I last wrote about ALK in June 2008. I first came upon it when sitting at the feet of Professor Dennis Wright who gave us weekly tutorials on lymphomas while I was working in Bournemouth. Anaplastic large cell lymphoma needs to be distinguished from Hodgkin's disease (both of which show CD30 positivity) and can be so distinguished because of a chromosomal translocation which produces the NPM-ALK fusion protein.
However ALK can have many other partners in lots of different cell types. The important thing about ALK is that it is a tyrosine kinase like Glivec and could be inhibited therapeutically.
In this week's New England Journal of Medicine there are a series of reports where this has happened. The new TKI (tyrosine kinase inhibitor) is called Crizotnib and the tumor it works in is non-small cell lung cancer. Like Glivec, its efficacy became apparent after a small phase I trial. This type of non-small cell lung cancer is a small subtype, comprising only 5.5%, but this might mean over 10,000 candidates a year in the USA alone. Most of this group are non-smokers with adenocarcinomas. They had mostly already had best available chemotherapy, so a 57% response rate in these patients is impressive. It is early days yet, but this represents another step along the pathway to tailored therapy for cancer.
Sunday, October 31, 2010
Has medicine been affected by the cuts?
How has the autumn spending review affected medicine in the UK? As you can imagine, the left-wing can pick holes in what the government is doing. The effects of the spending review are undoubtedly regressive - in that they hit the poor harder than the rich, but they have to be taken in the context of the two budgets that have been presented this year, the first by Labour and the second by George Osborne. When the whole package is examined it can be seen to be progressive, with the rich picking up the bigger bill.
The spending review has hit welfare benefits hardest. The main targets have been housing benefits, which have meant that the poorly paid and unemployed - including outrageous examples of recent immigrants with very large families living in luxury pads in West London - are subsidized to live in central London, while ordinary workers have to commute for several hours every day. I can certainly see the need to subsidize low-paid cleaners and essential workers like nurses and teachers etc to be able to do their jobs, but if you are unemployed in central London, then you really have no intention of working and you could be as indolent in Hull or Middlesboro, where you can buy a street for the cost of a house in London, no matter what your emotional ties to London.
There is also good news for those who are caught in a poverty trap. The welfare reforms should mean that it is always more profitable to work than accept benefits. At the moment there are perverse incentives not to work. Furthermore an element of fairness is being introduced. No-one should receive more in benefits than the average family income. After all the taxpayer funds these benefits, and were I earning only a small amount, I should protest at my taxes paying for my neighbor to get out of bed at 11 am, sit on the sofa, watch the racing on his flat screen TV eating Cherios and drinking cheap cider.
This may all sound like Daily-Mail-speak, and perhaps there are some harder cases that need consideration, but everyone puts up anecdotes to support their case. The Welfare Minister has presented some statistics which demonstrate that much of the hoohah is just that.
Of course, other departments have been hit by the cuts, but the government claim to have ring fenced the schools budget (though not the Department of Education itself), the NHS and the International AID budget. From today's Lancet we read - Although the health budget will increase by £10 billion to a total of £114 billion over the next 4 years—equivalent to a 0·1% rise per year in real terms—in recent years health spending has risen annually by over 4% in real terms. Many factors could lead to increased health-care costs, including the ageing population, a rising prevalence of obesity, the price of new medicines, the promised cancer drugs fund of £200 million, and the £1 billion a year needed to support social care that overlaps with the NHS (for example, rehabilitation care). This will, in fact, lead to cuts within the NHS, but then, in my time in NHS management, it was taken for granted that every year we had to find 2% 'efficiency savings'. This generally meant that somebody's pet project could not be taken forward next year or that we had to admit that last year we had 'banked' money - for example by buying a year's X-ray film in advance and holding it in cold storage.
What of medical research? Again the Lancet is encouraging: The UK has a tradition of excellence in science and medicine—this year Robert Edwards was awarded a Nobel prize for medicine, and David Weatherall won a Lasker Award. The UK is also the most productive research nation per head in the G8, producing 14% of the most highly-cited papers and 9% of total research publications, despite making up just 1% of the world's population. The Government has listened to the scientific community's argument that continued investment in science is vital to the UK's future success, and over £700 million a year on research and development from the Department of Health will be protected in real terms. Also, the spending review promises a real-term increase in the Medical Research Council's budget. “It is vital that we retain a good science budget and invest in our science base”, said Prime Minister David Cameron. The research community must now ensure that it delivers on this vote of confidence.
What about aid? Again the Lancet has a comment: The amount that the UK's Department for International Development (DfID) spends on overseas aid is to rise from £7 billion to £11·5 billion over the next 4 years, and by 2013 the UK should meet its UN commitment to spend 0·7% of national income on overseas development. The money spent on countries in conflict will increase to £3·8 billion, with a larger proportion going to Afghanistan at the expense of peaceful but equally impoverished African nations
There will be some readjustment as to where the aid goes - Russia, China and Singapore do seem to be inappropriate targets. I am in no doubt that Afghanistan is one of the most dangerous places on earth, especially on the Pakistani border. Whether you call it aid or not, that is where the International community needs to be focusing its efforts.
The spending review has hit welfare benefits hardest. The main targets have been housing benefits, which have meant that the poorly paid and unemployed - including outrageous examples of recent immigrants with very large families living in luxury pads in West London - are subsidized to live in central London, while ordinary workers have to commute for several hours every day. I can certainly see the need to subsidize low-paid cleaners and essential workers like nurses and teachers etc to be able to do their jobs, but if you are unemployed in central London, then you really have no intention of working and you could be as indolent in Hull or Middlesboro, where you can buy a street for the cost of a house in London, no matter what your emotional ties to London.
There is also good news for those who are caught in a poverty trap. The welfare reforms should mean that it is always more profitable to work than accept benefits. At the moment there are perverse incentives not to work. Furthermore an element of fairness is being introduced. No-one should receive more in benefits than the average family income. After all the taxpayer funds these benefits, and were I earning only a small amount, I should protest at my taxes paying for my neighbor to get out of bed at 11 am, sit on the sofa, watch the racing on his flat screen TV eating Cherios and drinking cheap cider.
This may all sound like Daily-Mail-speak, and perhaps there are some harder cases that need consideration, but everyone puts up anecdotes to support their case. The Welfare Minister has presented some statistics which demonstrate that much of the hoohah is just that.
Of course, other departments have been hit by the cuts, but the government claim to have ring fenced the schools budget (though not the Department of Education itself), the NHS and the International AID budget. From today's Lancet we read - Although the health budget will increase by £10 billion to a total of £114 billion over the next 4 years—equivalent to a 0·1% rise per year in real terms—in recent years health spending has risen annually by over 4% in real terms. Many factors could lead to increased health-care costs, including the ageing population, a rising prevalence of obesity, the price of new medicines, the promised cancer drugs fund of £200 million, and the £1 billion a year needed to support social care that overlaps with the NHS (for example, rehabilitation care). This will, in fact, lead to cuts within the NHS, but then, in my time in NHS management, it was taken for granted that every year we had to find 2% 'efficiency savings'. This generally meant that somebody's pet project could not be taken forward next year or that we had to admit that last year we had 'banked' money - for example by buying a year's X-ray film in advance and holding it in cold storage.
What of medical research? Again the Lancet is encouraging: The UK has a tradition of excellence in science and medicine—this year Robert Edwards was awarded a Nobel prize for medicine, and David Weatherall won a Lasker Award. The UK is also the most productive research nation per head in the G8, producing 14% of the most highly-cited papers and 9% of total research publications, despite making up just 1% of the world's population. The Government has listened to the scientific community's argument that continued investment in science is vital to the UK's future success, and over £700 million a year on research and development from the Department of Health will be protected in real terms. Also, the spending review promises a real-term increase in the Medical Research Council's budget. “It is vital that we retain a good science budget and invest in our science base”, said Prime Minister David Cameron. The research community must now ensure that it delivers on this vote of confidence.
What about aid? Again the Lancet has a comment: The amount that the UK's Department for International Development (DfID) spends on overseas aid is to rise from £7 billion to £11·5 billion over the next 4 years, and by 2013 the UK should meet its UN commitment to spend 0·7% of national income on overseas development. The money spent on countries in conflict will increase to £3·8 billion, with a larger proportion going to Afghanistan at the expense of peaceful but equally impoverished African nations
There will be some readjustment as to where the aid goes - Russia, China and Singapore do seem to be inappropriate targets. I am in no doubt that Afghanistan is one of the most dangerous places on earth, especially on the Pakistani border. Whether you call it aid or not, that is where the International community needs to be focusing its efforts.
Thursday, October 28, 2010
More good news
My old hospital had an iron lung on the ward 2 balcony. We never had to use it, but in 1956 children from my school died from polio and others were in leg irons. That was why we seldom went swimming.
26 October 2010 -- This week, Africa has the unprecedented chance to drive out polio when 15 countries across the continent launch a synchronized mass immunization campaign to reach 72 million children. Some 290 000 vaccinators will go door-to-door to deliver two drops of oral polio vaccine (OPV) to every child under five in "highest risk" areas for polio transmission.
It seems that one of the serotypes of wild poliovirus (type 2) has already been eradicated so the immunisation campaign is now concentrating on Types 1 and 3.
Attempts to control polio in Nigeria suffered a setback in 2003 when a group of Muslim clerics claimed that the conventional vaccine was tainted as part of a U.S. plot to make women there infertile.
There is now a new vaccine that is claimed to be four times more effective than the previous one. Although eradicated from most of the globe, polio can still be found in northern Nigeria, northern India and along the Pakistan-Afghanistan border. In 2007, 1,310 cases were reported worldwide, according the U.S. Centers for Disease Control and Prevention.
But this news item might yet prevent success: PESHAWAR, Oct 19: More than 26,000 families have refused to administer anti-polio drops to their children in Khyber Pakhtunkhwa. "These families refused administering oral vaccine to their children because the parents thought it turned the recipients infertile and impotent," they said. Two campaigns carried out from September 27 to 29 and October 11 to 13 showed that those parents flatly refused to get their children immunised on religious grounds. The Khyber Pakhtunkhwa and Fata together have reported 57 cases of polio this year so far.
Pakistan has become one of the poorly performing countries in the history of polio eradication programme,” they said. Other polio-endemic countries have shown tremendous progress in polio eradication as Nigeria reported 400 cases in 2009 but number of cases this year is only 8. India had brought down the cases to 31 compared to 385 last year while Afghanistan reported 75 cases in 2009 and this year only 18.
Pakistan had recorded 82 cases this year so far and it could easily surpass the 87 cases, which it reported last year.
26 October 2010 -- This week, Africa has the unprecedented chance to drive out polio when 15 countries across the continent launch a synchronized mass immunization campaign to reach 72 million children. Some 290 000 vaccinators will go door-to-door to deliver two drops of oral polio vaccine (OPV) to every child under five in "highest risk" areas for polio transmission.
It seems that one of the serotypes of wild poliovirus (type 2) has already been eradicated so the immunisation campaign is now concentrating on Types 1 and 3.
Attempts to control polio in Nigeria suffered a setback in 2003 when a group of Muslim clerics claimed that the conventional vaccine was tainted as part of a U.S. plot to make women there infertile.
There is now a new vaccine that is claimed to be four times more effective than the previous one. Although eradicated from most of the globe, polio can still be found in northern Nigeria, northern India and along the Pakistan-Afghanistan border. In 2007, 1,310 cases were reported worldwide, according the U.S. Centers for Disease Control and Prevention.
But this news item might yet prevent success: PESHAWAR, Oct 19: More than 26,000 families have refused to administer anti-polio drops to their children in Khyber Pakhtunkhwa. "These families refused administering oral vaccine to their children because the parents thought it turned the recipients infertile and impotent," they said. Two campaigns carried out from September 27 to 29 and October 11 to 13 showed that those parents flatly refused to get their children immunised on religious grounds. The Khyber Pakhtunkhwa and Fata together have reported 57 cases of polio this year so far.
Pakistan has become one of the poorly performing countries in the history of polio eradication programme,” they said. Other polio-endemic countries have shown tremendous progress in polio eradication as Nigeria reported 400 cases in 2009 but number of cases this year is only 8. India had brought down the cases to 31 compared to 385 last year while Afghanistan reported 75 cases in 2009 and this year only 18.
Pakistan had recorded 82 cases this year so far and it could easily surpass the 87 cases, which it reported last year.
Wednesday, October 27, 2010
Life expectancy
Last year there were 491,348 deaths in Britain - a 3.5 per cent drop from 2008. The number dying from coronary heart disease fell by 28 per cent in men and 32 per cent in women between 2004 and 2009.
The improvement is being attributed to the use of statins which have cut deaths from coronary thrombosis. However, it could as easily be attributed to fewer people smoking. I am told that heart attacks end in death in only 8% of incidents now and that this occurs almost entirely in smokers.
Infant mortality rate was also at its lowest point in 2009. There is no getting away from it: people are living longer.
At the same time there is news that Swine flu hit young children disproportionately and especially children from a Pakistani and Bangladeshi backgrounds. There were 457 reported and confirmed swine flu-related deaths across the UK between April last year and March this year. The highest death rate of 14 per million was for children aged less than a year old. Mortality rates were much higher for Bangladeshi children (47 deaths per million population) and Pakistani children (36 deaths per million) than for white English children (four deaths per million). Those with pre-existing conditions - especially neurological diseases such as cerebral palsy - were hardest hit.
The elephant in the room is the high incidence of inherited disease in families from the Indian sub-continent - especially in the Muslim community - because of consanguineous marriage. The impact on the health service is immense. Where the genetic defect is identified the cost of remedying it is huge, and where it is unidentified it brings unknown and expensive medical problems.
I am not one who would turn sick immigrants away - though I have been told that the assumptions made by patients' relatives that the NHS should provide a service that hasn't been paid for to anyone who turns up from anywhere in the world appears to the young doctors who must do the work as breathtakingly rude. I believe that the rich nations do have a responsibility to the needy of poor nations, but prevention is part of the remedy. There are no religious reasons for marrying your cousins. The motive is greed - to keep the family fortune from passing into the hands of strangers. It was the same thing that was practised in Britain before the 1st World War, when estates were entailed to the eldest son of a family. Try watching the new Julian Fellowes' country house drama, Downton Abbey.
My own particular objection to the inclusion of Bangladeshi and Pakistani statistics is that these have the effect of lowering the reputation of the NHS, which generally performs very well. It is the same effect that tells us that 41 million Americans carry no medical insurance. Many of them are illegal immigrants. We do not need across the board changes in the name of political correctness, to solve a problem that is very specific and particular. Resources must be directed at problems, not laid on with a trowel.
The improvement is being attributed to the use of statins which have cut deaths from coronary thrombosis. However, it could as easily be attributed to fewer people smoking. I am told that heart attacks end in death in only 8% of incidents now and that this occurs almost entirely in smokers.
Infant mortality rate was also at its lowest point in 2009. There is no getting away from it: people are living longer.
At the same time there is news that Swine flu hit young children disproportionately and especially children from a Pakistani and Bangladeshi backgrounds. There were 457 reported and confirmed swine flu-related deaths across the UK between April last year and March this year. The highest death rate of 14 per million was for children aged less than a year old. Mortality rates were much higher for Bangladeshi children (47 deaths per million population) and Pakistani children (36 deaths per million) than for white English children (four deaths per million). Those with pre-existing conditions - especially neurological diseases such as cerebral palsy - were hardest hit.
The elephant in the room is the high incidence of inherited disease in families from the Indian sub-continent - especially in the Muslim community - because of consanguineous marriage. The impact on the health service is immense. Where the genetic defect is identified the cost of remedying it is huge, and where it is unidentified it brings unknown and expensive medical problems.
I am not one who would turn sick immigrants away - though I have been told that the assumptions made by patients' relatives that the NHS should provide a service that hasn't been paid for to anyone who turns up from anywhere in the world appears to the young doctors who must do the work as breathtakingly rude. I believe that the rich nations do have a responsibility to the needy of poor nations, but prevention is part of the remedy. There are no religious reasons for marrying your cousins. The motive is greed - to keep the family fortune from passing into the hands of strangers. It was the same thing that was practised in Britain before the 1st World War, when estates were entailed to the eldest son of a family. Try watching the new Julian Fellowes' country house drama, Downton Abbey.
My own particular objection to the inclusion of Bangladeshi and Pakistani statistics is that these have the effect of lowering the reputation of the NHS, which generally performs very well. It is the same effect that tells us that 41 million Americans carry no medical insurance. Many of them are illegal immigrants. We do not need across the board changes in the name of political correctness, to solve a problem that is very specific and particular. Resources must be directed at problems, not laid on with a trowel.
Exercise for fatigue.
I have just signed up for an exercise programme similar to this one reported from the University of Alberta, Canada The video is worth watching because the results are impressive.
It looks as though there is a greater chance of completing chemotherapy successfully, a higher chance of complete remission, greater feeling of well being and perhaps a longer life with exercise.
Other studies have demonstrated that cancer-related fatigue is lessened by exercise and that, of course, muscles wasted by steroids can be strengthened again.
For myself I need to remedy my proximal myopathy, which the dexamethasone has produced and try to stop an hour's snoozing after lunch. The rest I will take on trust, but before I got ill, I used to attend a personal trainer every week and now i shall have one again thanks to the Oncology Center which is funding this project. It will be free for the first three months and if it seems to be working, then i shall continue to pay for it.
It looks as though there is a greater chance of completing chemotherapy successfully, a higher chance of complete remission, greater feeling of well being and perhaps a longer life with exercise.
Other studies have demonstrated that cancer-related fatigue is lessened by exercise and that, of course, muscles wasted by steroids can be strengthened again.
For myself I need to remedy my proximal myopathy, which the dexamethasone has produced and try to stop an hour's snoozing after lunch. The rest I will take on trust, but before I got ill, I used to attend a personal trainer every week and now i shall have one again thanks to the Oncology Center which is funding this project. It will be free for the first three months and if it seems to be working, then i shall continue to pay for it.
