is one of the most addicted to alcohol. Life expectancy in Scotland is lower than in the rest of the UK and drinking certainly plays a part in this. Objections have been made that this punishes the poorer drinker, but that is precisely why it is being introduced; it is the poorer drinker who is suffering from alcoholism, liver disease and domestic abuse. My own view is that while you have a national health service, with someone else picking up the tab for your bad behavior, then the insurer of last resort is fully justified in limiting his outgoings by whatever means.
Exactly the opposite problem is happening in Germany. There is a Federal ban on smoking in Federal buildings, and most of the States have introduced bans on smoking in restaurants, bars and pubs. However, a recent survey found that four out of five restaurants and pubs use legal loopholes to get round the smoking ban.
In the UK cigarette manufacturers are using psychological ploys to keep people smoking. There are selling cigarettes in packets of 14. Although these packets cost more per cigarette than packets of 20, it means that poorer smokers will have a smaller capital outlay per packet purchased. They have also determined that 14 cigarettes a day is a reasonable target to aim for poor smokers.
From 2012 large stores will no longer be able to display cigarettes for sale and even small tobacconists will be unable to do so from 2015.
I imagine that most right wing Americans are appalled by the proposed new health plan in Vermont. It would abolish most insurance plans and introduce a single payer. Apparently one in five people in Vermont is without health insurance. It is claimed that the Vermont plan would result in cost savings of 25% over 10 years by administrative simplification, the introduction of no-fault malpractice,, the elimination of perverse incentives like fees for service and the insulation of major healthcare decisions from politics. All I can say is ,”Good luck!”
Another current issue is the contribution of pharmaceutical companies to medical associations.. Many medical societies and non-profit disease awareness organizations receive much of their funding from drug and device manufacturers. Millions of dollars are involved. Although not necessarily applied primarily to sell their wares, these monies can easily taint the continuing medical education that they supposedly support.
However, doctors and nurses are reluctant to pay for CME activities themselves. Although most doctors recognize the potential for bias that drug company funded CME introduces, most underestimate exactly how much money the drug companies are putting in and how biased they are. Recently regulations about drug company funding have become more stringent. Applicants for EHA tell me it is much more difficult to obtain funds from Big Pharma now.
In other areas there is news about excess winter deaths in cold weather. Studies have shown that excess winter deaths in the UK are three times higher in the coldest houses compared to the warmest houses. Fuel poverty is defined as having to spend 10% or more of a household’s net income on heating the house to an adequate level. In 2008 it was estimated that 18% of households suffered from fuel poverty. The most easy to influence factor is house insulation and the 2011 Energy Bill seeks to produce a strategy to insulate enough homes to tackle fuel poverty.
Fewer children in England and Wales are dying violently. Numbers have fallen substantially in the past 30 years. From 1974 to 2008 the numbers of infants who died from assault fell from 5.6 per 100,000 to o.7 per 100,000. During the same period the death rate in all children from assault fell from 0.6 to 0.2 per 100,000. However, the death rate for 15-19 year old boys from assault has risen. Presumably this reflects gang warfare in inner cities.
One of the great successes of British Public Heath has been the reduction of road accidents as a cause of death. I remember in the 1950s when there were fewer than a million cars on the roads that there were over 7000 deaths on the roads annually. Today with 20 million+ vehicles on the roads, there are just over 2000 road deaths. Road deaths have been truly terrible in the past. During the time that 48,000 American soldiers were killed in World War I, 14,000 civilians were killed on American roads. In France road deaths have fallen from 16,000 to 4000 in 40 years.
Worldwide, nearly 1.3 million people are killed annually on the roads. It is the commonest cause of death among young people aged 15-29.. A quarter of these deaths occur in India and China. Brazil and Russia are other countries with high death rates. The WHO is keen to introduce a raft of measures that have proved successful in Britain, France, Australia and Sweden, including enforcement of traffic regulations, the wearing of seat belts, speed limits, motor cycle helmets and avoiding drink driving.
Exactly the opposite problem is happening in Germany. There is a Federal ban on smoking in Federal buildings, and most of the States have introduced bans on smoking in restaurants, bars and pubs. However, a recent survey found that four out of five restaurants and pubs use legal loopholes to get round the smoking ban.
In the UK cigarette manufacturers are using psychological ploys to keep people smoking. There are selling cigarettes in packets of 14. Although these packets cost more per cigarette than packets of 20, it means that poorer smokers will have a smaller capital outlay per packet purchased. They have also determined that 14 cigarettes a day is a reasonable target to aim for poor smokers.
From 2012 large stores will no longer be able to display cigarettes for sale and even small tobacconists will be unable to do so from 2015.
I imagine that most right wing Americans are appalled by the proposed new health plan in Vermont. It would abolish most insurance plans and introduce a single payer. Apparently one in five people in Vermont is without health insurance. It is claimed that the Vermont plan would result in cost savings of 25% over 10 years by administrative simplification, the introduction of no-fault malpractice,, the elimination of perverse incentives like fees for service and the insulation of major healthcare decisions from politics. All I can say is ,”Good luck!”
Another current issue is the contribution of pharmaceutical companies to medical associations.. Many medical societies and non-profit disease awareness organizations receive much of their funding from drug and device manufacturers. Millions of dollars are involved. Although not necessarily applied primarily to sell their wares, these monies can easily taint the continuing medical education that they supposedly support.
However, doctors and nurses are reluctant to pay for CME activities themselves. Although most doctors recognize the potential for bias that drug company funded CME introduces, most underestimate exactly how much money the drug companies are putting in and how biased they are. Recently regulations about drug company funding have become more stringent. Applicants for EHA tell me it is much more difficult to obtain funds from Big Pharma now.
In other areas there is news about excess winter deaths in cold weather. Studies have shown that excess winter deaths in the UK are three times higher in the coldest houses compared to the warmest houses. Fuel poverty is defined as having to spend 10% or more of a household’s net income on heating the house to an adequate level. In 2008 it was estimated that 18% of households suffered from fuel poverty. The most easy to influence factor is house insulation and the 2011 Energy Bill seeks to produce a strategy to insulate enough homes to tackle fuel poverty.
Fewer children in England and Wales are dying violently. Numbers have fallen substantially in the past 30 years. From 1974 to 2008 the numbers of infants who died from assault fell from 5.6 per 100,000 to o.7 per 100,000. During the same period the death rate in all children from assault fell from 0.6 to 0.2 per 100,000. However, the death rate for 15-19 year old boys from assault has risen. Presumably this reflects gang warfare in inner cities.
One of the great successes of British Public Heath has been the reduction of road accidents as a cause of death. I remember in the 1950s when there were fewer than a million cars on the roads that there were over 7000 deaths on the roads annually. Today with 20 million+ vehicles on the roads, there are just over 2000 road deaths. Road deaths have been truly terrible in the past. During the time that 48,000 American soldiers were killed in World War I, 14,000 civilians were killed on American roads. In France road deaths have fallen from 16,000 to 4000 in 40 years.
Worldwide, nearly 1.3 million people are killed annually on the roads. It is the commonest cause of death among young people aged 15-29.. A quarter of these deaths occur in India and China. Brazil and Russia are other countries with high death rates. The WHO is keen to introduce a raft of measures that have proved successful in Britain, France, Australia and Sweden, including enforcement of traffic regulations, the wearing of seat belts, speed limits, motor cycle helmets and avoiding drink driving.
John 3:17
For God did not send his Son into the world to condemn the world, but to save the world through him.
Too many see God as a present judge. The Law is there to reveal our sin and our need of a Savior. God has provided a remedy. He does not come to either condemn or condone, but to rescue. Imagine a number of people trapped in a forest fire. The fireman could bewail the fact that the forest is burning or could complain that those trapped by it must be arsonists. He could even pooh-pooh the whole idea of the fire and say it doesn't matter, but the real reason that he is a fireman is to rescue those who are perishing.
Too many see God as a present judge. The Law is there to reveal our sin and our need of a Savior. God has provided a remedy. He does not come to either condemn or condone, but to rescue. Imagine a number of people trapped in a forest fire. The fireman could bewail the fact that the forest is burning or could complain that those trapped by it must be arsonists. He could even pooh-pooh the whole idea of the fire and say it doesn't matter, but the real reason that he is a fireman is to rescue those who are perishing.
Sunday, May 15, 2011
The difficulties of assessing response in trials
One of the problems with clinical trials is that their interpretation is so subjective. Having spent a couple of years as part of an independent review panel looking at the outcome of a clinical trial I confess that I have found some of the decisions very difficult.
For example, to obtain a complete remission in CLL it is necessary for all evidence of the disease to disappear, but that is not enough. It is also necessary for the blood count to be restored to normal. It is not necessary to have the disappearance of the disease to be confirmed by CT or US scan, but it is necessary to demonstrate that there are fewer than 30% of lymphocytes in a bone marrow trephine. If for some reason there has been a CT scan or an US then far from making matters easier, they become more difficult.
If someone has simply been examined clinically then one has to feel the lymph nodes in neck, armpit and groin and note that none of them has a long diameter of greater than 1.5 cm - not easy to be sure if the patient is fat. Liver and spleen are measured in cm below the margin of the ribs. If, after treatment, no lymph nodes or liver or spleen can be felt then there is a chance of a complete remission. But if a scan is done we have to make a decision as to whether what we have imaged is normal tissue or abnormal and usually this is not possible. How large is a normal spleen? It is bigger for men than women and I take a longest diameter of 10 cm for women an 12 cm for men. But obviously it varies between individuals. Is 13 cms an enlarged spleen? If it has reduced from 19 cm is it a complete remission?
Livers are even more difficult. They can be enlarged in leukemia for other reasons than disease infiltration. Seldom do they return to a mid-axillary length of 12 cm after treatment. CT scans make things difficult. But if CT scans are not done there is a danger of missing important large retroperitoneal lymph nodes.
Bone marrow trephines post-chemotherapy are essential if there could be a CR. There has been a tendency to do bone marrow aspirates and look for minimal residual disease by flow cytometry, but this cuts no ice with those who are doing the assessing, even though it might be a more accurate and meaningful way of adjudicating on response. For a CR there must be fewer than 30% lymphocytes in the marrow trephine. Obviously we don't count every cell so someone makes an estimate. This is seldom done very accurately; someone just gives his best shot. Even if there are fewer than 30% the trephine must be free of nodules, since nodules are incalculable. If there are nodules then a CR becomes a nodular PR.
The bone marrow trephine must be normo- or hypercellular. If it is not, it must be repeated in 4 weeks. I can tell you that this is an instruction that is rarely fulfilled.
The net result is that when the rules are applied strictly there are few CRs and when they are not, the CRs that are declared cannot be trusted.
For example, to obtain a complete remission in CLL it is necessary for all evidence of the disease to disappear, but that is not enough. It is also necessary for the blood count to be restored to normal. It is not necessary to have the disappearance of the disease to be confirmed by CT or US scan, but it is necessary to demonstrate that there are fewer than 30% of lymphocytes in a bone marrow trephine. If for some reason there has been a CT scan or an US then far from making matters easier, they become more difficult.