Monday, October 25, 2010
Health report
Interesting evening yesterday. I developed severe spasm in my bowel as a consequence of the cholinergic syndrome. Irinotecan is famous for releasing a lot of acetylcholine (Ach) when it kills cells. This free ACh then attaches itself to Ach receptors on smooth muscle and stimulates them. Since most smooth muscle is in the gut, the gut goes into spasm. The remedy is atropine which blocks the receptors - you can see it work when you put atropine drops in the eye to dilate the pupil.
I had had a prophylactic injection of atropine the previous day while the irinotecan was dripping in, but it is a short-acting drug and by yesterday evening it had worn off. Apparently this was the first time that the ward had had such an emergency, and they took a bit of convincing that it was necessary, but when they eventually gave me the injection, I had instant relief. Buscopan is an alternative, but it is poorly absorbed and especially so after chemotherapy. Anyway today I am fine again, waiting to see whether I get mucositis with the lower dose.
I had had a prophylactic injection of atropine the previous day while the irinotecan was dripping in, but it is a short-acting drug and by yesterday evening it had worn off. Apparently this was the first time that the ward had had such an emergency, and they took a bit of convincing that it was necessary, but when they eventually gave me the injection, I had instant relief. Buscopan is an alternative, but it is poorly absorbed and especially so after chemotherapy. Anyway today I am fine again, waiting to see whether I get mucositis with the lower dose.
More on MBL
Two groups, Leeds and NIH, have done most of the work on Monoclonal B-cell lymphocytosis (MBL) and I can report on papers from both of them.
There is a good article in this weeks B J Haem on MBL from NIH. Goldin et al BJH 2010; 151:152-8 and also a very good review by Rawstron and Hillmen in Best Practice and Research Clinical Haematology 2010; 23:61-69.
Remember how surprised we were when Andy Rawstron told us in 2002 that one person in 30 over the age of 40 had a population of cells indistinguishable from CLL cells in their blood, and that in those who had a family history of CLL or other lymphomas it was nearer to one in seven? Gerald Marti's group in this study updates the story. They remind us that this was all discovered using 4-color flow cytometry, a sensitive way at looking at small populations in the blood. Newer studies using 8-color flow are even more sensitive and have found that one in five over-60s have an MBL population in their blood.
It has also been demonstrated from studies of stored samples that virtually all cases of CLL start off as MBL and this can be detected up to 6 years before the CLL is diagnosed.
The discovery of MBL has meant that there needs to be a numerical threshold between MBL and CLL. IT is a count of 5000 B cells per microliter in the blood. Previously, such cases would have been called stage 0 CLL, so there are a lot of people out there who have stage 0 CLL who under today's definition would not be called leukemia at all. For a rule of thumb, if you total lymphocyte count is less than 10,000 then you probably have MBL not CLL - unless you have enlarged lymph nodes, when you probably have SLL.
In general, it has been found that if you have MBL with a B-lymphocyte count of between 1000 and 4,999 per mictoliter then your prognosis is the same as if you had stage 0 CLL - about 1.1% of cases will become CLL formerly every year and most will not require treatment throughout their lifespan. The range of mutated v unmutated will be the same and the same biased use of individual IGHV genes will occur - VH1-69, VH3-07, VH3-21, VH3-23, and VH4-34.. Again the same prognostic factors as for CLL will apply. So del 13q is a good prognostic factor and del 11q is a poor prognostic factor.
By contrast, those cases of MBL with much lower counts - <10 cells per microliter - tend to use different IGHV genes like VH4-59 and VH4-61. This suggests that only those 'CLL' cels with thr 'right' receptor receive a signal to expand.
So what should happen if you are discovered to have MBL? most hematologist feel obliged to do follow-up interval blood tests, but is this wise? The majority of individuals who fall into this sub-group are elderly with all the attendant problems, and although Quality of Life studies in CLL patients show no difference to published population norms, Emotional Quality of Life scores are significantly worse. In part this is anxiety related to uncertainty about progression, and reassurances about CLL being a 'good cancer' actually increase anxiety.
The Leeds programme relies on local blood sampling once a year accompanied by a questionnaire and central processing of the sample which includes flow cytometry, since a rise in B-cell numbers may make no impact on the straight cbc.
There is also a population of individuals who do not have CLL marker MBL, who are CD5- or CD5+ but CD23-. Such individuals are more likely to have bulkier disease and in them bone marrow biopsy and/or CT scanning should be considered. Bone marrow biopsy should also be performed in those with MBL who have cytopenias.
As flow cytometry becomes more sensitive small MBL populations will be picked up in BMBs used for routine staging of NHS. This should not be taken as indicating stage IV disease. A bone marrow donor might have a small population of MBL cells. Should he be rejected as a donor?
It is clear that the discovery of MBL is going to throw up a whole range of difficult decisions.
The Goldin paper concentrates mainly on the familial cases and comes up with the statistic that by the age of 90, 60% of family members will have detectable MBL in their blood. In familial CLL, the presence of an MBL clone is confirmation of the genetic tendency, but as yet we don't know the genetic lesion.
There is a good article in this weeks B J Haem on MBL from NIH. Goldin et al BJH 2010; 151:152-8 and also a very good review by Rawstron and Hillmen in Best Practice and Research Clinical Haematology 2010; 23:61-69.
Remember how surprised we were when Andy Rawstron told us in 2002 that one person in 30 over the age of 40 had a population of cells indistinguishable from CLL cells in their blood, and that in those who had a family history of CLL or other lymphomas it was nearer to one in seven? Gerald Marti's group in this study updates the story. They remind us that this was all discovered using 4-color flow cytometry, a sensitive way at looking at small populations in the blood. Newer studies using 8-color flow are even more sensitive and have found that one in five over-60s have an MBL population in their blood.
It has also been demonstrated from studies of stored samples that virtually all cases of CLL start off as MBL and this can be detected up to 6 years before the CLL is diagnosed.
The discovery of MBL has meant that there needs to be a numerical threshold between MBL and CLL. IT is a count of 5000 B cells per microliter in the blood. Previously, such cases would have been called stage 0 CLL, so there are a lot of people out there who have stage 0 CLL who under today's definition would not be called leukemia at all. For a rule of thumb, if you total lymphocyte count is less than 10,000 then you probably have MBL not CLL - unless you have enlarged lymph nodes, when you probably have SLL.
In general, it has been found that if you have MBL with a B-lymphocyte count of between 1000 and 4,999 per mictoliter then your prognosis is the same as if you had stage 0 CLL - about 1.1% of cases will become CLL formerly every year and most will not require treatment throughout their lifespan. The range of mutated v unmutated will be the same and the same biased use of individual IGHV genes will occur - VH1-69, VH3-07, VH3-21, VH3-23, and VH4-34.. Again the same prognostic factors as for CLL will apply. So del 13q is a good prognostic factor and del 11q is a poor prognostic factor.
By contrast, those cases of MBL with much lower counts - <10 cells per microliter - tend to use different IGHV genes like VH4-59 and VH4-61. This suggests that only those 'CLL' cels with thr 'right' receptor receive a signal to expand.
So what should happen if you are discovered to have MBL? most hematologist feel obliged to do follow-up interval blood tests, but is this wise? The majority of individuals who fall into this sub-group are elderly with all the attendant problems, and although Quality of Life studies in CLL patients show no difference to published population norms, Emotional Quality of Life scores are significantly worse. In part this is anxiety related to uncertainty about progression, and reassurances about CLL being a 'good cancer' actually increase anxiety.
The Leeds programme relies on local blood sampling once a year accompanied by a questionnaire and central processing of the sample which includes flow cytometry, since a rise in B-cell numbers may make no impact on the straight cbc.
There is also a population of individuals who do not have CLL marker MBL, who are CD5- or CD5+ but CD23-. Such individuals are more likely to have bulkier disease and in them bone marrow biopsy and/or CT scanning should be considered. Bone marrow biopsy should also be performed in those with MBL who have cytopenias.
As flow cytometry becomes more sensitive small MBL populations will be picked up in BMBs used for routine staging of NHS. This should not be taken as indicating stage IV disease. A bone marrow donor might have a small population of MBL cells. Should he be rejected as a donor?
It is clear that the discovery of MBL is going to throw up a whole range of difficult decisions.
The Goldin paper concentrates mainly on the familial cases and comes up with the statistic that by the age of 90, 60% of family members will have detectable MBL in their blood. In familial CLL, the presence of an MBL clone is confirmation of the genetic tendency, but as yet we don't know the genetic lesion.
Saturday, October 23, 2010
healthcheck
Today I had my third course of chemotherapy. In view of the severe grade 3 mucositis last time and the fact that I had a neutorphil nadir of 1.0 they have reduced the dose of 5-FU by 20%, but they have kept the interval at 14 days. I have been tired an colicky today and not eating this evening. I am looking forward to an early night. My visual acuity has been affected by the atropine injection to counter the irinotecan, so if there are any typos, it's because I am blind to them.
Friday, October 22, 2010
Child poverty
I listened to a radio feature yesterday about child poverty, which successive governments have promised to abolish by 2020. Apparently, there are 4 million children living in poverty in the UK today. The problem is that they keep moving the goalposts. According to the last Labor government, child poverty is relative. To escape child poverty today, a child should have at least one family holiday a year - though not necessarily abroad; the ability to go swimming at least once a month; a hobby or leisure activity; friends round for tea or a snack once a fortnight; enough bedrooms for every child over 10 of different sex to have his or her bedroom; sports equipment or a bicycle; birthday parties and Christmas parties; play-group of alternative for all children of pre-school age; a school trips at least once a term.
These were 2003 Guidelines. The radio presenter updated them. Children should be able to go on such as foreign exchange trips to help them learn a foreign language and field trips for geography or history lessons. It goes without saying that they should have a color TV and so as not to feel excluded, a games console and access to the popular games. School uniform should be available where worn - the child should have access to a new uniform every year and not have to rely on hand-me-downs or home-made substitutes.
It is only now that I realise how poor I was as a child. During my entire childhood we had only two family holidays: both in a caravan by the seaside about 30 miles away. I went swimming about five times before I was 11 - this was provided freely by my school. The pool was unheated and I never even got a 10 yard swimming certificate. I remember once having a friend round to share my bread and jam for tea and once having it reciprocated. I had friends, but food was scarce in the 40s and 50s and nobody had enough to share. Besides for a lot of that time it was rationed. I shared a bed, not just a bedroom, with my younger brother until I left home for University. I finally got a bike when I was 12 - it was a rusty sit-up-and-beg machine that I sanded down and repainted. It cost £4 and when I grew out of it I never had anything better - just rusty machines that others had thrown away and my father salvaged. The same with sports equipment. Even my gym shoes were secondhand.
I did have a hobby. I collected train numbers. It cost nothing. Later I graduated to arranging cities in size of population - you could find the the numbers from the 1951 Census in an old AA book. When I finally got 6 pence a week pocket money, I used to go to football matches. I was pleased to find that libraries were free. They still are. Birthday and Christmas Parties were family affairs - we never had friends over for these. There were no pre-school groups in my day, but my parents taught me to read before I was 3 and I was doing cursive writing at home before I was 5. I went on my first and only school trip when I was 15. I soon learned that I was unable to take part in any school activity that cost money.
At home we never had a bathroom until I was 13. Before that it was a sink bath in the kitchen with hot water boiled in saucepans on the cooker. The WC was outside requiring a short, cold walk in the winter. The house was heated by a coal fire in one room. Our first black and white TV appeared when I was 13; it was so small that we couldn't all watch at the same time. We actually preferred to listen to the AM radio, even though it had to keep being adjusted as it lost the station. Games Consoles? We played Hangman or Noughts and Crosses with pencil and paper. Our clothes were home-made and hand-me-downs. My parents worked day and night at two jobs. There were no luxuries.
It's just that I never really knew I was poor. I was very happy.
These were 2003 Guidelines. The radio presenter updated them. Children should be able to go on such as foreign exchange trips to help them learn a foreign language and field trips for geography or history lessons. It goes without saying that they should have a color TV and so as not to feel excluded, a games console and access to the popular games. School uniform should be available where worn - the child should have access to a new uniform every year and not have to rely on hand-me-downs or home-made substitutes.
It is only now that I realise how poor I was as a child. During my entire childhood we had only two family holidays: both in a caravan by the seaside about 30 miles away. I went swimming about five times before I was 11 - this was provided freely by my school. The pool was unheated and I never even got a 10 yard swimming certificate. I remember once having a friend round to share my bread and jam for tea and once having it reciprocated. I had friends, but food was scarce in the 40s and 50s and nobody had enough to share. Besides for a lot of that time it was rationed. I shared a bed, not just a bedroom, with my younger brother until I left home for University. I finally got a bike when I was 12 - it was a rusty sit-up-and-beg machine that I sanded down and repainted. It cost £4 and when I grew out of it I never had anything better - just rusty machines that others had thrown away and my father salvaged. The same with sports equipment. Even my gym shoes were secondhand.
I did have a hobby. I collected train numbers. It cost nothing. Later I graduated to arranging cities in size of population - you could find the the numbers from the 1951 Census in an old AA book. When I finally got 6 pence a week pocket money, I used to go to football matches. I was pleased to find that libraries were free. They still are. Birthday and Christmas Parties were family affairs - we never had friends over for these. There were no pre-school groups in my day, but my parents taught me to read before I was 3 and I was doing cursive writing at home before I was 5. I went on my first and only school trip when I was 15. I soon learned that I was unable to take part in any school activity that cost money.
At home we never had a bathroom until I was 13. Before that it was a sink bath in the kitchen with hot water boiled in saucepans on the cooker. The WC was outside requiring a short, cold walk in the winter. The house was heated by a coal fire in one room. Our first black and white TV appeared when I was 13; it was so small that we couldn't all watch at the same time. We actually preferred to listen to the AM radio, even though it had to keep being adjusted as it lost the station. Games Consoles? We played Hangman or Noughts and Crosses with pencil and paper. Our clothes were home-made and hand-me-downs. My parents worked day and night at two jobs. There were no luxuries.
It's just that I never really knew I was poor. I was very happy.
Thursday, October 21, 2010
Chancellor's autumn spending review.
They say that the UK is being subjected to the greatest and most prolonged public spending cuts since the immediate post-war austerity program. In fact, public spending is still planned to rise with inflation until the end of this 4-year period, and all in all the true measure of the cuts is only undoing some of the profligacy of the past 5 years.
I think the most important feature of the cuts is the philosophy behind them and the nudge it will give to people to alter their behavior. For myself, I will be little affected by the two budgets and one spending review that we have seen this year. I will not creep into to 50% tax band, nor will I pay the extra 2% on national insurance. My old-age pension will not be affected and I have no child benefit to lose. My occupational pension will be frozen, but the Chancellor has kindly allowed me to keep my free bus pass (which has saved me £12 over the past 7 years) and my winter fuel payments. I would not have been miffed had he taken them away. My mother's TV licence is another thing. I would have paid it for her had she not had it free, but not everyone is in a position to do that for a relative who is over 75. The BBC has had to accept a lower settlement, which must be a good thing if they can afford to pay there Chief Executive over a million dollars a year.
I do not receive any means tested benefits; so there are none of those to lose. I will be hit by a 2.5% increase in VAT, but I buy very little that attracts VAT.
The message that no-one should receive more in benefits than the average family earns by working seems to me to be a valid one, and the cap on housing benefit is only right. The people who profit from huge housing subsidies are buy-to-let landlords who can make 10% income from property investment when the banks are only paying 2%. Again, arranging that you are always better off working than receiving benefits is only right.
Higher rate tax-payers will lose child benefit and probably the group earning between £40,000 and £70,000 a year will feel the pinch most as many will also lose child tax credits. There will be a greater incentive for parents and grandparents to help out and this may be a good thing. Money passed on to the next generation more than seven years before the final death will escape inheritance tax. For grandparents who start stakeholder pension funds for little children the government will give them their tax back for the fund. This will help those who under the new arrangements will find it harder to accumulate a large pension pot and will also again escape inheritance tax.
Raising the retirement age is a democratic necessity and we should be looking at ways of allowing people in work to slow down rather than stopping abruptly. Most people spend a much shorter proportion of their lives working than their parents did.
I suspect that there will be a lot of arrangements made to make the best of the new regime. The loss of public sector jobs will nudge people into being more entrepreneurial and risk-taking. New businesses will start and more private sector employment arise. Doing away with the idea that someone owes you a living can only help society. Shutting prisons for all except the dangerous and career criminals would make them a more sensible place and reforming Universities and the Health Service would have a lot of public support.
Removing the shackles that the last government placed around funding and strengthening localism seems to be sensible. I think that the 'Big Society' idea of involving communities in decision making, encouraging volunteerism and supporting local charities is a great one.
I am not so sure about increasing foreign aid. The trouble is that much of it feeds corruption abroad. Some of it is self-serving - a way of subsidising jobs at home. Some of it is actually military. And some of it just feeds the bureaucracy of large charities like OXFAM.
I have seen aid in third world countries succeed, but usually when it is applied by small charities who have people on the ground using the money in rural communities.
The relative sparing of the military is interesting. We must decide what role we really want for ourselves. The UK still spends more of its GPD on defence than most European countries. Is there an end-of-cold war dividend? The greatest danger to our country is not tanks, rockets or nuclear weapons, but unconventional warfare such as the recrudescent Irish question or Muslim extremism. Tanks are not useful here, nor Trident missiles. Are the Russians or Chinese likely to attack us? Which of the following are our nuclear missiles targeted at? India? Pakistan? Israel? North Korea? Iran? France? I know some who are certain it is the last.
I think the most important feature of the cuts is the philosophy behind them and the nudge it will give to people to alter their behavior. For myself, I will be little affected by the two budgets and one spending review that we have seen this year. I will not creep into to 50% tax band, nor will I pay the extra 2% on national insurance. My old-age pension will not be affected and I have no child benefit to lose. My occupational pension will be frozen, but the Chancellor has kindly allowed me to keep my free bus pass (which has saved me £12 over the past 7 years) and my winter fuel payments. I would not have been miffed had he taken them away. My mother's TV licence is another thing. I would have paid it for her had she not had it free, but not everyone is in a position to do that for a relative who is over 75. The BBC has had to accept a lower settlement, which must be a good thing if they can afford to pay there Chief Executive over a million dollars a year.
I do not receive any means tested benefits; so there are none of those to lose. I will be hit by a 2.5% increase in VAT, but I buy very little that attracts VAT.
The message that no-one should receive more in benefits than the average family earns by working seems to me to be a valid one, and the cap on housing benefit is only right. The people who profit from huge housing subsidies are buy-to-let landlords who can make 10% income from property investment when the banks are only paying 2%. Again, arranging that you are always better off working than receiving benefits is only right.
Higher rate tax-payers will lose child benefit and probably the group earning between £40,000 and £70,000 a year will feel the pinch most as many will also lose child tax credits. There will be a greater incentive for parents and grandparents to help out and this may be a good thing. Money passed on to the next generation more than seven years before the final death will escape inheritance tax. For grandparents who start stakeholder pension funds for little children the government will give them their tax back for the fund. This will help those who under the new arrangements will find it harder to accumulate a large pension pot and will also again escape inheritance tax.
Raising the retirement age is a democratic necessity and we should be looking at ways of allowing people in work to slow down rather than stopping abruptly. Most people spend a much shorter proportion of their lives working than their parents did.
I suspect that there will be a lot of arrangements made to make the best of the new regime. The loss of public sector jobs will nudge people into being more entrepreneurial and risk-taking. New businesses will start and more private sector employment arise. Doing away with the idea that someone owes you a living can only help society. Shutting prisons for all except the dangerous and career criminals would make them a more sensible place and reforming Universities and the Health Service would have a lot of public support.
Removing the shackles that the last government placed around funding and strengthening localism seems to be sensible. I think that the 'Big Society' idea of involving communities in decision making, encouraging volunteerism and supporting local charities is a great one.
I am not so sure about increasing foreign aid. The trouble is that much of it feeds corruption abroad. Some of it is self-serving - a way of subsidising jobs at home. Some of it is actually military. And some of it just feeds the bureaucracy of large charities like OXFAM.
I have seen aid in third world countries succeed, but usually when it is applied by small charities who have people on the ground using the money in rural communities.
The relative sparing of the military is interesting. We must decide what role we really want for ourselves. The UK still spends more of its GPD on defence than most European countries. Is there an end-of-cold war dividend? The greatest danger to our country is not tanks, rockets or nuclear weapons, but unconventional warfare such as the recrudescent Irish question or Muslim extremism. Tanks are not useful here, nor Trident missiles. Are the Russians or Chinese likely to attack us? Which of the following are our nuclear missiles targeted at? India? Pakistan? Israel? North Korea? Iran? France? I know some who are certain it is the last.
Wednesday, October 20, 2010
How to treat mucositis
Mucositis is a very painful complication of chemotherapy. Strictly speaking it can occur anywhere in the gastro-intestinal tract, but it is most prominent in the mouth, where it is called stomatitis. The surfaces that line the mouth and tongue become red, swollen and covered in ulcers. The pain can be so severe that it is very hard to eat, drink and speak. Stage 1 and 2 are mild and characterised by soreness and the beginning of ulceration. During stage 3 and 4, oral mucositis is more severe. At stage 3, sufferers cannot tolerate solid food so switch to a liquid only diet. Eating is not possible at stage 4 so people my need further help getting enough nutrients. My mucositis was stage 2 bordering on stage 3 before I started definitive treatment.
So what treatment is useful? The problem is that there have been hardly any decent clinical trials. I can understand why. If somebody asked me when I was suffering if I wanted to participate in a clinical trial I should have refused and asked for everything they had. The pain was so urgent, that I had no time to take part in a trial. Besides all the treatments are petty cheap so I'll have all of them in the hope that something would work.
That being so, there is an expensive drug that has been proven to work in a clinical trial and a cheap one that makes no difference. Simple chlorhexidine mouthwashes make no difference, but palifermin reduced the cumulative incidence of moderate to severe (grade 2 or higher) mucositis (44% vs. 88%; P < 0.001; difference, -44 percentage points [95% CI, -71 to -16 percentage points) and severe (grade 3 or 4) mucositis (13% vs. 51%; P = 0.002; difference, -38 percentage points [CI, -67 to -9 percentage points]). The trouble is that palifermin, which is a recombinant protein - keratinocyte growth factor - costs over $750 a shot and it is only licensed for transplants.
There are other, smaller trials that suggest that Calcium phosphate mouthwashes or allopurinol mouthwashes might be better than placebo - but no follow up studies seem to have been done.
So are there simple rules for preventing and treating mucositis? The first is to have good oral hygiene. A visit to the dentist beforehand is a good idea. Make sure there are no hidden caries and smooth down any rough edges likely to start ulcers.
Tooth cleaning is essential, but becomes difficult even with a soft brush when the gums get painful. A damp soft gauze is an alternative to a brush. Likewise flossing may be impossible. Mouthwashes with an alcohol based fluid is very painful, but Difflam, which contains a local anesthetic works better. Even cold water rinses are better than nothing. Bongela is useful to rub on sore spots and may help you to eat when you didn't think it possible.
Mucositis often accompanies neutropenia and this allows infection to set in. Nystatin drops, amphotericin lozenges, or fluconazole may be useful to prevent or treat thrush, which is especially likely if you are having steroids as part of your regimen. Mouth bacteria can be hit by metronidazole and a penicillin, and of course you have to be very wary of herpes simplex.
In my case when the ulcers got really painful and I started to get heartburn, I guessed it was Candida and started fluconazole and the next day added metronidazole and a penicillin for complete cover. Thankfully things are getting better today.
I think what I shall do for the next course is to monitor my white count and see when the neutrophil nadir occurs, planning to start G-CSF if I need it, or prophylactic antimicrobials if I don't.
So what treatment is useful? The problem is that there have been hardly any decent clinical trials. I can understand why. If somebody asked me when I was suffering if I wanted to participate in a clinical trial I should have refused and asked for everything they had. The pain was so urgent, that I had no time to take part in a trial. Besides all the treatments are petty cheap so I'll have all of them in the hope that something would work.
That being so, there is an expensive drug that has been proven to work in a clinical trial and a cheap one that makes no difference. Simple chlorhexidine mouthwashes make no difference, but palifermin reduced the cumulative incidence of moderate to severe (grade 2 or higher) mucositis (44% vs. 88%; P < 0.001; difference, -44 percentage points [95% CI, -71 to -16 percentage points) and severe (grade 3 or 4) mucositis (13% vs. 51%; P = 0.002; difference, -38 percentage points [CI, -67 to -9 percentage points]). The trouble is that palifermin, which is a recombinant protein - keratinocyte growth factor - costs over $750 a shot and it is only licensed for transplants.
There are other, smaller trials that suggest that Calcium phosphate mouthwashes or allopurinol mouthwashes might be better than placebo - but no follow up studies seem to have been done.
So are there simple rules for preventing and treating mucositis? The first is to have good oral hygiene. A visit to the dentist beforehand is a good idea. Make sure there are no hidden caries and smooth down any rough edges likely to start ulcers.
Tooth cleaning is essential, but becomes difficult even with a soft brush when the gums get painful. A damp soft gauze is an alternative to a brush. Likewise flossing may be impossible. Mouthwashes with an alcohol based fluid is very painful, but Difflam, which contains a local anesthetic works better. Even cold water rinses are better than nothing. Bongela is useful to rub on sore spots and may help you to eat when you didn't think it possible.
Mucositis often accompanies neutropenia and this allows infection to set in. Nystatin drops, amphotericin lozenges, or fluconazole may be useful to prevent or treat thrush, which is especially likely if you are having steroids as part of your regimen. Mouth bacteria can be hit by metronidazole and a penicillin, and of course you have to be very wary of herpes simplex.
In my case when the ulcers got really painful and I started to get heartburn, I guessed it was Candida and started fluconazole and the next day added metronidazole and a penicillin for complete cover. Thankfully things are getting better today.
I think what I shall do for the next course is to monitor my white count and see when the neutrophil nadir occurs, planning to start G-CSF if I need it, or prophylactic antimicrobials if I don't.
No Pressure
I thought I ought to comment on Scattergate, or "No Pressure" the 10:10 promotional film produced by Richard Curtis to support the concept of global warming. Click on the link to watch the video though I do warn you that many will find it offensive.
10:10 is a charity that has attracted financial support from the British Government, O2 and Sony and has other corporate sponsors. None of the sponsors had editorial control over the video. 10:10 is suggesting that everybody should reduce his carbon footprint by 10%.
Having seen the video which was described as 'ironic' 10:10 has taken it down because some supporters felt it was offensive, and they have issued a sort of apology.
For myself, I think it was an honest attempt by Richard Curtis and his friends to state quite clearly that the eco-warriors are climate fascists. Curtis and his chums are subversives. Their output - Backadder, Four Weddings and Funeral, Notting Hill and The Boat that Rocked are all subversive. This is what they do. They took the money and made a film telling the world that Climate warmers are authoritarian blackguards. But they did it is an 'ironic' way so that everyone would get the joke except the blowhards themselves.
10:10 is a charity that has attracted financial support from the British Government, O2 and Sony and has other corporate sponsors. None of the sponsors had editorial control over the video. 10:10 is suggesting that everybody should reduce his carbon footprint by 10%.
Having seen the video which was described as 'ironic' 10:10 has taken it down because some supporters felt it was offensive, and they have issued a sort of apology.
For myself, I think it was an honest attempt by Richard Curtis and his friends to state quite clearly that the eco-warriors are climate fascists. Curtis and his chums are subversives. Their output - Backadder, Four Weddings and Funeral, Notting Hill and The Boat that Rocked are all subversive. This is what they do. They took the money and made a film telling the world that Climate warmers are authoritarian blackguards. But they did it is an 'ironic' way so that everyone would get the joke except the blowhards themselves.
Monday, October 18, 2010
Paul confronts Peter - Galatians chapter 2
I guess few of my readers will have followed the acting career of Ian McShane. He is a man of my age whom I first noticed in a film, The Wild and the Willing about student life in the sixties. He had just started in the business and was immediately noticeable for his film presence. To my young mind the attractions of the film were Samantha Eggar, Lincoln Cathedral and Rachmaninoff's Rhapsody on a theme from Paganini. It also provided early screen appearances for John Hurt and Jeremy Brett. The latest news is that McShane will appear as the villain in the latest Pirates of the Caribbean movie, released next spring. In the meantime he has graduated into the most prominent player of villains on TV or the Movies. It started with Lovejoy, who was just a lovable rogue antique dealer who had his heart in the right place, but he had already played Judas Iscariot in Jesus of Nazareth. He appeared in Dallas and The West Wing, but reached the epitome of nastiness in Deadwood, which was altogether too unpleasant for me to watch. He has even been a villain in Kung Fu Panda and Shrek. In the recently screened mini-series, Pillars of the Earth he appears as the wicked Bishop Waleran and this is so unpleasant, I doubt that I will watch the remainder. It is set in the Cadfael territory of 12th Century England during the war of succession between Stephen and Matilda. But Cadfael, he ain't.
We always say that English actors make the best Hollywood villains. This is probably because they can act whereas most Hollywood stars just play themselves (but perhaps it's the other way round?)
In the Bible there is one character who keeps turning up as a villain - The Apostle Peter. The Bible certainly doesn't whitewash its heroes! First, he appears to be full of himself with a big mouth, which gets him into trouble with Jesus 'Get thee behind me, Satan!' then he denies Jesus at his trial and has to suffer the humiliating restoration at the Lake of Galilee and now in Galatians we have the unusual occasion when Paul has to call him out publicly.
The back story is told by Luke in Acts chapter 10 and onwards. Peter was staying with a friend in Joppa (modern day Haifa), while in Caesarea, a town about 30 miles north populated by retired Roman soldiers, Cornelius, a centurion and a God fearing man who gave generously to the Jews, had a vision in which an angel told him to seek out Peter. Immediately, he arranged for men to go to Joppa to find Peter. The next day Peter himself had a vision while going to pray on the roof of his friend's house:
He saw heaven opened and something like a large sheet being let down to earth by its four corners. It contained all kinds of four-footed animals, as well as reptiles of the earth and birds of the air. Then a voice told him, "Get up, Peter. Kill and eat."
"Surely not, Lord!" Peter replied. "I have never eaten anything impure or unclean."
The voice spoke to him a second time, "Do not call anything impure that God has made clean."
This happened three times, and immediately the sheet was taken back to heaven.
So Peter welcomed the men into his house and the next day returned to Caesarea with them. He began to speak to a large gathering of people there. He said to them: "You are well aware that it is against our law for a Jew to associate with a Gentile or visit him. But God has shown me that I should not call any man impure or unclean. So when I was sent for, I came without raising any objection.
Peter began to speak: "I now realize how true it is that God does not show favoritism but accepts men from every nation who fear him and do what is right. You know the message God sent to the people of Israel, telling the good news of peace through Jesus Christ, who is Lord of all.
"We are witnesses of everything he did in the country of the Jews and in Jerusalem. They killed him by hanging him on a tree, but God raised him from the dead on the third day and caused him to be seen. He was not seen by all the people, but by witnesses whom God had already chosen—by us who ate and drank with him after he rose from the dead. He commanded us to preach to the people and to testify that he is the one whom God appointed as judge of the living and the dead. All the prophets testify about him that everyone who believes in him receives forgiveness of sins through his name."
While Peter was still speaking these words, the Holy Spirit came on all who heard the message. The circumcised believers who had come with Peter were astonished that the gift of the Holy Spirit had been poured out even on the Gentiles. For they heard them speaking in tongues and praising God.
Then Peter said, "Can anyone keep these people from being baptized with water? They have received the Holy Spirit just as we have." So he ordered that they be baptized in the name of Jesus Christ. Then they asked Peter to stay with them for a few days.
There it was. A clear signal from God that the gospel was to go to non-Jews, who were not to be encumbered with the old Law and ritual. Moreover, there was not one law for Jews and another for Gentiles. There was now one means of access to God; through Jesus Christ, the resurrected Messiah and "everyone who believes in him receives forgiveness of sins through his name." Not just Gentiles but Jews also.
In chapter 11 we read that Peter went to Jerusalem he was criticised by the 'circumcised believers', "You went into the house of uncircumcised men and ate with them."
Peter then went and explained everything that happened and by verse 18 we read, When they heard this, they had no further objections and praised God, saying, "So then, God has granted even the Gentiles repentance unto life."
Luke doesn't tell us when the incident of Paul calling out Peter actually occurred. We know it took place in Antioch when certain men came from James. First Peter, and then other Jews who took their example from him, and even Barnabas, withdrew from eating with the Gentiles as had been their former practice and began eating only with Jews, for fear of the Circumcision Party.
It seems clear to me that this must have been later than Acts 11 and almost certainly after the Council of Jerusalem which is reported in Acts 15, or just possibly immediately before when "Some men came down from Judea to Antioch..." verse 1. Perhaps this incident was what prompted Paul and Barnabas to go to Jerusalem and initiate the Council. At any rate, at the Council both Peter and James supported the Pauline position. For Peter to renege on the Jerusalem Council decision so soon afterwards would seem strange, but in any case he was reneging on his own practice immediately before which had been base on his vision in Joppa. But this is Peter's personality, returning to his default settings. He always was a coward. He did things for show.
Look at Ian McShane's face and you will see the years of smoking and drinking vodka for breakfast and womanizing etched upon it. He may be a changed person now, having been happily married for nearly 30 years and gone teetotal, but the years of abuse are etched on his face fitting him to play villains. How hard it is for the Holy Spirit to keep the man of Romans 7 down.
In any Christian church you will find people struggling with their past. It may be the legalism that they were brought up with; it may be some besetting sin that they can't shake free from; it may be something in their past that they still feel guilty about. The truth of the Gospel, and why it really is good news is that it is in the past.
In Christopher Marlowe's The Jew of Malta he has Barabbas saying in exculpation, "Thou hast committed-- Fornication: but that was in another country, And besides, the wench is dead."
But just being in the past doesn't make it right; what makes it right is that Jesus has taken the punishment for us and exchanged it for his righteousness. We are right with God! As a free gift! Because he loves us! I think Peter eventually got the message.
Sunday, October 17, 2010
Healthcheck
I think I have managed the side effects better this course. I have avoided colic and diarrhea by judicious us of Buscopan and codeine phosphate. However, yesterday I spent most of the time sleeping and today the mucositis has been sore, requiring regular Bongella and Difflam mouth washes. I have rediscovered my liking for pink blancmange.
The way things pan out I shall be spending Christmas Day with the most severe side effects, so I am not making any plans this year.
There have been calls in the newspapers today for the withdrawal of codeine from over-the-counter prescriptions, especially those aimed at children. The reason for this is that codeine has no action of its own, but depends on its effectiveness on the liver turning it into morphine. Unfortunately, different people have different capacities for this transformation; in some it is very fast and in others very slow.
Despite the scares about it, morphine is our best pain medication and giving it as codeine allows it to be given in very small doses to most people.
The main effects of morphine/codeine are pain relief. When enough is given it will eliminate virtually all pain.
Constipation. It is the best anti-diarrheal and works when loperamide is found wanting
Cough suppression. It certainly works for non-productive cough and is especially useful in terminal lung cancer.
Sedation. It gives a feeling that everything else going on in the world is unimportant. It takes away anxiety and allows relaxation.
Elation. This is very variable and not something I have experienced, though I am willing to agree that some people find this the most attractive thing about the drug.