If someone has simply been examined clinically then one has to feel the lymph nodes in neck, armpit and groin and note that none of them has a long diameter of greater than 1.5 cm - not easy to be sure if the patient is fat. Liver and spleen are measured in cm below the margin of the ribs. If, after treatment, no lymph nodes or liver or spleen can be felt then there is a chance of a complete remission. But if a scan is done we have to make a decision as to whether what we have imaged is normal tissue or abnormal and usually this is not possible. How large is a normal spleen? It is bigger for men than women and I take a longest diameter of 10 cm for women an 12 cm for men. But obviously it varies between individuals. Is 13 cms an enlarged spleen? If it has reduced from 19 cm is it a complete remission?
Livers are even more difficult. They can be enlarged in leukemia for other reasons than disease infiltration. Seldom do they return to a mid-axillary length of 12 cm after treatment. CT scans make things difficult. But if CT scans are not done there is a danger of missing important large retroperitoneal lymph nodes.
Bone marrow trephines post-chemotherapy are essential if there could be a CR. There has been a tendency to do bone marrow aspirates and look for minimal residual disease by flow cytometry, but this cuts no ice with those who are doing the assessing, even though it might be a more accurate and meaningful way of adjudicating on response. For a CR there must be fewer than 30% lymphocytes in the marrow trephine. Obviously we don't count every cell so someone makes an estimate. This is seldom done very accurately; someone just gives his best shot. Even if there are fewer than 30% the trephine must be free of nodules, since nodules are incalculable. If there are nodules then a CR becomes a nodular PR.
The bone marrow trephine must be normo- or hypercellular. If it is not, it must be repeated in 4 weeks. I can tell you that this is an instruction that is rarely fulfilled.
The net result is that when the rules are applied strictly there are few CRs and when they are not, the CRs that are declared cannot be trusted.
John 3:16
For God so loved the world that he gave his one and only Son, that whoever believes in him shall not perish but have eternal life.
Perhaps the most famous verse in the whole Bible. Hard to believe that God loved the world that much. Hard to believe that he gave his one and only Son. Hard to believe that anyone who believed. Hard to believe in eternal life. Yet it is true.
This is what the Gospel is about. If you reject this you reject everything. You may as well be a worm. The corrolary is that those who do not believe in him, shall perish.
Perhaps the most famous verse in the whole Bible. Hard to believe that God loved the world that much. Hard to believe that he gave his one and only Son. Hard to believe that anyone who believed. Hard to believe in eternal life. Yet it is true.
This is what the Gospel is about. If you reject this you reject everything. You may as well be a worm. The corrolary is that those who do not believe in him, shall perish.
Saturday, May 14, 2011
FCM v FCM-R
A randomized phase II trial is designed to discover whether one treatment has more responses than another one. This means that historical controls do not need to be used, but it tells us nothing about how long the responses last or whether the overall survival differs between the two treatments.
Some years ago the idea that mitoxantrone might be a good drug for CLL was floated and the British group have conducted at trial comparing FCM with FCM-R. The patient group looked at were those who required treatment according to the NCI guidelines, who had had at least one previous course of treatment. 52 patients were randomized between the two arms. The median age was 68 (32-79) with 79% male. 23/37 had a beta-2M >4. The median number of prior therapies was 2 (1-6). 63% had had prior fludarabine. 21% were either refractory to fludarabine or had relapsed within 6 months of having fludarabine. 26/45 had unmutated IGHV genes, 11 had del 11q, and one del 17p. The two groups were well balanced. 69% received at least 4 cycles of treatment but 50% failed to receive all 6 prescribed cycles. reasons for early discontinuation were: death (1), toxicity (7), chest infection (2), patient choice (1) and the other unknown.
The treatment arms were Fludarabine 24mg/sq m/d for 5 days orally, Cyclophosphamide 150 mg/sq m/d for 5 days orally, Mitoxantrone 6 mg/sq m iv on day 1 plus or minus rituximab 375 mg/sq m on day 1 of the first course and 500 mg/sq m on day 1 of subsequent courses.
The overall response rate was 58% for FCM and 65% for FCM-R (not significantly different). The CR + CRi rate was 15% for FCM and 42% for FCM-R (not significantly different). Similarly the MRD negative rates were similar at 12% and 19%.
Forty-one serious adverse events were reported, equally distributed between the two arms. Thirty-one were thought to be treatment related. The safety profile for both arms was found to be similar.
The authors conclude that these regimens should be tested in larger studies and in fact this is being done in the ARCTIC and ADMIRE trials.
Some years ago the idea that mitoxantrone might be a good drug for CLL was floated and the British group have conducted at trial comparing FCM with FCM-R. The patient group looked at were those who required treatment according to the NCI guidelines, who had had at least one previous course of treatment. 52 patients were randomized between the two arms. The median age was 68 (32-79) with 79% male. 23/37 had a beta-2M >4. The median number of prior therapies was 2 (1-6). 63% had had prior fludarabine. 21% were either refractory to fludarabine or had relapsed within 6 months of having fludarabine. 26/45 had unmutated IGHV genes, 11 had del 11q, and one del 17p. The two groups were well balanced. 69% received at least 4 cycles of treatment but 50% failed to receive all 6 prescribed cycles. reasons for early discontinuation were: death (1), toxicity (7), chest infection (2), patient choice (1) and the other unknown.
The treatment arms were Fludarabine 24mg/sq m/d for 5 days orally, Cyclophosphamide 150 mg/sq m/d for 5 days orally, Mitoxantrone 6 mg/sq m iv on day 1 plus or minus rituximab 375 mg/sq m on day 1 of the first course and 500 mg/sq m on day 1 of subsequent courses.