Nausea. With oral or parenteral morphine it always makes me feel sick so that I must have an anti-emetic with it. When I take it as codeine, this is not a problem.
Addiction. Much could be written about this. I must say I am not tempted.
Habituation. It is said that those who are used to it require bigger and bigger doses for the same effect. Again I haven't noticed this with codeine.
The way things pan out I shall be spending Christmas Day with the most severe side effects, so I am not making any plans this year.
There have been calls in the newspapers today for the withdrawal of codeine from over-the-counter prescriptions, especially those aimed at children. The reason for this is that codeine has no action of its own, but depends on its effectiveness on the liver turning it into morphine. Unfortunately, different people have different capacities for this transformation; in some it is very fast and in others very slow.
Despite the scares about it, morphine is our best pain medication and giving it as codeine allows it to be given in very small doses to most people.
The main effects of morphine/codeine are pain relief. When enough is given it will eliminate virtually all pain.
Constipation. It is the best anti-diarrheal and works when loperamide is found wanting
Cough suppression. It certainly works for non-productive cough and is especially useful in terminal lung cancer.
Sedation. It gives a feeling that everything else going on in the world is unimportant. It takes away anxiety and allows relaxation.
Elation. This is very variable and not something I have experienced, though I am willing to agree that some people find this the most attractive thing about the drug.
Nausea. With oral or parenteral morphine it always makes me feel sick so that I must have an anti-emetic with it. When I take it as codeine, this is not a problem.
Addiction. Much could be written about this. I must say I am not tempted.
Habituation. It is said that those who are used to it require bigger and bigger doses for the same effect. Again I haven't noticed this with codeine.
Saturday, October 16, 2010
the 14 queue
At the long end of chromosome 14 is the little gene mechanism that protects us from infection. It is a very complex sequence of genes that generates the diversity necessary to make antibodies. There are millions of germs out there and the body needs to react rapidly to produce a defence against them. It does so by already having the templates ready to go for any possible germ. There are a few hundred components that can be mixed and matched and assembled in an appropriate way, and when they are put together properly there is another 'promoter' gene that ensures that the antibody is made in huge quantities.
I call the promoter gene the 'make a lot of' gene, and normally it makes a lot of antibody. The trouble with this area on the long arm of chromosome 14 is that because of all that mixing and matching going on, very occasionally the chromosomes mix inappropriately and the 'make a lot of' gene gets stuck somewhere it shouldn't causing the cell to make a lot of the wrong stuff. It can even get stuck next to a gene on a different chromosome. Such events are called translocations and they often result in lymphomas.
For example in the t(8;14) translocation the 'make a lot gene of' is put next to c-myc and you end up with Burkitt'slymphoma; in the t(11;14) translocation it is put next to CCND1 and you get mantle cell lymphoma; in the t(14:18) translocation it is put next to bcl-2 and you get follicular lymphoma and in the t(14;19) translocation it is put next to bcl-3 and you get a rather atypical form of CLL.
Sometimes, however, the end of chromosome 14 is missing and no-one knows where it has gone. It does not turn up partnering another chromosome. This topic is discussed in the October Brit J Haem in an article by Reindl from Munich.
They have looked at 3054 patients with mature B cell neoplasms and identified 47 cases with deletion at the end of 14q (the long end of the chromosome is called 'q' and the short end is called 'p'). 35 of the cases had CLL/SLL, 10 had CLL/PLL and one had lymphoplasmacytic lymphoma and one marginal zone lymphoma. (NB: this is a biased sample; only about 18% of chromosomal specimens with del 14q come from CLL patients according to the Mitelman database.) This tells us that del 14q is rare in CLL at 1.9%, but significantly commoner in CLL/PLL at 9%.
Despite careful searches for translocations, there was no corresponing partner chromosome to which the broken off piece had been moved; these were all true deletions - a bit of the chromosome had been lost. The exact amount of the chromosome that was lost was variable, and two thirds a timy bit had been left at the end. There were three broad patterns, but some variation, even with these.
80% of the cases had extra chromosomal abnormalities, - most commonly trisomy 12. There were 17 cases with very complex chromosomal abnormalities and these tended to have del 17p, as you might expect, since loss of TP53 function does lead to that. There were significantly more patients with del 14q among those with unmutated IGHV genes - again not unexpected.
Compared with other cases of CLL or CLL/PLL, having a 14q deletion did not impact of the 3-year overall survival, but the time to first treatment was much shorter at 21 months vs 80.1 months. However, compared to patients who had trisomy 12 without del 14q, those who had the extra deletion had a significantly shorter time to first treatment and overall survival.
So, does this paper tell us much? Not yet. It further defines a small group of patients and confirms that there is something odd about trisomy 12 cases that makes them stand out from the rest of CLLs. There is a small prognostic impact which is extra information, but I have to think that this is a work in progress. Which is why it has been published in B J Haem and not in Blood.
I call the promoter gene the 'make a lot of' gene, and normally it makes a lot of antibody. The trouble with this area on the long arm of chromosome 14 is that because of all that mixing and matching going on, very occasionally the chromosomes mix inappropriately and the 'make a lot of' gene gets stuck somewhere it shouldn't causing the cell to make a lot of the wrong stuff. It can even get stuck next to a gene on a different chromosome. Such events are called translocations and they often result in lymphomas.
For example in the t(8;14) translocation the 'make a lot gene of' is put next to c-myc and you end up with Burkitt'slymphoma; in the t(11;14) translocation it is put next to CCND1 and you get mantle cell lymphoma; in the t(14:18) translocation it is put next to bcl-2 and you get follicular lymphoma and in the t(14;19) translocation it is put next to bcl-3 and you get a rather atypical form of CLL.
Sometimes, however, the end of chromosome 14 is missing and no-one knows where it has gone. It does not turn up partnering another chromosome. This topic is discussed in the October Brit J Haem in an article by Reindl from Munich.
They have looked at 3054 patients with mature B cell neoplasms and identified 47 cases with deletion at the end of 14q (the long end of the chromosome is called 'q' and the short end is called 'p'). 35 of the cases had CLL/SLL, 10 had CLL/PLL and one had lymphoplasmacytic lymphoma and one marginal zone lymphoma. (NB: this is a biased sample; only about 18% of chromosomal specimens with del 14q come from CLL patients according to the Mitelman database.) This tells us that del 14q is rare in CLL at 1.9%, but significantly commoner in CLL/PLL at 9%.
Despite careful searches for translocations, there was no corresponing partner chromosome to which the broken off piece had been moved; these were all true deletions - a bit of the chromosome had been lost. The exact amount of the chromosome that was lost was variable, and two thirds a timy bit had been left at the end. There were three broad patterns, but some variation, even with these.
80% of the cases had extra chromosomal abnormalities, - most commonly trisomy 12. There were 17 cases with very complex chromosomal abnormalities and these tended to have del 17p, as you might expect, since loss of TP53 function does lead to that. There were significantly more patients with del 14q among those with unmutated IGHV genes - again not unexpected.
Compared with other cases of CLL or CLL/PLL, having a 14q deletion did not impact of the 3-year overall survival, but the time to first treatment was much shorter at 21 months vs 80.1 months. However, compared to patients who had trisomy 12 without del 14q, those who had the extra deletion had a significantly shorter time to first treatment and overall survival.
So, does this paper tell us much? Not yet. It further defines a small group of patients and confirms that there is something odd about trisomy 12 cases that makes them stand out from the rest of CLLs. There is a small prognostic impact which is extra information, but I have to think that this is a work in progress. Which is why it has been published in B J Haem and not in Blood.
How to make new drugs available earlier and cheaper.
In today's BMJ there is an open letter to the Secretary of State for Health from Professor Peter Lachmann, the retired professor of immunology from Cambridge University and past-president of the Academy of Medical Sciences. In it he makes this interesting suggestion:
About 60% if drug development is taken up by late stage, Phase III trials. Phase I trials ensure safety and phase II trials demonstrate efficacy. Both require small numbers of patients and are relatively cheap to run. Phase III trials are expensive to run and require large numbers of patients, but still cannot detect side effects that occur in fewer than one in a thousand patients.
He says that the population now believes that drugs have to be absolutely safe ans that if anybody comes to harm from them they should be able seek compensation from the courts, and that this has led to drugs being hugely expensive and very slow to bring into use. It is now estimated that to develop a novel drug costs several hundreds of millions of dollars and takes at least 10 years.
In his opinion there is a strong case for making drugs available after phase II trials have shown that they work and to rely on post-marketing surveillance for detecting rare side effects. This would make new drugs much cheaper and available much earlier. It is arguable that phase III trials save fewer lives from avoided side effects than they cause by delaying their availability.
Initially patients should be able to get these new drugs by signing a waiver indemnifying the manufacturer from damages should there be any harm from the drug.
In any case the practice of suing drug companies for adverse effects is pointless. It does the company no financial harm, since the cost is passed on to the consumer. Only lawyers benefit. Legal redress should be reserved for negligence of other malfeasance.
It is probable that many useful drugs are never developed because the potential market is too small and the financial risks too great.
I can see merit in this approach, but Lachmann misses out on the benefits of phase III trials. Phase II trials will show you that a drug has activity in a particular disease and by doing randomized phase II trials (which are a bit more expensive) you can even see if it is more active than the best available alternative, but without phase III trials you will never know whether the new drug gives you a better lifestyle or a longer life than what went before. And you certainly won't know whether it is worth buying.
About 60% if drug development is taken up by late stage, Phase III trials. Phase I trials ensure safety and phase II trials demonstrate efficacy. Both require small numbers of patients and are relatively cheap to run. Phase III trials are expensive to run and require large numbers of patients, but still cannot detect side effects that occur in fewer than one in a thousand patients.
He says that the population now believes that drugs have to be absolutely safe ans that if anybody comes to harm from them they should be able seek compensation from the courts, and that this has led to drugs being hugely expensive and very slow to bring into use. It is now estimated that to develop a novel drug costs several hundreds of millions of dollars and takes at least 10 years.
In his opinion there is a strong case for making drugs available after phase II trials have shown that they work and to rely on post-marketing surveillance for detecting rare side effects. This would make new drugs much cheaper and available much earlier. It is arguable that phase III trials save fewer lives from avoided side effects than they cause by delaying their availability.
Initially patients should be able to get these new drugs by signing a waiver indemnifying the manufacturer from damages should there be any harm from the drug.
In any case the practice of suing drug companies for adverse effects is pointless. It does the company no financial harm, since the cost is passed on to the consumer. Only lawyers benefit. Legal redress should be reserved for negligence of other malfeasance.
It is probable that many useful drugs are never developed because the potential market is too small and the financial risks too great.
I can see merit in this approach, but Lachmann misses out on the benefits of phase III trials. Phase II trials will show you that a drug has activity in a particular disease and by doing randomized phase II trials (which are a bit more expensive) you can even see if it is more active than the best available alternative, but without phase III trials you will never know whether the new drug gives you a better lifestyle or a longer life than what went before. And you certainly won't know whether it is worth buying.
Friday, October 15, 2010
Idolatry
We have got used to footballers making the sign of the cross when they join the pitch. Since players on both sides do it, how does God choose which side wins? Lately I have seen the referees doing it. Is he praying for a tie?
When does religion become ritual?
We have been thinking about the Ten Commandments. In my Bible the second Commandment says "You shall not make for yourself an idol in the form of anything in heaven above or on the earth beneath or in the waters below." This is the typical Protestant view, but the Roman Catholic tradition and some Lutheran churches conflate verses 2-6 of Exodus chapter 20 into a single Commandment and to split the Tenth Commandment into number nine about coveting your neighbor's wife and number ten about coveting everything else he owns. This idea comes from St Augustine and presumably reflects the Jewish opinion in the synagogues during the fifth century AD.
On the other hand the whole history of images has been a fluid one. When several years ago I journeyed to Capodocia on a lecture tour I was fascinated by the underground churches built in the sandstone 'chimneys' there. There was evidence of successive paintings of saintly images there followed by their destruction by iconoclasts. In England it is usual these days for TV programs to decry the destruction of medieval statuary from parish churches under Cromwell.
In defence of imagery is the fact that at a time of illiteracy, pictures are an effective way of getting the message of the Gospel across. Few would condemn the use of the 'Jesus' film in cross cultural evangelism and even Mel Gibson's quasi-horror film has its place. On the other hand to see the toes of statues of the Virgin kissed shiny in some Catholic countries smacks to me of the worst type of superstition.
Some lawyers have taken refuge in the King James Bible which states "Thou shalt not make unto thee any graven image" taking its meaning as images are OK as long as they are not 'graven' images, but that is mere sophistry.
The whole question of idolatry is about putting something in front of God in our estimation: just as it says in Exodus 20:2. Protestants can be as guilty of this just as much as Catholics. My wife tells me that the first time she flew on an aeroplane the person sitting next to her took out a rosary and squeezed it intently as the plane took off; on the other hand my Pastor told me a tale of a man sitting across the aisle who took out his Bible as the plane drew along the runway. He was expecting a Scriptural conversation, but as the plane took off the man held the Bible aloft until the plane was safely in the air and then put it away again.
Things to do with religion can easily be the substitute for the real thing.
No-one has household gods in the Western world, but plenty of us have things that we put before God: house, family, career, our appearance, sports starts or Thespians, musicians or politicians.
One of the things I do as I am writing is to play through my Classical Music CDs. Apart from the first rank composers - Bach, Beethoven, Mozart etc I have a carousel that contains the second rank composers - Dvorak, Elgar, Sibelius, Cesar Franck and the rest They are arranged alphabetically and I have just reached Handel. Generations of English people have regarded Handel's Messiah as a religious event. Of course, the music is wonderful and the subject is Biblical, but we delight in the performance that gives us an emotional high. I similarly delight in Bach's Lutheran music and in Palestrina and Mozart's Requiem and in Orthodox plainsong performed by a Bulgarian choir. But if I put all these before God, they are idols.
At my funeral I want them to sing "I know whom I have believed and am persuaded - made popular by the Billy Graham rallies. I like that music. But if I put it before God, it is an idol. Many young people go to services with an hour of modern music and a ten minute sermonette. It is their metier; it wouldn't be mine. But if they put it before God, it is an idol.
In Jonah 2:8 when he is in the belly of the great fish, he sings, "Those who cling to worthless idols forfeit the grace that could be theirs" Another version has it as "They who observe lying vanities forsake their own mercy." Whether it was his own disobedience to God or his reliance on his being a Hebrew that was the lying vanity that Jonah was referring too, it was time for Jonah to get real with God.
I am convinced that tokenism is the great besetting sin of the Western church, whether Catholic or Protestant. In a recent survey 71% of British people claimed to be Christians. But in what sense. I think for most this would be a cultural answer to a question; most would not be able to define their beliefs nor would they be able to point to a relationship with the Lord Jesus. They would be scared off if one were suggested. Even among churchgoers - let's be generous, say 10% of the population, such a relationship would be a scary suggestion.
But if we are to avoid idolatry it is that relationship with Jesus that matters.
The dearest idol I have known,
Whate'er that idol be,
Help me to tear it from thy throne,
And worship only thee.
So shall my walk be close with God,
Calm and serene my frame;
So purer light shall mark the road
That leads me to the Lamb.
Willimam Cowper from the Olney Hymns.
When does religion become ritual?
We have been thinking about the Ten Commandments. In my Bible the second Commandment says "You shall not make for yourself an idol in the form of anything in heaven above or on the earth beneath or in the waters below." This is the typical Protestant view, but the Roman Catholic tradition and some Lutheran churches conflate verses 2-6 of Exodus chapter 20 into a single Commandment and to split the Tenth Commandment into number nine about coveting your neighbor's wife and number ten about coveting everything else he owns. This idea comes from St Augustine and presumably reflects the Jewish opinion in the synagogues during the fifth century AD.
On the other hand the whole history of images has been a fluid one. When several years ago I journeyed to Capodocia on a lecture tour I was fascinated by the underground churches built in the sandstone 'chimneys' there. There was evidence of successive paintings of saintly images there followed by their destruction by iconoclasts. In England it is usual these days for TV programs to decry the destruction of medieval statuary from parish churches under Cromwell.
In defence of imagery is the fact that at a time of illiteracy, pictures are an effective way of getting the message of the Gospel across. Few would condemn the use of the 'Jesus' film in cross cultural evangelism and even Mel Gibson's quasi-horror film has its place. On the other hand to see the toes of statues of the Virgin kissed shiny in some Catholic countries smacks to me of the worst type of superstition.
Some lawyers have taken refuge in the King James Bible which states "Thou shalt not make unto thee any graven image" taking its meaning as images are OK as long as they are not 'graven' images, but that is mere sophistry.
The whole question of idolatry is about putting something in front of God in our estimation: just as it says in Exodus 20:2. Protestants can be as guilty of this just as much as Catholics. My wife tells me that the first time she flew on an aeroplane the person sitting next to her took out a rosary and squeezed it intently as the plane took off; on the other hand my Pastor told me a tale of a man sitting across the aisle who took out his Bible as the plane drew along the runway. He was expecting a Scriptural conversation, but as the plane took off the man held the Bible aloft until the plane was safely in the air and then put it away again.
Things to do with religion can easily be the substitute for the real thing.
No-one has household gods in the Western world, but plenty of us have things that we put before God: house, family, career, our appearance, sports starts or Thespians, musicians or politicians.
One of the things I do as I am writing is to play through my Classical Music CDs. Apart from the first rank composers - Bach, Beethoven, Mozart etc I have a carousel that contains the second rank composers - Dvorak, Elgar, Sibelius, Cesar Franck and the rest They are arranged alphabetically and I have just reached Handel. Generations of English people have regarded Handel's Messiah as a religious event. Of course, the music is wonderful and the subject is Biblical, but we delight in the performance that gives us an emotional high. I similarly delight in Bach's Lutheran music and in Palestrina and Mozart's Requiem and in Orthodox plainsong performed by a Bulgarian choir. But if I put all these before God, they are idols.
At my funeral I want them to sing "I know whom I have believed and am persuaded - made popular by the Billy Graham rallies. I like that music. But if I put it before God, it is an idol. Many young people go to services with an hour of modern music and a ten minute sermonette. It is their metier; it wouldn't be mine. But if they put it before God, it is an idol.
In Jonah 2:8 when he is in the belly of the great fish, he sings, "Those who cling to worthless idols forfeit the grace that could be theirs" Another version has it as "They who observe lying vanities forsake their own mercy." Whether it was his own disobedience to God or his reliance on his being a Hebrew that was the lying vanity that Jonah was referring too, it was time for Jonah to get real with God.
I am convinced that tokenism is the great besetting sin of the Western church, whether Catholic or Protestant. In a recent survey 71% of British people claimed to be Christians. But in what sense. I think for most this would be a cultural answer to a question; most would not be able to define their beliefs nor would they be able to point to a relationship with the Lord Jesus. They would be scared off if one were suggested. Even among churchgoers - let's be generous, say 10% of the population, such a relationship would be a scary suggestion.
But if we are to avoid idolatry it is that relationship with Jesus that matters.
The dearest idol I have known,
Whate'er that idol be,
Help me to tear it from thy throne,
And worship only thee.
So shall my walk be close with God,
Calm and serene my frame;
So purer light shall mark the road
That leads me to the Lamb.
Willimam Cowper from the Olney Hymns.
Good News Day!
I picked up on this announcement yesterday which seems to have got little attention, but despite the rescue of the Chilean miners, this has to be the best news for many a day. Rinderpest, a virus that causes devastating cattle plague, has been wiped out, the first time such an announcement has been made since the end of smallpox more than 30 years ago. John Anderson, the head of the UN's Food and Agriculture Organisation, called the success "the biggest achievement of veterinary history". Rinderpest is the first animal virus to be contained and then eradicated in the wild.
Cattle plagues have recurred throughout history, often accompanying war. They hit Europe during the 18th century, with three long pandemics which took place in the periods of 1709–1720, 1742–1760, and 1768–1786. There was a major outbreak covering the whole of Britain in 1865/66. Later, an outbreak in the 1890s killed 80 to 90 percent of all cattle in Southern Africa. More recently, another rinderpest outbreak that raged across much of Africa in 1982–84 is estimated to have cost at least US$500 million in stock losses.
The rinderpest virus (RPV) is closely related to the measles and canine distemper viruses. Throughout the eighteenth century there were numerous attempts to control the disease by deliberate innoculation of the virus (a process akin to variolation in smallpox), but a true vaccine does not seem to have been developed until the South African, Sir Arnold Theiler, did so during the Boer War, 1899-1902. Theiler's son, Max received the 1951 Nobel Prize in Physiology or Medicine for developing an effective vaccine against yellow fever.
Walter Plowright, CMG, FRS, FRCVS was the British veterinary scientist whose work in Kenya led to the development of the Plowright tissue culture rinderpest vaccine, which eventually eliminated the disease worldwide. For this achievement, Plowright was named the 1999 World Food Prize Laureate. Unfortunately, Plowright died in February this year before the elimination was confirmed.
The Institute for Animal Health's (IAH) Pirbright laboratory in Surrey, where my brother spent his scientific career, developed a diagnostic kit that was used in the eradication program that began in 1994. I must ask Chris how much he knows about it, next time he phones.
Cattle plagues have recurred throughout history, often accompanying war. They hit Europe during the 18th century, with three long pandemics which took place in the periods of 1709–1720, 1742–1760, and 1768–1786. There was a major outbreak covering the whole of Britain in 1865/66. Later, an outbreak in the 1890s killed 80 to 90 percent of all cattle in Southern Africa. More recently, another rinderpest outbreak that raged across much of Africa in 1982–84 is estimated to have cost at least US$500 million in stock losses.
The rinderpest virus (RPV) is closely related to the measles and canine distemper viruses. Throughout the eighteenth century there were numerous attempts to control the disease by deliberate innoculation of the virus (a process akin to variolation in smallpox), but a true vaccine does not seem to have been developed until the South African, Sir Arnold Theiler, did so during the Boer War, 1899-1902. Theiler's son, Max received the 1951 Nobel Prize in Physiology or Medicine for developing an effective vaccine against yellow fever.
Walter Plowright, CMG, FRS, FRCVS was the British veterinary scientist whose work in Kenya led to the development of the Plowright tissue culture rinderpest vaccine, which eventually eliminated the disease worldwide. For this achievement, Plowright was named the 1999 World Food Prize Laureate. Unfortunately, Plowright died in February this year before the elimination was confirmed.
The Institute for Animal Health's (IAH) Pirbright laboratory in Surrey, where my brother spent his scientific career, developed a diagnostic kit that was used in the eradication program that began in 1994. I must ask Chris how much he knows about it, next time he phones.
Wednesday, October 13, 2010
Obeying the Law: Galatians chapters 1 and 2
My friend Martin Gore and I were swapping stories. Martin has a fund of very funny Jewish jokes and of course on an evening like that you get competitive, so I began one of my own. "There was this Jewish princess who lived with her parents in Manhattan. One day, after picking up two-year old Lorrie, the doctor, from Kindergarten and six year old Solly, the lawyer from...." "Yes," says Martin, "what about the rest?" "Oh no," I reply, "you have to be Jewish to tell Jewish jokes. I am only one sixteenth Jewish, so that was one sixteenth of the joke."
On a less mathematical way of accounting I am fully Jewish since my mother's mother's mother was wholly Jew and ethnicity is guaranteed down the female line, so I'll risk another story. It happened that Moshe went up Mount Horeb and came back with two stone tablets. He had been negotiating with God like a Union leader. He addresses the Israelites, "Sorry, Izzy, He wouldn't budge on bacon sandwiches, but I managed to get us one whole day off every week."
Many people run their Christian lives according to the Ten Commandments. What's wrong with that? I am sometimes amused that people major on the Ten Commandments yet take a 'modern' view on evolution and, if they are Creationists, tend still to believe in an earth that's billions of years old, when the Fourth Commandment says, "Remember the Sabbath day by keeping it holy. Six days you shall labor and do all your work, but the seventh day is a Sabbath to the LORD your God. On it you shall not do any work, neither you, nor your son or daughter, nor your manservant or maidservant, nor your animals, nor the alien within your gates. For in six days the LORD made the heavens and the earth, the sea, and all that is in them, but he rested on the seventh day. Therefore the LORD blessed the Sabbath day and made it holy." (Exodus 20:8-11)
The trouble with law is the lawyers. Fiction paints lawyers either as heroes or villains. On the one side you have heroic figures like Ironside or Rumpole of the Bailey, or any one of the John Grisham characters, who seem to be seeking justice, often for the poor or oppressed; on the other hand there are the sleazy lawyers that Dirty Harry encounters, whose main task seems to be to abuse the police and engineer the escape of wicked men. There is a British lawyer whom the tabloids have named, Mr Loophole. He specialises in finding ways to get celebrities off driving bans. You might say he is a menace to society, but he makes a lot of money at it.
The truth is that it is the job of the lawyer to get the best result for his client. A good lawyer finds a way round the law just as a good accountant tries to find a way for his client to avoid paying so much tax.
That joke I told sounds as though Moses was a lawyer negotiating with God, trying to see how little the Israelites could get away with. Why just one Holy Day a week, for instance? Would a Christian not say that every day should be a Holy Day? In fact, the Ten Commandments are just a brief synopsis of the whole Law. I shall have more to say about the whole Law in another blog.
In the first two chapters of Galatians Paul rails against circumcision; but it is important to recognize that he is using circumcision as a metonym. 'Metonymy' is a technical word of English grammar which means to use an attribute of something to represent the whole thing. For example, we talk about the 'crown' when we really mean the Queen, or we might talk about having someone's 'ear' when we mean we have their attention. Paul uses 'circumcision party' to refer to those who retain subjection to Old Testament Law.
As proof of this we could turn to 1 Corinthians chapter 5. Paul has discovered that a man has his father's wife. He is sleeping with his step-mother! All Paul had to do about this was to point out that it was against the Seventh Commandment; but he doesn't. Instead, he appeals to the fact that Christ, the Passover Lamb, has been sacrificed. It is an offence, not against the Law, but against Christ.
In the first two chapters of his letter to the Galatians Paul insists that his gospel came directly from Christ in his road to Damascus encounter. He has already told us that he didn't get it second-hand. Now, fourteen years later he takes Barnabas and Titus up to Jerusalem on a private visit to meet Peter and James, the Lord's brother. Titus was a Gentile Christian, so note: Peter and James did not insist that he be circumcised. In fact when Paul explained the gospel he was preaching that he had received from his encounter with the risen Lord, he found that it was no different from the gospel Peter had received from Jesus as a 3-year apprentice, and no different from what James had gathered from his elder brother. Indeed, these two agreed that Paul had been appointed as an apostle to the Gentiles just as Peter had been to the Jews, and that God was at work in both of them. The only injunction that they gave Paul was to remember the poor - presumably with regard to the famine in Jerusalem, and Paul was very eager to do this.
Let's open this up a little more. How did Jesus relate the gospel to the law? We have it recorded in the Sermon on the Mount. "Do not think that I have come to abolish the Law or the Prophets; I have not come to abolish them but to fulfil them. I tell you the truth, until heaven and earth disappear, not the smallest letter, not the least stroke of a pen, will by any means disappear from the Law until everything is accomplished." (Matthew 5:17-18)
But the Law, as interpreted by Jesus, is much more stringent than anything the teachers of the Law (the lawyers) were spelling out. Jesus goes on "You have heard that it was said to the people long ago, 'Do not murder, and anyone who murders will be subject to judgment.' But I tell you that anyone who is angry with his brother will be subject to judgment. Again, anyone who says to his brother, 'Raca,' is answerable to the Sanhedrin. But anyone who says, 'You fool!' will be in danger of the fire of hell." (Matthew 5:21-22)
You may be law-abiding, but who has avoided that flash of anger?
Then again "You have heard that it was said, 'Do not commit adultery.' But I tell you that anyone who looks at a woman lustfully has already committed adultery with her in his heart." (Matthew 5:27-28)
Isn't the whole structure of modern advertising designed to induce those feelings in men by showing scantily clad women?
No-one is that law-abiding.
Jesus goes on to demonstrate that the Law is a lot more than keeping rules. He is scathing about the Pharisaic approach. "Woe to you, teachers of the law and Pharisees, you hypocrites! You give a tenth of your spices — mint, dill and cumin. But you have neglected the more important matters of the law — justice, mercy and faithfulness. You should have practiced the latter, without neglecting the former. You blind guides! You strain out a gnat but swallow a camel. (Matthew 23:23-24)
Like lawyers everywhere, the Pharisees twisted and turned the statutes to make themselves look good by obeying the pettifogging letter while neglecting the Spirit.
Jesus preaching to the crowd on the Mount tells them "I tell you that unless your righteousness surpasses that of the Pharisees and the teachers of the law, you will certainly not enter the kingdom of heaven." (Matthew 5:20)
No wonder Paul writes to the Roman church that all have sinned and fallen short of the glory of God. For the final thing about the Law is that we cannot keep it. Only one perfect man ever could and we rely on his excellence and his merit for our salvation. Our puny efforts which would only besmirch the picture are covered by his blood.
On a less mathematical way of accounting I am fully Jewish since my mother's mother's mother was wholly Jew and ethnicity is guaranteed down the female line, so I'll risk another story. It happened that Moshe went up Mount Horeb and came back with two stone tablets. He had been negotiating with God like a Union leader. He addresses the Israelites, "Sorry, Izzy, He wouldn't budge on bacon sandwiches, but I managed to get us one whole day off every week."
Many people run their Christian lives according to the Ten Commandments. What's wrong with that? I am sometimes amused that people major on the Ten Commandments yet take a 'modern' view on evolution and, if they are Creationists, tend still to believe in an earth that's billions of years old, when the Fourth Commandment says, "Remember the Sabbath day by keeping it holy. Six days you shall labor and do all your work, but the seventh day is a Sabbath to the LORD your God. On it you shall not do any work, neither you, nor your son or daughter, nor your manservant or maidservant, nor your animals, nor the alien within your gates. For in six days the LORD made the heavens and the earth, the sea, and all that is in them, but he rested on the seventh day. Therefore the LORD blessed the Sabbath day and made it holy." (Exodus 20:8-11)
The trouble with law is the lawyers. Fiction paints lawyers either as heroes or villains. On the one side you have heroic figures like Ironside or Rumpole of the Bailey, or any one of the John Grisham characters, who seem to be seeking justice, often for the poor or oppressed; on the other hand there are the sleazy lawyers that Dirty Harry encounters, whose main task seems to be to abuse the police and engineer the escape of wicked men. There is a British lawyer whom the tabloids have named, Mr Loophole. He specialises in finding ways to get celebrities off driving bans. You might say he is a menace to society, but he makes a lot of money at it.
The truth is that it is the job of the lawyer to get the best result for his client. A good lawyer finds a way round the law just as a good accountant tries to find a way for his client to avoid paying so much tax.
That joke I told sounds as though Moses was a lawyer negotiating with God, trying to see how little the Israelites could get away with. Why just one Holy Day a week, for instance? Would a Christian not say that every day should be a Holy Day? In fact, the Ten Commandments are just a brief synopsis of the whole Law. I shall have more to say about the whole Law in another blog.
In the first two chapters of Galatians Paul rails against circumcision; but it is important to recognize that he is using circumcision as a metonym. 'Metonymy' is a technical word of English grammar which means to use an attribute of something to represent the whole thing. For example, we talk about the 'crown' when we really mean the Queen, or we might talk about having someone's 'ear' when we mean we have their attention. Paul uses 'circumcision party' to refer to those who retain subjection to Old Testament Law.
As proof of this we could turn to 1 Corinthians chapter 5. Paul has discovered that a man has his father's wife. He is sleeping with his step-mother! All Paul had to do about this was to point out that it was against the Seventh Commandment; but he doesn't. Instead, he appeals to the fact that Christ, the Passover Lamb, has been sacrificed. It is an offence, not against the Law, but against Christ.
In the first two chapters of his letter to the Galatians Paul insists that his gospel came directly from Christ in his road to Damascus encounter. He has already told us that he didn't get it second-hand. Now, fourteen years later he takes Barnabas and Titus up to Jerusalem on a private visit to meet Peter and James, the Lord's brother. Titus was a Gentile Christian, so note: Peter and James did not insist that he be circumcised. In fact when Paul explained the gospel he was preaching that he had received from his encounter with the risen Lord, he found that it was no different from the gospel Peter had received from Jesus as a 3-year apprentice, and no different from what James had gathered from his elder brother. Indeed, these two agreed that Paul had been appointed as an apostle to the Gentiles just as Peter had been to the Jews, and that God was at work in both of them. The only injunction that they gave Paul was to remember the poor - presumably with regard to the famine in Jerusalem, and Paul was very eager to do this.
Let's open this up a little more. How did Jesus relate the gospel to the law? We have it recorded in the Sermon on the Mount. "Do not think that I have come to abolish the Law or the Prophets; I have not come to abolish them but to fulfil them. I tell you the truth, until heaven and earth disappear, not the smallest letter, not the least stroke of a pen, will by any means disappear from the Law until everything is accomplished." (Matthew 5:17-18)
But the Law, as interpreted by Jesus, is much more stringent than anything the teachers of the Law (the lawyers) were spelling out. Jesus goes on "You have heard that it was said to the people long ago, 'Do not murder, and anyone who murders will be subject to judgment.' But I tell you that anyone who is angry with his brother will be subject to judgment. Again, anyone who says to his brother, 'Raca,' is answerable to the Sanhedrin. But anyone who says, 'You fool!' will be in danger of the fire of hell." (Matthew 5:21-22)
You may be law-abiding, but who has avoided that flash of anger?
Then again "You have heard that it was said, 'Do not commit adultery.' But I tell you that anyone who looks at a woman lustfully has already committed adultery with her in his heart." (Matthew 5:27-28)
Isn't the whole structure of modern advertising designed to induce those feelings in men by showing scantily clad women?
No-one is that law-abiding.
Jesus goes on to demonstrate that the Law is a lot more than keeping rules. He is scathing about the Pharisaic approach. "Woe to you, teachers of the law and Pharisees, you hypocrites! You give a tenth of your spices — mint, dill and cumin. But you have neglected the more important matters of the law — justice, mercy and faithfulness. You should have practiced the latter, without neglecting the former. You blind guides! You strain out a gnat but swallow a camel. (Matthew 23:23-24)
Like lawyers everywhere, the Pharisees twisted and turned the statutes to make themselves look good by obeying the pettifogging letter while neglecting the Spirit.
Jesus preaching to the crowd on the Mount tells them "I tell you that unless your righteousness surpasses that of the Pharisees and the teachers of the law, you will certainly not enter the kingdom of heaven." (Matthew 5:20)
No wonder Paul writes to the Roman church that all have sinned and fallen short of the glory of God. For the final thing about the Law is that we cannot keep it. Only one perfect man ever could and we rely on his excellence and his merit for our salvation. Our puny efforts which would only besmirch the picture are covered by his blood.
Draft article for GPs
I have been asked to write a short article on CLL for GPs and palliative care staff. Here is the first draft. Any comments?
Chronic lymphocytic leukaemia (CLL) is the commonest type of leukaemia in Europe and North America. It has an incidence of between 4 and 5 per 100,000 in the general population and the median age of presentation is 70, though occasional patients as young as 20 are seen and the disease becomes commoner still in very old age. It is about twice as common in men as women and much less common in individuals with African and especially East Asian ethnicity. The cause is unknown, though in 5-10 percent of cases there is a family history of CLL or other lymphoid neoplasm. American authorities have recognised exposure to the defoliant, Agent Orange, in Viet Nam as justification for receiving compensation.