The overall response rate was 58% for FCM and 65% for FCM-R (not significantly different). The CR + CRi rate was 15% for FCM and 42% for FCM-R (not significantly different). Similarly the MRD negative rates were similar at 12% and 19%.
Forty-one serious adverse events were reported, equally distributed between the two arms. Thirty-one were thought to be treatment related. The safety profile for both arms was found to be similar.
The authors conclude that these regimens should be tested in larger studies and in fact this is being done in the ARCTIC and ADMIRE trials.
The Sound Barrier
Last night we watched another David Lean film, The Sound Barrier. Again it starred his wife, Ann Todd, together with Ralph Richardson, Nigel Patrick and Denholm Elliot. Like Psycho, it dispensed with it's Box Office attractions half way through the film.
Although ostensibly a story about technical advances, with the early days of jet airplanes glorified, but became a male versus female thing. Men believed things were worth doing, because they were there; women caring more for preserving life and limb. We hear the same battle when men go to war. Men can justify being in Iraq and Afghanistan, but women see the body bags and coffins.
Again the film showed what a great artist David Lean was, even before Lawrence of Arabia.
Although ostensibly a story about technical advances, with the early days of jet airplanes glorified, but became a male versus female thing. Men believed things were worth doing, because they were there; women caring more for preserving life and limb. We hear the same battle when men go to war. Men can justify being in Iraq and Afghanistan, but women see the body bags and coffins.
Again the film showed what a great artist David Lean was, even before Lawrence of Arabia.
John 3:14-15
Just as Moses lifted up the snake in the wilderness, so the Son of Man must be lifted up, that everyone who believes may have eternal life in him.”
The reference is to Numbers 21:8-9; the story of the bronze snake made by Moses when the Israelites were bitten by the snakes in the wilderness. I suppose this is a reference to the snake in the garden of Eden whose curse condemned mankind. The only way to be free from the curse of sin is by looking to Jesus. Note that jesus must be lifted up. There is no point in his just being there. We must make him known.
The reference is to Numbers 21:8-9; the story of the bronze snake made by Moses when the Israelites were bitten by the snakes in the wilderness. I suppose this is a reference to the snake in the garden of Eden whose curse condemned mankind. The only way to be free from the curse of sin is by looking to Jesus. Note that jesus must be lifted up. There is no point in his just being there. We must make him known.
Friday, May 13, 2011
Madeleine
The other night we watched an old David Lean film, Madelaine. It starred his wife, Ann Todd, and was the story of the Glasgow alleged murderess, Madelaine Smith. The case was famous for the Scottish verdict of 'not-proven'.
From time to time the old murder mystery is revisited on TV and most experts today consider her guilty, but she got away with it. The story was set in the 1850s and it was beautifully filmed in black and white. The attention to detail and the careful atmosphere that was developed show that Lean was one of the great directors. If you get a chance to see this great film, don't miss it.
From time to time the old murder mystery is revisited on TV and most experts today consider her guilty, but she got away with it. The story was set in the 1850s and it was beautifully filmed in black and white. The attention to detail and the careful atmosphere that was developed show that Lean was one of the great directors. If you get a chance to see this great film, don't miss it.
John 3:13
No one has ever gone into heaven except the one who came from heaven—the Son of Man.
What is there to do except to accept this statement at face value? Jesus spoke as one who had authority and this was why. He had the authority of God because he is God.
When we encounter the Jesus of the gospels we think of him as a man; he calls himself the son of man. But we must never forget that he is also God. There is no disputing with him. We cannot treat him as an equal. Although he subjected himself to the same traumas of life that we suffer, although he died on the cross, although he was betrayed and spat upon and hurt in so many ways; he was still God. We would do well to humble ourselves before him.
What is there to do except to accept this statement at face value? Jesus spoke as one who had authority and this was why. He had the authority of God because he is God.
When we encounter the Jesus of the gospels we think of him as a man; he calls himself the son of man. But we must never forget that he is also God. There is no disputing with him. We cannot treat him as an equal. Although he subjected himself to the same traumas of life that we suffer, although he died on the cross, although he was betrayed and spat upon and hurt in so many ways; he was still God. We would do well to humble ourselves before him.
New health bulletin
I have had a good week healthwise. I have been able to work quite hard on an international review panel for a clinical trial of a CLL drug, which necessitated 4 hours on the telephone to America and another 10 hours studying documents. As well as that, yesterday I attended a small group meeting from our church, which lasted two and a half hours. I was quite ‘buzzy’ by bed time and woke up at 3 am. I shall have to reduce the steroid dose.
Also this week we managed to spend a couple of hours in the New Forest. Tuesday was a balmy Spring day and we walked for 45 minutes among the tall trees at Rhinefelt near where Richard Branson owns a restaurant. Giant redwoods and Douglas Firs are among the tallest trees in the UK. The plantation has been run by the Forestry Commission since 1829 and it is a splendid facility. We met four other old couples walking round in the opposite direction, so we had the place almost to ourselves. It was certainly superior to the facility we visited just outside San Francisco.
The very hot weather has passed and the climate has returned to normal for mid Spring in England. Bright days with occasional showers. The flowers are about two weeks ahead of normal, but the garden is looking well. We have a new young gardener, our old one having had to give up with a bad back. It’s good to see young men picking up the old skills.
Also this week we managed to spend a couple of hours in the New Forest. Tuesday was a balmy Spring day and we walked for 45 minutes among the tall trees at Rhinefelt near where Richard Branson owns a restaurant. Giant redwoods and Douglas Firs are among the tallest trees in the UK. The plantation has been run by the Forestry Commission since 1829 and it is a splendid facility. We met four other old couples walking round in the opposite direction, so we had the place almost to ourselves. It was certainly superior to the facility we visited just outside San Francisco.
The very hot weather has passed and the climate has returned to normal for mid Spring in England. Bright days with occasional showers. The flowers are about two weeks ahead of normal, but the garden is looking well. We have a new young gardener, our old one having had to give up with a bad back. It’s good to see young men picking up the old skills.
John 3:11-12
Blogger has been down all day and it looks as though yesterday's posting on John has been lost. I will try to reconstruct it.
Very truly I tell you, we speak of what we know, and we testify to what we have seen, but still you people do not accept our testimony. I have spoken to you of earthly things and you do not believe; how then will you believe if I speak of heavenly things?
Were ever two at more of a cross purpose? Nicodemus is down-to-earth, logical, practically minded but Jesus is speaking of heavenly things. Dawkins and his ilk believe that the physical is all that there is, but Christianity is predicated on there being a supernatural existence.
Do you have a supernatural life and do you water it with prayer?
Very truly I tell you, we speak of what we know, and we testify to what we have seen, but still you people do not accept our testimony. I have spoken to you of earthly things and you do not believe; how then will you believe if I speak of heavenly things?
Were ever two at more of a cross purpose? Nicodemus is down-to-earth, logical, practically minded but Jesus is speaking of heavenly things. Dawkins and his ilk believe that the physical is all that there is, but Christianity is predicated on there being a supernatural existence.
Do you have a supernatural life and do you water it with prayer?
Hsp-90 revisited
It is always nice to see one’s old research fellows doing well. A couple of years ago Giles Best was working in our lab on CLL and I see he is now in Australia, working with Stephen Mulligan in Sydney. He has just published a paper in the British Journal of Haematology on a novel Hsp-90 inhibitor, SNX7081.
Readers will remember that there was a lot of excitement about the Hsp90 inhibitor, 17-AAG, particularly since the up-regulation of ZAP-70 used Hsp-90 as a chaperon. Recently there are suggestions that Hsp-90 inhibitors have promise in targeting cells with mutations of ATM and TP53. However, because of its quinine moiety at its core, 17-AAG looks like proving too toxic for clinical use.
Consequently, novel synthetic inhibitors have been developed including a family of products by Serenex. One of these is studied here. They have looked at the activity of an inhibitor, SNX7801, against a panel of eight haematological cell lines and 23 CLL patient samples. They found that SNX7081 is significantly more potent than 17-AAG in reducing the number of viable tumour cells by causing dramatic cell-cycle arrest without necessitating the TP53 pathway to be intact and by significantly reducing the amount of ZAP-70 expressed.
SNX7081 is recommended for clinical trials
Readers will remember that there was a lot of excitement about the Hsp90 inhibitor, 17-AAG, particularly since the up-regulation of ZAP-70 used Hsp-90 as a chaperon. Recently there are suggestions that Hsp-90 inhibitors have promise in targeting cells with mutations of ATM and TP53. However, because of its quinine moiety at its core, 17-AAG looks like proving too toxic for clinical use.
Consequently, novel synthetic inhibitors have been developed including a family of products by Serenex. One of these is studied here. They have looked at the activity of an inhibitor, SNX7801, against a panel of eight haematological cell lines and 23 CLL patient samples. They found that SNX7081 is significantly more potent than 17-AAG in reducing the number of viable tumour cells by causing dramatic cell-cycle arrest without necessitating the TP53 pathway to be intact and by significantly reducing the amount of ZAP-70 expressed.
SNX7081 is recommended for clinical trials
Thursday, May 12, 2011
John 3:11-12
Very truly I tell you, we speak of what we know, and we testify to what we have seen, but still you people do not accept our testimony. I have spoken to you of earthly things and you do not believe; how then will you believe if I speak of heavenly things?
If ever people were talking at cross purposes it was these two. Nicodemus, being logical, down-to-earth, matter-of-fact; Jesus speaking of heavenly things; the two had no point of contact.
What we have to convince people of is that the physical is not all there is. Dawkins and his cohort would insist that it is, but the whole idea of Christianity is predicated on that there is more than the physical.
Do you have a spiritual life? Do you appreciate the supernatural and do you relate to it in prayer?
If ever people were talking at cross purposes it was these two. Nicodemus, being logical, down-to-earth, matter-of-fact; Jesus speaking of heavenly things; the two had no point of contact.
What we have to convince people of is that the physical is not all there is. Dawkins and his cohort would insist that it is, but the whole idea of Christianity is predicated on that there is more than the physical.
Do you have a spiritual life? Do you appreciate the supernatural and do you relate to it in prayer?
Wednesday, May 11, 2011
What is wrong with the NHS
The NHS is being reorganized again - or is it. In the wake of the Liberal Democrats defeat at the polls they are stiffening up their opposition to Andrew Lansley's Health Bill in the hope that they will be seen by the electorate as still having some backbone.
The Health Bill was an attempt to make the NHS more accountable to its users by giving control of the budgets to consortia of local family doctors instead of administrators. The government has ring fenced the budget of the NHS, but since there is a built-in inflation in health spending due to demographic drift and scientific development, even a stand-still budget seems like cuts.
So what is wrong with the NHS and what needs fixing?
The last Labour government threw a lot of money at the NHS and brought average spending up to where it was in most of Europe - but of course during the same period Europe also increased its spending so that the NHS still lags behind Germany, Spain and France in its spending. The criticism was made that much of the money was wasted because productivity actually fell while the spending increased. I contend that this was because the government did not believe how hard doctors and nurses were working. The contracts were made more watertight so that people were actually paid for their work and discouraged from doing unpaid overtime by the European Working Time Directive. So it appeared that people were doing less for more. More jobs were created to fill in the gaps.