There is a long history of changes in the definition of the condition and the latest World Health Organisation classification couples it with small lymphocytic lymphoma (SLL), a histologically and immunologically identical condition without overspill into the blood, as a single entity, CLL/SLL.
There are many causes of chronic lymphocytosis and CLL cannot be definitively diagnosed without the aid of flow cytometry to detect the range of marker molecules on the surface of the leukaemia cells. They should first be monoclonal, defined for simplicity by the presence of only one immunoglobulin light chain type – either kappa or lambda, but not both – on the cell surface. The following markers should also be present: CD5, CD19, CD20 and CD23. Expression of surface immunoglobulin, CD79b and CD20 is usually less dense than is normally found on normal B lymphocytes and the antibody, FMC7, which detects an epitope of CD20, usually fails to react. There are, however, atypical cases with aberrant markers that require expert diagnosis, which should be available from the laboratory performing the assay.
All cases of CLL are now known to be tumours of B lymphocytes. Previous reports of T-lymphocyte CLL are now known to refer either to cases of T-prolymphocytic leukaemia of to cases of T-cell large granular lymphocytic leukaemia. Other conditions that cause diagnostic difficulties include splenic marginal zone lymphoma, mantle cell lymphoma and polyclonal B-cell lymphocytosis.
Since all cases of CLL have to be diagnosed by flow cytometry, it has been possible to refine further the diagnosis. Rather surprisingly, it was found in 2002 that one normal individual in thirty over the age of 40 has a population of cells identical to CLL cells in his or her blood, and in people who have a family history of CLL the prevalence of this monoclonal B-cell lymphocytosis (MBL) is nearer one in seven. In some cases the population is tiny and only detectable by careful scrutiny, but in sizeable numbers the population is easily detectable by routine blood count, and many individuals have been told that they have leukaemia. Since individuals with MBL have only an annual risk of one in a hundred of their condition becoming CLL they have, in my opinion, been worried unnecessarily.
In order to prevent this new Guidelines have been produced by the International Workshop (IW) on CLL which require the presence of at least 5 x 109 B lymphocytes/L in the peripheral blood to make the diagnosis of CLL. Fewer lymphocytes than this establishes the diagnosis of MBL, or SLL if there is lymph node enlargement.
CLL is staged according to the Binet system in Europe and the Rai system in North America. (Table 1) Both depend on the clinical assessment of tumour bulk and the laboratory assessment of the degree of bone marrow suppression reflected in anaemia and thrombocytopenia. The natural history of the condition depends on the pace of progression. Staging tells us how far that progression has gone. Since CLL may be asymptomatic at first, many patients, three-quarters in one series, are diagnosed by a blood test done for something else entirely. Rate of progression was formerly only assessable by measuring the rate of increase of lymphocyte count. A decade ago it was discovered that the biological nature of the leukaemia determined progression rates.
As a B-lymphocyte matures it rearranges its immunoglobulin genes so as to eventually produce an antibody that fits best to its target antigen. The final rearrangement takes place in germinal centres of lymph nodes and is known as somatic mutation. The degree of somatic mutation is thought to influence cell signalling through receptor molecules. It turns out that patients whose CLL is derived from somatically mutated lymphocytes have a much more benign prognosis than those derived from unmutated cells, with a median survival of 25 years against 8 years. in clinical trials, mutational analysis also predicts the length of remission attainable. Unfortunately, this test, though standardised and much cheaper than a single course of chemotherapy, is only available from a few specialised centres and is mainly used for clinical trials. Surrogate tests using flow cytometry, such as CD38 or ZAP-70 levels are much less reliable.
All patients with CLL have impaired immunity. In two thirds of patients there is hypogammaglobulinaemia, but even in untreated stage A patients there is a reduced response to vaccinations. The immunodeficiency is complex and involves both B cell and T cell arms of the immune response. It never recovers, even after treatment; indeed treatment can make it much worse and render the patient susceptible to unusual viral and fungal infections. Impaired immune surveillance is also blamed for an apparent increase in second malignancies, especially those with an obvious viral origin such as Merckel cell tumours. As far as the common carcinomas are concerned the picture is confused because of so many confounding variables.
An ominous form of progression in CLL is the development of Richter’s syndrome, usually a diffuse large B cell lymphoma though some authors include aggressive forms of Hodgkin’s disease or even T-cell lymphomas within the definition. It is now clear that although some forms of Richter’s disease involve transformation of the CLL clone, others are quite separate B-cell tumours.
Another well-recognised form of progression is prolymphocytoid transformation. This is also a confused area. CLL does not transform into prolymphocytic leukaemia, which is a quite separate disease, but may accumulate increased numbers of prolymphocytes in the blood. Sometimes this is a transient phenomenon associated with infection or even vaccination, sometimes it is a stable state, often previously overlooked and frequently associated with the presence of the chromosomal abnormality, trisomy 12. In less than a third of instances it may represent an aggressive change in the nature of the leukaemia.
Paradoxically, as well as immune deficiency, patients with CLL experience autoimmune complications. Most commonly, it is autoimmune haemolytic anaemia (AIHA), which occurs in about 15 per cent of patients, while CLL is itself the commonest known cause of AIHA. Exactly why AIHA is so common in CLL has not been worked out completely, but it is known that it can be triggered by treatment, particularly with the drug, fludarabine, and it is commoner in late stage, multiply-treated disease. Of other types of autoimmune disease, immune thrombocytopenia occurs in about 2 per cent of patients (in one third accompanied by AIHA) and paraneoplastic pemphigus, though even rarer, may also be triggered by fludarabine treatment.
Management
There is no indication for treating CLL merely because it is there. Early trials demonstrated that there was no benefit to the patient from early treatment. A ‘watch and wait’ approach is generally adopted, though patients often call it ‘wait and worry’. Indications for beginning treatment are given in Table 2.
CLL will usually respond well to a variety of drug treatments and it is usual for patients to receive several rounds of chemotherapy, which depending on response may be repeated or varied. Until recently there was no evidence that the order which treatment was given in affected the eventual outcome. However, the CLL 8 trial of the German CLL Study Group has clearly demonstrated a superiority of the combination of fludarabine, cyclophosphamide and rituximab (FCR) over the previous best buy (FC) in terms of overall survival. The large size and well-conducted nature of this randomized controlled trial makes it believable by most haematologist, and measures are being taken for this to become standard therapy, even in countries where the monoclonal antibody, rituximab, was thought too expensive for CLL by regulatory authorities.
The median age for patients entered in this trial was only 61, but patients who were over-65 and over-70 did just as well as the younger individuals. What was crucial was performance status. Other phase II studies have suggested that older patients, especially those with co-morbidities would find difficulties in withstanding the rigours of FCR.
Other agents currently used for treatment include chlorambucil, bendamustine, high dose steroids, lenalidomide, and the monoclonal antibodies, alemtuzumab and ofatumumab. In many countries some of these agents are only available on clinical trials. Interpretation of some clinical trials involving these agents is complex, but chlorambucil is a very safe, cheap and well-tested agent with a reasonable success profile for older patients with co-morbidities, and early phase II data suggest that its effect may be enhanced by combining it with rituximab. With chlorambucil dose is important and in many comparative trials an inadvertently chosen low dose seems to have been used. A dose of 70 mg/m2 every 28 days is recommended.
Trials have shown that certain chromosomal abnormalities predict poor response to standard therapies. Deletions at 11q23, which sometimes involve the ATM gene are associated with poor responses and short remissions following standard chemotherapy, but the addition of rituximab to the cocktail remedies this. Deletions at 17p or mutations of the critical gene at this site (TP53) predicts very poor response to most treatments including FCR. This lesion should be tested for by fluorescent in-situ hybridisation (FISH) before beginning any new therapy. Agents that may be suitable for such patients include high dose steroids, alemtuzumab, flavopiridol and lenalidomide. However, if eligible, such patients should be considered for allogeneic haematopoietic stem cell transplantation. Such a procedure may be performed up to the age of seventy, but carries a high mortality and morbidity.
Supportive care
Often the best support a patient can be given is to remove the inappropriate label of ‘leukaemia’ that has been attached. Patients may need to be supported through autoimmune complications and marrow failure, but the commonest cause of death in CLL is infection. Intravenous immunoglobulin in fusions are recommended for patients with serum IgG levels less than 3g/L who have suffered more than one serious bacterial infection in one year. Prophylactic antibiotics are not recommended except to cover short periods of neutropenia or specific treatments that reduce T cell levels, such as treatment with purine analogues (fludarabine, cladribine or pentostatin) or alemtuzumab. Such patients require prophylaxis against herpes viruses, fungal infections and Pneumocystis jirovecii. Patients receiving alemtuzumab should be screened for reactivation of cytomegalovirus and started on gancyclovir should reactivation occur.
Chronic lymphocytic leukaemia (CLL) is the commonest type of leukaemia in Europe and North America. It has an incidence of between 4 and 5 per 100,000 in the general population and the median age of presentation is 70, though occasional patients as young as 20 are seen and the disease becomes commoner still in very old age. It is about twice as common in men as women and much less common in individuals with African and especially East Asian ethnicity. The cause is unknown, though in 5-10 percent of cases there is a family history of CLL or other lymphoid neoplasm. American authorities have recognised exposure to the defoliant, Agent Orange, in Viet Nam as justification for receiving compensation.
There is a long history of changes in the definition of the condition and the latest World Health Organisation classification couples it with small lymphocytic lymphoma (SLL), a histologically and immunologically identical condition without overspill into the blood, as a single entity, CLL/SLL.
There are many causes of chronic lymphocytosis and CLL cannot be definitively diagnosed without the aid of flow cytometry to detect the range of marker molecules on the surface of the leukaemia cells. They should first be monoclonal, defined for simplicity by the presence of only one immunoglobulin light chain type – either kappa or lambda, but not both – on the cell surface. The following markers should also be present: CD5, CD19, CD20 and CD23. Expression of surface immunoglobulin, CD79b and CD20 is usually less dense than is normally found on normal B lymphocytes and the antibody, FMC7, which detects an epitope of CD20, usually fails to react. There are, however, atypical cases with aberrant markers that require expert diagnosis, which should be available from the laboratory performing the assay.
All cases of CLL are now known to be tumours of B lymphocytes. Previous reports of T-lymphocyte CLL are now known to refer either to cases of T-prolymphocytic leukaemia of to cases of T-cell large granular lymphocytic leukaemia. Other conditions that cause diagnostic difficulties include splenic marginal zone lymphoma, mantle cell lymphoma and polyclonal B-cell lymphocytosis.
Since all cases of CLL have to be diagnosed by flow cytometry, it has been possible to refine further the diagnosis. Rather surprisingly, it was found in 2002 that one normal individual in thirty over the age of 40 has a population of cells identical to CLL cells in his or her blood, and in people who have a family history of CLL the prevalence of this monoclonal B-cell lymphocytosis (MBL) is nearer one in seven. In some cases the population is tiny and only detectable by careful scrutiny, but in sizeable numbers the population is easily detectable by routine blood count, and many individuals have been told that they have leukaemia. Since individuals with MBL have only an annual risk of one in a hundred of their condition becoming CLL they have, in my opinion, been worried unnecessarily.
In order to prevent this new Guidelines have been produced by the International Workshop (IW) on CLL which require the presence of at least 5 x 109 B lymphocytes/L in the peripheral blood to make the diagnosis of CLL. Fewer lymphocytes than this establishes the diagnosis of MBL, or SLL if there is lymph node enlargement.
CLL is staged according to the Binet system in Europe and the Rai system in North America. (Table 1) Both depend on the clinical assessment of tumour bulk and the laboratory assessment of the degree of bone marrow suppression reflected in anaemia and thrombocytopenia. The natural history of the condition depends on the pace of progression. Staging tells us how far that progression has gone. Since CLL may be asymptomatic at first, many patients, three-quarters in one series, are diagnosed by a blood test done for something else entirely. Rate of progression was formerly only assessable by measuring the rate of increase of lymphocyte count. A decade ago it was discovered that the biological nature of the leukaemia determined progression rates.
As a B-lymphocyte matures it rearranges its immunoglobulin genes so as to eventually produce an antibody that fits best to its target antigen. The final rearrangement takes place in germinal centres of lymph nodes and is known as somatic mutation. The degree of somatic mutation is thought to influence cell signalling through receptor molecules. It turns out that patients whose CLL is derived from somatically mutated lymphocytes have a much more benign prognosis than those derived from unmutated cells, with a median survival of 25 years against 8 years. in clinical trials, mutational analysis also predicts the length of remission attainable. Unfortunately, this test, though standardised and much cheaper than a single course of chemotherapy, is only available from a few specialised centres and is mainly used for clinical trials. Surrogate tests using flow cytometry, such as CD38 or ZAP-70 levels are much less reliable.
All patients with CLL have impaired immunity. In two thirds of patients there is hypogammaglobulinaemia, but even in untreated stage A patients there is a reduced response to vaccinations. The immunodeficiency is complex and involves both B cell and T cell arms of the immune response. It never recovers, even after treatment; indeed treatment can make it much worse and render the patient susceptible to unusual viral and fungal infections. Impaired immune surveillance is also blamed for an apparent increase in second malignancies, especially those with an obvious viral origin such as Merckel cell tumours. As far as the common carcinomas are concerned the picture is confused because of so many confounding variables.
An ominous form of progression in CLL is the development of Richter’s syndrome, usually a diffuse large B cell lymphoma though some authors include aggressive forms of Hodgkin’s disease or even T-cell lymphomas within the definition. It is now clear that although some forms of Richter’s disease involve transformation of the CLL clone, others are quite separate B-cell tumours.
Another well-recognised form of progression is prolymphocytoid transformation. This is also a confused area. CLL does not transform into prolymphocytic leukaemia, which is a quite separate disease, but may accumulate increased numbers of prolymphocytes in the blood. Sometimes this is a transient phenomenon associated with infection or even vaccination, sometimes it is a stable state, often previously overlooked and frequently associated with the presence of the chromosomal abnormality, trisomy 12. In less than a third of instances it may represent an aggressive change in the nature of the leukaemia.
Paradoxically, as well as immune deficiency, patients with CLL experience autoimmune complications. Most commonly, it is autoimmune haemolytic anaemia (AIHA), which occurs in about 15 per cent of patients, while CLL is itself the commonest known cause of AIHA. Exactly why AIHA is so common in CLL has not been worked out completely, but it is known that it can be triggered by treatment, particularly with the drug, fludarabine, and it is commoner in late stage, multiply-treated disease. Of other types of autoimmune disease, immune thrombocytopenia occurs in about 2 per cent of patients (in one third accompanied by AIHA) and paraneoplastic pemphigus, though even rarer, may also be triggered by fludarabine treatment.
Management
There is no indication for treating CLL merely because it is there. Early trials demonstrated that there was no benefit to the patient from early treatment. A ‘watch and wait’ approach is generally adopted, though patients often call it ‘wait and worry’. Indications for beginning treatment are given in Table 2.
CLL will usually respond well to a variety of drug treatments and it is usual for patients to receive several rounds of chemotherapy, which depending on response may be repeated or varied. Until recently there was no evidence that the order which treatment was given in affected the eventual outcome. However, the CLL 8 trial of the German CLL Study Group has clearly demonstrated a superiority of the combination of fludarabine, cyclophosphamide and rituximab (FCR) over the previous best buy (FC) in terms of overall survival. The large size and well-conducted nature of this randomized controlled trial makes it believable by most haematologist, and measures are being taken for this to become standard therapy, even in countries where the monoclonal antibody, rituximab, was thought too expensive for CLL by regulatory authorities.
The median age for patients entered in this trial was only 61, but patients who were over-65 and over-70 did just as well as the younger individuals. What was crucial was performance status. Other phase II studies have suggested that older patients, especially those with co-morbidities would find difficulties in withstanding the rigours of FCR.
Other agents currently used for treatment include chlorambucil, bendamustine, high dose steroids, lenalidomide, and the monoclonal antibodies, alemtuzumab and ofatumumab. In many countries some of these agents are only available on clinical trials. Interpretation of some clinical trials involving these agents is complex, but chlorambucil is a very safe, cheap and well-tested agent with a reasonable success profile for older patients with co-morbidities, and early phase II data suggest that its effect may be enhanced by combining it with rituximab. With chlorambucil dose is important and in many comparative trials an inadvertently chosen low dose seems to have been used. A dose of 70 mg/m2 every 28 days is recommended.
Trials have shown that certain chromosomal abnormalities predict poor response to standard therapies. Deletions at 11q23, which sometimes involve the ATM gene are associated with poor responses and short remissions following standard chemotherapy, but the addition of rituximab to the cocktail remedies this. Deletions at 17p or mutations of the critical gene at this site (TP53) predicts very poor response to most treatments including FCR. This lesion should be tested for by fluorescent in-situ hybridisation (FISH) before beginning any new therapy. Agents that may be suitable for such patients include high dose steroids, alemtuzumab, flavopiridol and lenalidomide. However, if eligible, such patients should be considered for allogeneic haematopoietic stem cell transplantation. Such a procedure may be performed up to the age of seventy, but carries a high mortality and morbidity.
Supportive care
Often the best support a patient can be given is to remove the inappropriate label of ‘leukaemia’ that has been attached. Patients may need to be supported through autoimmune complications and marrow failure, but the commonest cause of death in CLL is infection. Intravenous immunoglobulin in fusions are recommended for patients with serum IgG levels less than 3g/L who have suffered more than one serious bacterial infection in one year. Prophylactic antibiotics are not recommended except to cover short periods of neutropenia or specific treatments that reduce T cell levels, such as treatment with purine analogues (fludarabine, cladribine or pentostatin) or alemtuzumab. Such patients require prophylaxis against herpes viruses, fungal infections and Pneumocystis jirovecii. Patients receiving alemtuzumab should be screened for reactivation of cytomegalovirus and started on gancyclovir should reactivation occur.