Another criticism of the NHS was that priorities for treatment had become distorted. Waiting lists had been shortened to no more than 18 weeks anywhere, but this had sometimes meant that things like cosmetic surgery were given priority over mental health services or even cancer surgery. Cancer referrals was supposed to take no more than 2 weeks, but there were built in delays waiting for scans and follow-up appointments. Again every breast lump was placed at the head of the queue even though many of them would be benign cysts.
By giving GPs the budget the idea would be that they could better decide on priorities and not make the same basic errors that administrators would make. On the other hand GPs are themselves providers to the NHS and might find it profitable to favor their own services at the expense of other providers. Near-patient testing or the use of 'factory laboratories' without pathologist's supervision, might be preferred to our conventional model. GPs certainly favored themselves when abandoning night duties to private services for a very small cut in income. The private night services have scored some spectacular own-goals.
One possible drive behind the Conservative reforms has been the possibility of private providers supplying some of the services. I have no problem with this as long as they are professionally scrutinized. We have private catering and waste disposal, and why not. The attempt by Blair's government to introduce private treatment centers for orthopedic operations was disastrous. They cherry-picked the easy options and left their complications to be picked up by the NHS.
The other drawback of private treatment centers is their lack of commitment to training and research which are an essential element of the NHS. One remedy for this would be to ensure that hospital specialists had a say in the purchasing of services, but Lansley is resisting this. Lansley has family members who are family doctors and his might not be an unjaundiced eye.
It seems to me that there some elements of health that have to be provided by the public sector. This is recognized even in America where the CDC and VA are both provided at public expense.
Another question is whether it is possible to restrain the costs of drugs. In any market any product can price itself out of contention. The very rich, like Steve Jobs, will be able to buy anything to keep himself alive; the indigenous poor will not. An insurance system, however provided, evens out the difference, but it will not be attractive to everybody. Attempts to arbitrarily control what is spent will fall foul of individual unfair exceptions. The UK government has set up a cancer fund to deal with these exceptions when NICE seems harsh. It has not been universally acceptable.
I suppose what is wrong with the NHS is what is wrong with modern medicine. It is not universally successful.
The Health Bill was an attempt to make the NHS more accountable to its users by giving control of the budgets to consortia of local family doctors instead of administrators. The government has ring fenced the budget of the NHS, but since there is a built-in inflation in health spending due to demographic drift and scientific development, even a stand-still budget seems like cuts.
So what is wrong with the NHS and what needs fixing?
The last Labour government threw a lot of money at the NHS and brought average spending up to where it was in most of Europe - but of course during the same period Europe also increased its spending so that the NHS still lags behind Germany, Spain and France in its spending. The criticism was made that much of the money was wasted because productivity actually fell while the spending increased. I contend that this was because the government did not believe how hard doctors and nurses were working. The contracts were made more watertight so that people were actually paid for their work and discouraged from doing unpaid overtime by the European Working Time Directive. So it appeared that people were doing less for more. More jobs were created to fill in the gaps.
Another criticism of the NHS was that priorities for treatment had become distorted. Waiting lists had been shortened to no more than 18 weeks anywhere, but this had sometimes meant that things like cosmetic surgery were given priority over mental health services or even cancer surgery. Cancer referrals was supposed to take no more than 2 weeks, but there were built in delays waiting for scans and follow-up appointments. Again every breast lump was placed at the head of the queue even though many of them would be benign cysts.
By giving GPs the budget the idea would be that they could better decide on priorities and not make the same basic errors that administrators would make. On the other hand GPs are themselves providers to the NHS and might find it profitable to favor their own services at the expense of other providers. Near-patient testing or the use of 'factory laboratories' without pathologist's supervision, might be preferred to our conventional model. GPs certainly favored themselves when abandoning night duties to private services for a very small cut in income. The private night services have scored some spectacular own-goals.
One possible drive behind the Conservative reforms has been the possibility of private providers supplying some of the services. I have no problem with this as long as they are professionally scrutinized. We have private catering and waste disposal, and why not. The attempt by Blair's government to introduce private treatment centers for orthopedic operations was disastrous. They cherry-picked the easy options and left their complications to be picked up by the NHS.
The other drawback of private treatment centers is their lack of commitment to training and research which are an essential element of the NHS. One remedy for this would be to ensure that hospital specialists had a say in the purchasing of services, but Lansley is resisting this. Lansley has family members who are family doctors and his might not be an unjaundiced eye.
It seems to me that there some elements of health that have to be provided by the public sector. This is recognized even in America where the CDC and VA are both provided at public expense.
Another question is whether it is possible to restrain the costs of drugs. In any market any product can price itself out of contention. The very rich, like Steve Jobs, will be able to buy anything to keep himself alive; the indigenous poor will not. An insurance system, however provided, evens out the difference, but it will not be attractive to everybody. Attempts to arbitrarily control what is spent will fall foul of individual unfair exceptions. The UK government has set up a cancer fund to deal with these exceptions when NICE seems harsh. It has not been universally acceptable.
I suppose what is wrong with the NHS is what is wrong with modern medicine. It is not universally successful.
John 3:9-10
“How can this be?” Nicodemus asked. “You are Israel’s teacher,” said Jesus, “and do you not understand these things?
Jesus gently mocks Nicodemus, but at the same time continues to undermine the Old religion. First the purification rituals, then the idea of Temple sacrifice, now the Rabbinical authority. The old has gone.
Jesus gently mocks Nicodemus, but at the same time continues to undermine the Old religion. First the purification rituals, then the idea of Temple sacrifice, now the Rabbinical authority. The old has gone.
Tuesday, May 10, 2011
John 3:5-8
Jesus answered, “Very truly I tell you, no one can enter the kingdom of God unless they are born of water and the Spirit. Flesh gives birth to flesh, but the Spirit gives birth to spirit. You should not be surprised at my saying, ‘You must be born again.’ The wind blows wherever it pleases. You hear its sound, but you cannot tell where it comes from or where it is going. So it is with everyone born of the Spirit.”
A lot of nonsense is talked about 'spirituality'. It is all about letting go of your body, letting your mind drift and surrendering to the 'forces of the Universe'. It goes with Green issues, Gaia, wind chimes, crystals, Nature, sustainability, vegetarianism, and macrobiotic diets, and it goes against anything to do with reason, logic, planning, chemicals, genetics, science or materials.
Not so with the Holy Spirit. The Spirit is purposeful, thoughtful, concerned and a person. He is there to point people to Jesus. He stands alongside, encouraging, controling, thinking, planning, guarding and protecting. That 'other' spirituality is just about being controled by your emotions.
A lot of nonsense is talked about 'spirituality'. It is all about letting go of your body, letting your mind drift and surrendering to the 'forces of the Universe'. It goes with Green issues, Gaia, wind chimes, crystals, Nature, sustainability, vegetarianism, and macrobiotic diets, and it goes against anything to do with reason, logic, planning, chemicals, genetics, science or materials.
Not so with the Holy Spirit. The Spirit is purposeful, thoughtful, concerned and a person. He is there to point people to Jesus. He stands alongside, encouraging, controling, thinking, planning, guarding and protecting. That 'other' spirituality is just about being controled by your emotions.
Monday, May 09, 2011
John 3:4
"How can a man be born when he is old?" Nicodemas asked. "Surely he cannot enter a second time into his mother's womb to be born!"
The supreme example of taking things too literally! This seems to have been a common failing with the Jews, yet Jesus was a a wonderful teacher in his use of metaphor and other figures of speech. Today many of our greatest scientists are of Jewish extraction. Is it a genetic thing, the ability to think logically in straight lines? Yet the Bible shows us that Jewish literature is filled with flights of fancy and invention. Perhaps it is just down to individuals, but Nicodemus is being obtuse here.
The supreme example of taking things too literally! This seems to have been a common failing with the Jews, yet Jesus was a a wonderful teacher in his use of metaphor and other figures of speech. Today many of our greatest scientists are of Jewish extraction. Is it a genetic thing, the ability to think logically in straight lines? Yet the Bible shows us that Jewish literature is filled with flights of fancy and invention. Perhaps it is just down to individuals, but Nicodemus is being obtuse here.
Sunday, May 08, 2011
John 3:3
In reply Jesus declared, "I tell you the truth, no-one can see the kingdom of God unless he is born again
Being born again has become a cliche, but it is still true. The rebirth is not physical but spiritual and very specific - not spiritual in the sense of crystals and meditation. It involves starting over in a transformed way and it is not something you can do for yourself -as we shall see.
You can't give birth to yourself; you need to be delivered.
Being born again has become a cliche, but it is still true. The rebirth is not physical but spiritual and very specific - not spiritual in the sense of crystals and meditation. It involves starting over in a transformed way and it is not something you can do for yourself -as we shall see.
You can't give birth to yourself; you need to be delivered.
Richter's Syndrome: important new information
Richter's syndrome (RS) is the development of a diffuse large cell lymphoma from a background of conventional CLL. It has clearly been recognized that this can occur in two separate ways: either from the progression of the CLL clone to a different, more aggressive, histology or by the development of a clonally unrelated large cell lymphoma.
Much of the literature about Richter's syndrome is inadequate, relying on small or old series, often not confirmed histologically, so the paper in Blood of March 24th is welcome. This Italian study looks at a series of 86 patients.
Median time from the diagnosis of CLL to the diagnosis of RS was 3.7 years (range 0.2-6.7 years). 83/86 were evaluable for survival.The median survival time was 19 months. The follow up was 57 months during which 62.6% had died. Only 40 of the cases of RS were CD5 positive (48.2%); 92.7% displayed a non-germinal center type cell of origin and EBV infection was demonstrated in only 5.9%. The IGHV genes were unmutated in 64.7% and stereotyped VH CDR3 occurred in 36.4%
47.1% carried disruption of TP53 by either deletion or mutation or both. c-MYC abnormalities were present in 26.3%, but BCL2 and BCL6 translocations did not occur. In 50% of cases the c-MYC abnormality was paired with a TP53 abnormality.
Disruption of TP53 was a major prognostic factor. Median survival for those with a disruption was 9.4 months versus 47.1 months for those without a problem at TP53. By univariate analysis other factors associated with poor survival were age over 60, Performance score of >1, tumor size >5cm, platelet count <100, LDH >1.5 x upper limit of normal. Associated with good survival were achievement of CR after remission induction therapy and allogeneic transplant after remission.
By multivariate analysis TP53 disruption was an independent predictor of poor survival along with failure of achievement of CR after remission induction therapy and poor performance score. Use of these three factors stratifies patients into risk groups. Patients with poor performance status had a median survival of 7.8 months. Patients with good performance status but harboring TP53 disruption or not achieving a CR had a median survival of 24.6 months. Patients with none of the adverse risk factors had a 5-year survival of 70%.
It was not possible to determine the clonal relationship between the CLL and RS in 23 cases because paired material was not available, but in the remainder there was a clonal relationship in 79.3% of cases. Those that were clonally unrelated had significantly less TP53 disruption (3 of 13 compared with 30 of 50) and had a lower prevalence of stereotyped VH CDR3. Clonally unrelated cases had a longer median survival (62.5 months) compared to clonally related cases (14.2 months).