Tuesday, October 12, 2010
Autumn
Seasons
First wisps of coldness catch the wind to wake
me from the summer lethargy. The stars,
more crystal than before, no truck will take
with lazy observations of Renoirs.
The air has found a sweetness it had lost
in acrid August. But though death has browned
the leaves, life breathes again in early frost
and work is joy, my stake set in the ground.
Winter camellias, snowdrops, crocuses
color my worklife with impetus and style.
A new vitality refocuses
the sharpness and precision for a while.
But always the sun sets up its honey-traps,
the damsel coolly dressed in white chiffon
strikes down resolve, condemns me to collapse,
back to the even-tempered amnion
First wisps of coldness catch the wind to wake
me from the summer lethargy. The stars,
more crystal than before, no truck will take
with lazy observations of Renoirs.
The air has found a sweetness it had lost
in acrid August. But though death has browned
the leaves, life breathes again in early frost
and work is joy, my stake set in the ground.
Winter camellias, snowdrops, crocuses
color my worklife with impetus and style.
A new vitality refocuses
the sharpness and precision for a while.
But always the sun sets up its honey-traps,
the damsel coolly dressed in white chiffon
strikes down resolve, condemns me to collapse,
back to the even-tempered amnion
One to read
After two boring books, here is one to read. Val McDermid is not part of the Edinburgh reading set which includes Ian Rankin, Alexander McCall Smith, JK Rowling and Iain Banks, all of whom I delight in but she writes about the same locus. She calls it "Tartan noir".
Val writes thrillers and "The Distant Echo" is from 2003. This is a stand alone book, unconnected with Kate Brannigan and Tony Hill, who feature in her thriller series. What I liked about it was its use of the 'cold case' formula which allowed her to contrast police methods from the seventies and the noughties. I also was pleased not to guess the identity of the killer until about a hundred pages from the end and even there, there was a sting in the tail.
It is usually the case that the killer in real-life murders is a family member or the one who found the body. Val explores how such an assumption can ruin lives. She also gives a surprisingly sympathetic portrayal of an evangelical preacher, for one who comes from her (lesbian) background.
I recommend the book which can be obtained from Amazon for a penny or from all good charity shops for a pound.
Val writes thrillers and "The Distant Echo" is from 2003. This is a stand alone book, unconnected with Kate Brannigan and Tony Hill, who feature in her thriller series. What I liked about it was its use of the 'cold case' formula which allowed her to contrast police methods from the seventies and the noughties. I also was pleased not to guess the identity of the killer until about a hundred pages from the end and even there, there was a sting in the tail.
It is usually the case that the killer in real-life murders is a family member or the one who found the body. Val explores how such an assumption can ruin lives. She also gives a surprisingly sympathetic portrayal of an evangelical preacher, for one who comes from her (lesbian) background.
I recommend the book which can be obtained from Amazon for a penny or from all good charity shops for a pound.
Monday, October 11, 2010
Teenagers
The Teenager
All that emotion! DNA demanding to be shed
to populate the planet on its own
and in its image. Those young men all led
to reckless dances in a torrid zone
of cyclones, thundercracks and grand affairs;
enduring disappointment, triumph, hope
and ordinariness. The crises, cares
and spots all settle back. Somehow they cope
with analytic algebra and trig,
rift valleys, enzymes, Molière or Keats,
and wait, anticipating that their big
romance won’t peter out in dull defeats.
All that emotion! DNA demanding to be shed
to populate the planet on its own
and in its image. Those young men all led
to reckless dances in a torrid zone
of cyclones, thundercracks and grand affairs;
enduring disappointment, triumph, hope
and ordinariness. The crises, cares
and spots all settle back. Somehow they cope
with analytic algebra and trig,
rift valleys, enzymes, Molière or Keats,
and wait, anticipating that their big
romance won’t peter out in dull defeats.
Latest news
Yesterday, for what I imagine to be the first time, Lansdowne Baptist Church became a chemotherapy suite. I felt so well during my infusion that I was able to go to church in the morning with my pump running. It is very unobtrusive, so nobody was distracted.
I was so glad to be able to go. The music was terrific. Often with modern tunes nobody quite knows when to come in so there is a lot of stuttering around the first, second and subsequent beats, but the pianist was excellent and gave us a clear indication of when to start singing. I was very pleased to hear one of my hymns used in the service - it shows that it is used even when I am not expected to be there - makes the hard work worthwhile.
We had a wonderful sermon from Chris Kelly on I Samuel chapter 8, where the Israelites demand a King - they got that fathead, Saul. The main points were that rejection hurts - Samuel was rejected a] because he was old, b] because his grown up sons were crooks, and c] because he wouldn't bend to the ways of the world. His response was to pray and submit to God's will.
Secondly, the Israelites - read Christians - were doing the rejecting. What right have we to reject God's servant? If he were leading an ungodly life - sexual immorality, exploiting the poor, fraud, theft, or bullying - or if he were teaching a false doctrine - conjuring trick with bones, for instance - then it would not only be right, but our duty to reject him, but if we reject God's man for sticking too close to Jesus, then we are rejecting God, we are not being spiritual and ultimately hurting ourselves. If we get into a mess over it don't expect God to run to our aid. God has sometimes been silent for decades - even centuries when his people rebel against him. Sometimes he lets us have our head.
Finally God does not force his way upon us, but despite our resistance we cannot thwart him, "Even the wrath of man shall praise him," says the Scripture, and "you meant it for evil, but God meant it for good." Such mistakes as choosing Saul are there for us to learn from.
I am expecting my pump to be disconnected in a couple of hours and then, I hope no side effects until later in the week.
I'm still awake for half the night, but I am using the time profitably. See next post.
I was so glad to be able to go. The music was terrific. Often with modern tunes nobody quite knows when to come in so there is a lot of stuttering around the first, second and subsequent beats, but the pianist was excellent and gave us a clear indication of when to start singing. I was very pleased to hear one of my hymns used in the service - it shows that it is used even when I am not expected to be there - makes the hard work worthwhile.
We had a wonderful sermon from Chris Kelly on I Samuel chapter 8, where the Israelites demand a King - they got that fathead, Saul. The main points were that rejection hurts - Samuel was rejected a] because he was old, b] because his grown up sons were crooks, and c] because he wouldn't bend to the ways of the world. His response was to pray and submit to God's will.
Secondly, the Israelites - read Christians - were doing the rejecting. What right have we to reject God's servant? If he were leading an ungodly life - sexual immorality, exploiting the poor, fraud, theft, or bullying - or if he were teaching a false doctrine - conjuring trick with bones, for instance - then it would not only be right, but our duty to reject him, but if we reject God's man for sticking too close to Jesus, then we are rejecting God, we are not being spiritual and ultimately hurting ourselves. If we get into a mess over it don't expect God to run to our aid. God has sometimes been silent for decades - even centuries when his people rebel against him. Sometimes he lets us have our head.
Finally God does not force his way upon us, but despite our resistance we cannot thwart him, "Even the wrath of man shall praise him," says the Scripture, and "you meant it for evil, but God meant it for good." Such mistakes as choosing Saul are there for us to learn from.
I am expecting my pump to be disconnected in a couple of hours and then, I hope no side effects until later in the week.
I'm still awake for half the night, but I am using the time profitably. See next post.
Sunday, October 10, 2010
So now you want a King?
Have you ever wondered why we don't want big government. You will find a Biblical answer in 1 Samuel chapter 8. The Israelites were clamouring for king, even though Samuel was against it. God told Samuel to tell them why they didn't need one, but if they really pressed he should give them one. They got a tall dark and handsome one. What a disaster! Ring any bells?
"This is what the king who will reign over you will do: He will take your sons and make them serve with his chariots and horses, and they will run in front of his chariots. Some he will assign to be commanders of thousands and commanders of fifties, and others to plow his ground and reap his harvest, and still others to make weapons of war and equipment for his chariots. He will take your daughters to be perfumers and cooks and bakers. He will take the best of your fields and vineyards and olive groves and give them to his attendants. He will take a tenth of your grain and of your vintage and give it to his officials and attendants. Your menservants and maidservants and the best of your cattle and donkeys he will take for his own use. He will take a tenth of your flocks, and you yourselves will become his slaves."
I like the bit about donkeys.
"This is what the king who will reign over you will do: He will take your sons and make them serve with his chariots and horses, and they will run in front of his chariots. Some he will assign to be commanders of thousands and commanders of fifties, and others to plow his ground and reap his harvest, and still others to make weapons of war and equipment for his chariots. He will take your daughters to be perfumers and cooks and bakers. He will take the best of your fields and vineyards and olive groves and give them to his attendants. He will take a tenth of your grain and of your vintage and give it to his officials and attendants. Your menservants and maidservants and the best of your cattle and donkeys he will take for his own use. He will take a tenth of your flocks, and you yourselves will become his slaves."
I like the bit about donkeys.
Saturday, October 09, 2010
The ultimate FCR advice
After all those sleepless nights fueled by dexamethasone working on CLL8 I think it right that I should put FCR into context. In this I am helped by an editorial by Zenz, Mertens and Stilgenbauer from the German group published in Haematologica. It is available by open access so everybody can read it.
The first thing to say is that FCR requires an intact p53 pathway to work and if this is impaired and a patient needs treatment. FCR should not be used. I have already been involved in one court case where a hospital ignored this advice and the patient received substantial damages. I would be prepared to act as an expert witness if such a thing occurred again. Here's what the Germans say about this issue: "Cases with 17p deletion have a very poor prognosis (median survival of less than 2 years from first treatment indication) with alkylator and nucleoside-based chemo(immuno)therapy (chlorambucil, fludarabine, fludarabine + cyclophosphamide, or fludarabine + cyclophosphamide + rituximab). Since a number of agents have been shown to act independently of functional p53 in CLL, current treatment approaches in clinical trials use these agents upfront with early allogeneic stem cell transplantation as consolidation after remission has been achieved in eligible patients."
Those agents include high dose steroids, Alemtuzumab, flavopiridol, possibly revlimid and some of the second and third generation anti-CD20 antibodies.
"In addition to CLL with 17p deletion, the group of patients with TP53 mutations (even in the absence of 17p deletion) is a subgroup gaining increasing attention. TP53 mutations are found in 8–12% of patients with an indication for first-line treatment. The incidence increases during the course of disease and was 37% in a cohort of fludarabine-refractory cases. In a recent study within the German CLL4 study (which compared fludarabine and fludarabine + cyclophosphamide treatment), the incidence of TP53 mutations in the absence of 17p deletion was similar to that of 17p deletions and the clinical course of patients with these forms of CLL was very similar. These data –as well as information from a number of retrospective cohort studies – suggest that TP53 mutation should be added to the diagnostic work-up of patients with CLL in need of treatment"
This is certainly the German view, though there is not yet international consensus on this. Certainly there are extra refractory cases with TP53 mutations in the absence of 17p deletions, but others have found these to be sometimes quite benign. We will have to await further developments on this. But CLL8 does tell us that patients without del 17p who have stable or progressive disease after three courses of FCR should be treated in the same way as the del 17p groups - which means getting them into remission by one of the non-p43 dependent cocktails and then if at all feasible doing an allograft as soon as possible.
How about the rest of the patients? This is the slide that the Germans have produced for risk adapted treatment. Click to enlarge.
"Based on a number of studies including prospective trial data, patients with unmutated IGHV, 11q deletion, V3-21 usage and high levels of serum markers (e.g. β-2 microglobulin) form a high-risk group with a median survival in the range of 53 months following an indication for first-line treatment. These patients are now generally treated with the combination of fludarabine + cyclophosphamide + rituximab (if fit and younger), but future trials may consider maintenance strategies in such patients"
Chris is absolutely right to stress that these trials were conducted in younger, fitter individuals and the results cannot be applied to older unfit patients. It is also important to recognise that CLL8 did include some fit older patients (even up to 80-years olds) who did no worse than the younger patients. However, most older patients will find it hard to manage FCR and dose reduction (as occurred for stage C patients) seems to subtract from the overall survival advantage. It is also wise to remember the results of the REACH trial in which there was no overall survival advantage (as yet) for giving FCR over FC as a second or third line treatment and which was accompanied by problems of long term and late neutropenia (for which we looked for but couldn't substantiate MDS as the cause). The message is that if FCR looks to be an option for your disease, it is better to get it in sooner rather than later, while your still young enough and fit enough to manage it, and before you begin to suffer marrow failure. If you are already stage C disease, you may have to dose-reduce at first, but this should eventually lead to the marrow recovering, and my personal advice is that you should then get back up to full doses. I agree with the Germans that this is the group that we need to see maintenance trials with.
It is important to recognize that the del 11q patients now fall into this intermediate group. CLL8 has removed indecision as to whether they should be intermediate or high risk. If they are getting FCR they are at intermediate risk.
What should happen to intermediate risk patients who are less well or have co-morbidities? I know many people opt for bentamustine-rituximab for this group, but I favor chlorambucil-rituximab as a less toxic and equally effective regimen, but the dose of chlorambucil has to be a proper one, not a 'Smarties' dose (fill in your own national children's sweet instead of 'Smarties' if you don't have them).
AS the Germans say: "While risk-adapted treatment approaches are generally used interchangeably with different treatments for certain prognostic risk groups, future risk-adapted treatment strategies will undoubtedly also have to integrate the patient’s performance status, co-morbidities and age, which is of particular importance considering that the median age at diagnosis is over 70 years old"
This is an interesting suggestion:
"The group of patients with none of the above aberrations and mutated IGHV status have a very favorable outcome and could even be considered for de-escalation studies."
This suggestion is one that I have made in the UK Clinical trials group and we are implimenting trials involving chlorambucil-rituximab and chlorambucil-ofaftumumab in this group.
"In spite of this clinically relevant risk hierarchy, the decision to treat is currently not based on the risk profile but on symptomatic disease. This is important and further supported by the observation that in some subgroups of patients, such as those with 17p deletion (and mutated IGHV), the disease may have an indolent course."
I agree.
The first thing to say is that FCR requires an intact p53 pathway to work and if this is impaired and a patient needs treatment. FCR should not be used. I have already been involved in one court case where a hospital ignored this advice and the patient received substantial damages. I would be prepared to act as an expert witness if such a thing occurred again. Here's what the Germans say about this issue: "Cases with 17p deletion have a very poor prognosis (median survival of less than 2 years from first treatment indication) with alkylator and nucleoside-based chemo(immuno)therapy (chlorambucil, fludarabine, fludarabine + cyclophosphamide, or fludarabine + cyclophosphamide + rituximab). Since a number of agents have been shown to act independently of functional p53 in CLL, current treatment approaches in clinical trials use these agents upfront with early allogeneic stem cell transplantation as consolidation after remission has been achieved in eligible patients."
Those agents include high dose steroids, Alemtuzumab, flavopiridol, possibly revlimid and some of the second and third generation anti-CD20 antibodies.
"In addition to CLL with 17p deletion, the group of patients with TP53 mutations (even in the absence of 17p deletion) is a subgroup gaining increasing attention. TP53 mutations are found in 8–12% of patients with an indication for first-line treatment. The incidence increases during the course of disease and was 37% in a cohort of fludarabine-refractory cases. In a recent study within the German CLL4 study (which compared fludarabine and fludarabine + cyclophosphamide treatment), the incidence of TP53 mutations in the absence of 17p deletion was similar to that of 17p deletions and the clinical course of patients with these forms of CLL was very similar. These data –as well as information from a number of retrospective cohort studies – suggest that TP53 mutation should be added to the diagnostic work-up of patients with CLL in need of treatment"
This is certainly the German view, though there is not yet international consensus on this. Certainly there are extra refractory cases with TP53 mutations in the absence of 17p deletions, but others have found these to be sometimes quite benign. We will have to await further developments on this. But CLL8 does tell us that patients without del 17p who have stable or progressive disease after three courses of FCR should be treated in the same way as the del 17p groups - which means getting them into remission by one of the non-p43 dependent cocktails and then if at all feasible doing an allograft as soon as possible.
How about the rest of the patients? This is the slide that the Germans have produced for risk adapted treatment. Click to enlarge.
"Based on a number of studies including prospective trial data, patients with unmutated IGHV, 11q deletion, V3-21 usage and high levels of serum markers (e.g. β-2 microglobulin) form a high-risk group with a median survival in the range of 53 months following an indication for first-line treatment. These patients are now generally treated with the combination of fludarabine + cyclophosphamide + rituximab (if fit and younger), but future trials may consider maintenance strategies in such patients"
Chris is absolutely right to stress that these trials were conducted in younger, fitter individuals and the results cannot be applied to older unfit patients. It is also important to recognise that CLL8 did include some fit older patients (even up to 80-years olds) who did no worse than the younger patients. However, most older patients will find it hard to manage FCR and dose reduction (as occurred for stage C patients) seems to subtract from the overall survival advantage. It is also wise to remember the results of the REACH trial in which there was no overall survival advantage (as yet) for giving FCR over FC as a second or third line treatment and which was accompanied by problems of long term and late neutropenia (for which we looked for but couldn't substantiate MDS as the cause). The message is that if FCR looks to be an option for your disease, it is better to get it in sooner rather than later, while your still young enough and fit enough to manage it, and before you begin to suffer marrow failure. If you are already stage C disease, you may have to dose-reduce at first, but this should eventually lead to the marrow recovering, and my personal advice is that you should then get back up to full doses. I agree with the Germans that this is the group that we need to see maintenance trials with.
It is important to recognize that the del 11q patients now fall into this intermediate group. CLL8 has removed indecision as to whether they should be intermediate or high risk. If they are getting FCR they are at intermediate risk.
What should happen to intermediate risk patients who are less well or have co-morbidities? I know many people opt for bentamustine-rituximab for this group, but I favor chlorambucil-rituximab as a less toxic and equally effective regimen, but the dose of chlorambucil has to be a proper one, not a 'Smarties' dose (fill in your own national children's sweet instead of 'Smarties' if you don't have them).
AS the Germans say: "While risk-adapted treatment approaches are generally used interchangeably with different treatments for certain prognostic risk groups, future risk-adapted treatment strategies will undoubtedly also have to integrate the patient’s performance status, co-morbidities and age, which is of particular importance considering that the median age at diagnosis is over 70 years old"
This is an interesting suggestion:
"The group of patients with none of the above aberrations and mutated IGHV status have a very favorable outcome and could even be considered for de-escalation studies."
This suggestion is one that I have made in the UK Clinical trials group and we are implimenting trials involving chlorambucil-rituximab and chlorambucil-ofaftumumab in this group.
"In spite of this clinically relevant risk hierarchy, the decision to treat is currently not based on the risk profile but on symptomatic disease. This is important and further supported by the observation that in some subgroups of patients, such as those with 17p deletion (and mutated IGHV), the disease may have an indolent course."
I agree.
Friday, October 08, 2010
German CLL8 part 12.
This is the final posting on CLL 8 and I just want to make the final point that the usual prognostic factors that we have known about for up to ten years have turned up trumps again in this trial.
Click to enlarge. These prognostic factors were originally discovered to predict prognosis in retrospective series, but they have been tested regularly in prospective studies and almost always they have been useful to predict what will happen in trials. The stand out prognostic factor is del 17p, and although it only represents about 5% of patients, these patients do so badly on either FC or FCR that they have to be excluded from these treatments. The other important message is that del 11q, always thought to be a bad deal, loses its grim future if FCR is used first line.
A high Beta-2 microglobulin is now a useful predictor of shorter pfs and OS and unmutated IGVH genes a useful predictor of a shorter remission, though not of overall survival yet in a multivariate analysis. We will have to watch how that pans out with longer follow up. As might be expected, a poor performance score leads to a shorter survival than a good one. Serum thymidine kinase levels are only measured in Germany, so we can't comment on their usefulness elsewhere. They require a radioassay. Beware of anyone offering you this test as an ELISA.
In conclusion:
* The addition of rituximab to FC first line therapy improves the outcome of patients with advanced, symptomatic CLL with regard to
* Response rates (CR, ORR, MRD)
* Progression-free survival
* Overall survival
* Achieving a CR produces longer survival.
* This is the first randomized trial to demonstrate that the choice of first line therapy improves the natural course of CLL.
Click to enlarge. These prognostic factors were originally discovered to predict prognosis in retrospective series, but they have been tested regularly in prospective studies and almost always they have been useful to predict what will happen in trials. The stand out prognostic factor is del 17p, and although it only represents about 5% of patients, these patients do so badly on either FC or FCR that they have to be excluded from these treatments. The other important message is that del 11q, always thought to be a bad deal, loses its grim future if FCR is used first line.
A high Beta-2 microglobulin is now a useful predictor of shorter pfs and OS and unmutated IGVH genes a useful predictor of a shorter remission, though not of overall survival yet in a multivariate analysis. We will have to watch how that pans out with longer follow up. As might be expected, a poor performance score leads to a shorter survival than a good one. Serum thymidine kinase levels are only measured in Germany, so we can't comment on their usefulness elsewhere. They require a radioassay. Beware of anyone offering you this test as an ELISA.
In conclusion:
* The addition of rituximab to FC first line therapy improves the outcome of patients with advanced, symptomatic CLL with regard to
* Response rates (CR, ORR, MRD)
* Progression-free survival
* Overall survival
* Achieving a CR produces longer survival.
* This is the first randomized trial to demonstrate that the choice of first line therapy improves the natural course of CLL.
German CLL8 - part 11
The graph I want to show today makes a simple point, and one that Peter Hillmen has made previously.
It is a simple point. The better the response to treatment, the longer the overall survival. It doesn't matter whether the CR was achieved with FC or FCR. However, this relates to the nature of the disease. Those with good prognostic factors obrtain the best remissions. What is not clear is that extraordinary means to achieve a CR with the more difficult cases will achieve such long remissions. Bad risk cases grow more quickly. You may get rid of more disease, but recrudescence may also be at a faster pace.
It is a simple point. The better the response to treatment, the longer the overall survival. It doesn't matter whether the CR was achieved with FC or FCR. However, this relates to the nature of the disease. Those with good prognostic factors obrtain the best remissions. What is not clear is that extraordinary means to achieve a CR with the more difficult cases will achieve such long remissions. Bad risk cases grow more quickly. You may get rid of more disease, but recrudescence may also be at a faster pace.
It's unfair
George Osborne has not just been bashing the rich, he has also had a go at the poor. Another of the cuts revealed at the Tory Party Conference was a decision that no-one should receive benefits worth more than the average wage - this is about $40,000 a year. It would be unfair - it is unfair - that someone earning $40,000 a year should be paying taxes to fund a non-worker living on payouts worth more than this.
Another outcry - what about the children?
The biggest element of the benefit culture is housing benefit. This is to be capped at a maximum of $750 a month.
One of the daytime TV programs that I watch (along with all the old detectives) is 'Homes under the Hammer' The format is the same every day. Three homes are bought at auction and we then get feedback on what has happened to them. What is remarkable is how run down property is transformed in a few weeks. Typically, a Victorian terraced house that sells for $150,000 will have $30,000 spent on it and come out as a luxury home with UPVC double glazed windows, gas-fired central heating, new kitchen and bathroom, totally redecorated and carpeted and worth $230,000. What amazes me is that they can command a rental income of $750 a month. That is a 5% return on investment when the banks are paying 1%. Some people are managing 14% return. Why isn't everybody doing it?
However, when it comes to central London we are talking about several hundred dollars a week. On family of Somali immigrants with 7 children were placed in a mansion in St John's Wood near Lord's Cricket Ground at $2000 a week. They complained that their previous accommodation was in a poor area. Yes, I know this is the Daily Mail's worst example, but the principle is that unemployed people on benefits are currently living in very expensive areas, while people who work in central London are facing 2-3 hours of commuting because housing in unavailable near their work.
There is no reason not to be unemployed in Doncaster if you are going to be unemployed in central London. A couple of years ago you could buy a whole street in Doncaster for a quarter of a million dollars. Because there was no demand the houses were pulled down. Instead some of these property developers could refurbish houses for Somali immigrants and the indolent poor.
William Booth talked about the deserving and the undeserving poor. The Bible says, "He who will not work; neither shall he eat." We ought to be talking about responsibility not what we deserve. As a Calvinist I can see that we deserve punishment. Grace spares us that and modern society is very gracious. But benefit recipients are taking the mickey.
They protest that they are not being allowed to have as many children as they like; that it's just like the Chinese one-child policy. As far as I am concerned they can have as many children as they like. But not on my dollar.
Another outcry - what about the children?
The biggest element of the benefit culture is housing benefit. This is to be capped at a maximum of $750 a month.
One of the daytime TV programs that I watch (along with all the old detectives) is 'Homes under the Hammer' The format is the same every day. Three homes are bought at auction and we then get feedback on what has happened to them. What is remarkable is how run down property is transformed in a few weeks. Typically, a Victorian terraced house that sells for $150,000 will have $30,000 spent on it and come out as a luxury home with UPVC double glazed windows, gas-fired central heating, new kitchen and bathroom, totally redecorated and carpeted and worth $230,000. What amazes me is that they can command a rental income of $750 a month. That is a 5% return on investment when the banks are paying 1%. Some people are managing 14% return. Why isn't everybody doing it?
However, when it comes to central London we are talking about several hundred dollars a week. On family of Somali immigrants with 7 children were placed in a mansion in St John's Wood near Lord's Cricket Ground at $2000 a week. They complained that their previous accommodation was in a poor area. Yes, I know this is the Daily Mail's worst example, but the principle is that unemployed people on benefits are currently living in very expensive areas, while people who work in central London are facing 2-3 hours of commuting because housing in unavailable near their work.
There is no reason not to be unemployed in Doncaster if you are going to be unemployed in central London. A couple of years ago you could buy a whole street in Doncaster for a quarter of a million dollars. Because there was no demand the houses were pulled down. Instead some of these property developers could refurbish houses for Somali immigrants and the indolent poor.
William Booth talked about the deserving and the undeserving poor. The Bible says, "He who will not work; neither shall he eat." We ought to be talking about responsibility not what we deserve. As a Calvinist I can see that we deserve punishment. Grace spares us that and modern society is very gracious. But benefit recipients are taking the mickey.
They protest that they are not being allowed to have as many children as they like; that it's just like the Chinese one-child policy. As far as I am concerned they can have as many children as they like. But not on my dollar.
Universal Benefits
When a country is paying more in interest payments on government borrowing than it is on the Defence of the Realm, it really is time to consider how it should set out its stall. In many ways England is a victim of its own success. It is one of the most densely populated countries in the world - only small island states like Singapore exceed it in population density. Yet people still want to come here. True, the other countries of the United Kingdom - Wales, Scotland and Northern Ireland are less densely populated, but, the first two, at least, are very mountainous and not many immigrants want to set up shanty towns on Snowdon or Ben Nevis.
By victim of its own success, I mean that this was where the Industrial Revolution took place, which first drew people from the land into cities and when that began to wear out, the financial big-bang established London anew as a city with streets paved with gold. All those immigrants are not financial advisers, but they are there to service many who are. When you hear of banks paying 6 million dollars as an end of year bonus to some financial barrow-boy - yes, I know this is a headline-grabbing exception - you can see that his spending supports an awful lot of Polish plumbers, Indian chefs and eventually, Pakistani terrorists. Mrs Thatcher called it 'a trickle down economy'.
For the past twenty years I have always been able to earn more than I needed to live and my first responsibility was to support my own family. I bought a a small but new house in Oxford for my two children at University there to share. When they left my younger son spent some time painting it before they sold it. While up the ladder he could see into the garden of an identical house next-door where his neighbor, a girl of African-Caribbean extraction was entertaining a friend. The conversation went something like, Friend: << This is a fab house. How did you manage to get it?>>
Neighbor: << Simple. Just get yourself a kid and the benefit pays for it.>>
I am not making this up. Evidence is not the plural of anecdote, but there seems to be evidence that the welfare system is systematically abused in the UK by many who are workshy. What they are doing is not necessarily illegal, though every day I read an account of someone defrauding the benefit system, but the incentives are acting in such a way that someone would have to be saint to avoid the temptation.
Before anyone jumps in and says that taxpayers who avoid their responsibilities are a more important problem, I don't doubt it and would be willing to launch a diatribe against the way the tax system is ordered too.
This week at the Tory Party Conference, preliminary measures have been announced to begin to sort out the problem. In many ways this initiative could not have taken place without a coalition government. Undoubtedly, any attack on benefits would have been attacked from the Left and with only one party in favor. Even with a majority in Parliament, there would have been anger and resistance, even with strike action. Having the Liberal-Democrats on board, not only gives a Parliamentary majority, but carries with it a numerical majority of voters.
The first measure announced was aimed at the relatively rich. Child benefit would be withdrawn from higher rate tax payers. Child benefit was introduced after the war as a universal benefit for children. Originally it was paid to second and subsequent children up to the age of 15, but nowadays it is paid to all children while they are in full time education. The eldest child gets $1600 a year and subsequent children $1000 a year. The money is paid to the mother or other responsible adult if there is no mother.
It is to be withdrawn by 2015 to those paying higher rate income tax. That means to those earning more than $66,000 a year. This represents 15% of those receiving it and it will save the taxpayer $1.5 billion a year which can be used to pay off foreign debt, so that less interest needs to be paid, which will in turn save the taxpayer more money.
There was an immediate outcry. Not that the rich actually need the child benefit - it often goes into a savings account for the child to start a pension fund or to pay for school fees - but because there is a hidden dollop of unfairness. It comes from Mrs Thatcher again. She introduced separate taxation for husbands and wives. Previously a wife was regarded as a husband's possession and he was given a tax threshold that accounted for his having to support two individuals on one salary. This was lost when his wife was taxed separately. So we have the situation whereby there could be a family income of $130,000 with neither parent paying higher rate tax and the mother still drawing child benefit, while next door the mother stays at home to look after the children, does not work to earn money, yet the family income just crosses the threshold and child benefit is lost.
Unfairness is anathema to the British voter. They still remember that Diego Maradonna goal in the 1986 world cup. But is this a real issue? We know that for 50% of families with a stay-at-home mum, the family income exceeds $112,500 a year. Even if it is less, we find that many stay-at-home mums are able to do a small job for their husbands that reduces his taxable income and enables her use her tax allowance and to save more than the child benefit in tax that does not need to be paid. There is also a promise that sometime this parliament there will be a Bill introduced that allows all stay-at-home mums to receive this sort of redress (though not by the full amount).
The principle of Universal Benefits was a Liberal Party one, introduced by the Beveridge report of 1944. So the Tory's coalition partners have an emotional tie to them. It was very different in 1944 when the housing stock had been seriously depleted by bombing and poverty was extremely severe. Today poverty means you don't have a flat screen TV.. The other Universal Benefits (introduced only later) include a free TV licence for the over-75s, free bus passes for the over-60s (not actually used by higher rate tax-payers) and a winter fuel allowance for the over 60s so that no-one need die of hypothermia. There are suggestions that some of these are vulnerable to the chancellor's axe in the Autumn spending review. I shan't lose any sleep if I lose them. I have been eligible for a bus-pass for 7 years. I have used it 4 times. That's saved me $12.
I shall return to this topic, but now I must go and paint a doorpost.
By victim of its own success, I mean that this was where the Industrial Revolution took place, which first drew people from the land into cities and when that began to wear out, the financial big-bang established London anew as a city with streets paved with gold. All those immigrants are not financial advisers, but they are there to service many who are. When you hear of banks paying 6 million dollars as an end of year bonus to some financial barrow-boy - yes, I know this is a headline-grabbing exception - you can see that his spending supports an awful lot of Polish plumbers, Indian chefs and eventually, Pakistani terrorists. Mrs Thatcher called it 'a trickle down economy'.
For the past twenty years I have always been able to earn more than I needed to live and my first responsibility was to support my own family. I bought a a small but new house in Oxford for my two children at University there to share. When they left my younger son spent some time painting it before they sold it. While up the ladder he could see into the garden of an identical house next-door where his neighbor, a girl of African-Caribbean extraction was entertaining a friend. The conversation went something like, Friend: << This is a fab house. How did you manage to get it?>>
Neighbor: << Simple. Just get yourself a kid and the benefit pays for it.>>
I am not making this up. Evidence is not the plural of anecdote, but there seems to be evidence that the welfare system is systematically abused in the UK by many who are workshy. What they are doing is not necessarily illegal, though every day I read an account of someone defrauding the benefit system, but the incentives are acting in such a way that someone would have to be saint to avoid the temptation.
Before anyone jumps in and says that taxpayers who avoid their responsibilities are a more important problem, I don't doubt it and would be willing to launch a diatribe against the way the tax system is ordered too.
This week at the Tory Party Conference, preliminary measures have been announced to begin to sort out the problem. In many ways this initiative could not have taken place without a coalition government. Undoubtedly, any attack on benefits would have been attacked from the Left and with only one party in favor. Even with a majority in Parliament, there would have been anger and resistance, even with strike action. Having the Liberal-Democrats on board, not only gives a Parliamentary majority, but carries with it a numerical majority of voters.
The first measure announced was aimed at the relatively rich. Child benefit would be withdrawn from higher rate tax payers. Child benefit was introduced after the war as a universal benefit for children. Originally it was paid to second and subsequent children up to the age of 15, but nowadays it is paid to all children while they are in full time education. The eldest child gets $1600 a year and subsequent children $1000 a year. The money is paid to the mother or other responsible adult if there is no mother.
It is to be withdrawn by 2015 to those paying higher rate income tax. That means to those earning more than $66,000 a year. This represents 15% of those receiving it and it will save the taxpayer $1.5 billion a year which can be used to pay off foreign debt, so that less interest needs to be paid, which will in turn save the taxpayer more money.
There was an immediate outcry. Not that the rich actually need the child benefit - it often goes into a savings account for the child to start a pension fund or to pay for school fees - but because there is a hidden dollop of unfairness. It comes from Mrs Thatcher again. She introduced separate taxation for husbands and wives. Previously a wife was regarded as a husband's possession and he was given a tax threshold that accounted for his having to support two individuals on one salary. This was lost when his wife was taxed separately. So we have the situation whereby there could be a family income of $130,000 with neither parent paying higher rate tax and the mother still drawing child benefit, while next door the mother stays at home to look after the children, does not work to earn money, yet the family income just crosses the threshold and child benefit is lost.
Unfairness is anathema to the British voter. They still remember that Diego Maradonna goal in the 1986 world cup. But is this a real issue? We know that for 50% of families with a stay-at-home mum, the family income exceeds $112,500 a year. Even if it is less, we find that many stay-at-home mums are able to do a small job for their husbands that reduces his taxable income and enables her use her tax allowance and to save more than the child benefit in tax that does not need to be paid. There is also a promise that sometime this parliament there will be a Bill introduced that allows all stay-at-home mums to receive this sort of redress (though not by the full amount).
The principle of Universal Benefits was a Liberal Party one, introduced by the Beveridge report of 1944. So the Tory's coalition partners have an emotional tie to them. It was very different in 1944 when the housing stock had been seriously depleted by bombing and poverty was extremely severe. Today poverty means you don't have a flat screen TV.. The other Universal Benefits (introduced only later) include a free TV licence for the over-75s, free bus passes for the over-60s (not actually used by higher rate tax-payers) and a winter fuel allowance for the over 60s so that no-one need die of hypothermia. There are suggestions that some of these are vulnerable to the chancellor's axe in the Autumn spending review. I shan't lose any sleep if I lose them. I have been eligible for a bus-pass for 7 years. I have used it 4 times. That's saved me $12.
I shall return to this topic, but now I must go and paint a doorpost.