I think this is an extremely important paper because we are at a loss as where to go with RS. Generally, patients are treated on clinical suspicion of RS without histological proof and without molecular dissection of the tumor, usually with CHOP-R. What this paper tells us is that while resembling diffuse large B-cell lymphoma (DLBCL), RS is mostly very different. Approximately 4 in 5 cases derive from the CLL clone and in these cases particularly the pattern is quite distinct. DLBCL carries mutated IGHV genes and is usually positive for BCL2 and BCL6. RS carries unmutated IGHV genes in 60% of cases and is negative for BCL2 and BCL6. RS tends to be like refractory CLL in having disruption of TP53 and is therefore unlikely to respond to conventional drugs.
The RS cases that are unrelated to the CLL presumabl occur because of the genetic damage inflicted on normal tissue by the cytotoxic drugs and the release of T-cell suppression caused by drugs like fludarabine. Thankfully, CHOP-R is a good choice in this context, but it just isn't going to work in TP53 disrupted cases.
How then should we proceed? It seems to me that there should be a high index of suspicion. The old literature suggested that the incidence of RS in CLL was 3.5%, but with the advent of more aggressive therapy it might be as high as 10% in multiply treated patients. It is important to treat early when performance status is still good and the tumor small. It is also important to get histological proof so the physician knows what he is dealing with. One thing that should be avoided is blind treatment with CHOP-R, which in many cases will be futile and only serve to impair performance status of the patient.
Which drugs are useful in TP53 resistant cases of intermediate grade lymphoma? Only one that we are sure of, high dose steroids. Other drugs like Revlimid, Campath and flavapiridol have no track record in DLBCL. Perhaps the Btk or PI3Kdelta inhibitors might have a place?
Much of the literature about Richter's syndrome is inadequate, relying on small or old series, often not confirmed histologically, so the paper in Blood of March 24th is welcome. This Italian study looks at a series of 86 patients.
Median time from the diagnosis of CLL to the diagnosis of RS was 3.7 years (range 0.2-6.7 years). 83/86 were evaluable for survival.The median survival time was 19 months. The follow up was 57 months during which 62.6% had died. Only 40 of the cases of RS were CD5 positive (48.2%); 92.7% displayed a non-germinal center type cell of origin and EBV infection was demonstrated in only 5.9%. The IGHV genes were unmutated in 64.7% and stereotyped VH CDR3 occurred in 36.4%
47.1% carried disruption of TP53 by either deletion or mutation or both. c-MYC abnormalities were present in 26.3%, but BCL2 and BCL6 translocations did not occur. In 50% of cases the c-MYC abnormality was paired with a TP53 abnormality.
Disruption of TP53 was a major prognostic factor. Median survival for those with a disruption was 9.4 months versus 47.1 months for those without a problem at TP53. By univariate analysis other factors associated with poor survival were age over 60, Performance score of >1, tumor size >5cm, platelet count <100, LDH >1.5 x upper limit of normal. Associated with good survival were achievement of CR after remission induction therapy and allogeneic transplant after remission.
By multivariate analysis TP53 disruption was an independent predictor of poor survival along with failure of achievement of CR after remission induction therapy and poor performance score. Use of these three factors stratifies patients into risk groups. Patients with poor performance status had a median survival of 7.8 months. Patients with good performance status but harboring TP53 disruption or not achieving a CR had a median survival of 24.6 months. Patients with none of the adverse risk factors had a 5-year survival of 70%.
It was not possible to determine the clonal relationship between the CLL and RS in 23 cases because paired material was not available, but in the remainder there was a clonal relationship in 79.3% of cases. Those that were clonally unrelated had significantly less TP53 disruption (3 of 13 compared with 30 of 50) and had a lower prevalence of stereotyped VH CDR3. Clonally unrelated cases had a longer median survival (62.5 months) compared to clonally related cases (14.2 months).
I think this is an extremely important paper because we are at a loss as where to go with RS. Generally, patients are treated on clinical suspicion of RS without histological proof and without molecular dissection of the tumor, usually with CHOP-R. What this paper tells us is that while resembling diffuse large B-cell lymphoma (DLBCL), RS is mostly very different. Approximately 4 in 5 cases derive from the CLL clone and in these cases particularly the pattern is quite distinct. DLBCL carries mutated IGHV genes and is usually positive for BCL2 and BCL6. RS carries unmutated IGHV genes in 60% of cases and is negative for BCL2 and BCL6. RS tends to be like refractory CLL in having disruption of TP53 and is therefore unlikely to respond to conventional drugs.
The RS cases that are unrelated to the CLL presumabl occur because of the genetic damage inflicted on normal tissue by the cytotoxic drugs and the release of T-cell suppression caused by drugs like fludarabine. Thankfully, CHOP-R is a good choice in this context, but it just isn't going to work in TP53 disrupted cases.
How then should we proceed? It seems to me that there should be a high index of suspicion. The old literature suggested that the incidence of RS in CLL was 3.5%, but with the advent of more aggressive therapy it might be as high as 10% in multiply treated patients. It is important to treat early when performance status is still good and the tumor small. It is also important to get histological proof so the physician knows what he is dealing with. One thing that should be avoided is blind treatment with CHOP-R, which in many cases will be futile and only serve to impair performance status of the patient.
Which drugs are useful in TP53 resistant cases of intermediate grade lymphoma? Only one that we are sure of, high dose steroids. Other drugs like Revlimid, Campath and flavapiridol have no track record in DLBCL. Perhaps the Btk or PI3Kdelta inhibitors might have a place?
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