Yesterday President Obama assured us that healthcare reform was at the top of his agenda. Opponents raise the spectre of socialized medicine and Britain's NHS is held up as an example of what lies down that path.
The truth is that both Britain and America have a mixed economy of social and private healthcare.
The great worry is that socialized medicine leads to rationing. At one time the NHS had a waiting list of five years for a hip replacement and there is a built in delay in getting the new cancer drugs, some of which have not been and may not be approved by NICE.
However, this indictment of the NHS does not tell the whole story. Even when it took 5 years to get a hip replacement on the NHS you could get one next week if you had health insurance. At the time I was practising around 20% of the population had healthcare insurance. This is a far lower percentage than in America, of course, but there are reasons for this, which I will explain. Health insurance for the 20% is largely provided by employers who naturally enough regard it as a good investment since it gives them control over when their employees will be absent on health grounds. The whole private healthcare industry is geared towards elective surgery, since it is this area that is easiest for socialized medicine to ration. If you were paying through your taxes for someone else's treatment you would be happy to cover treatment for cancer and heart attacks but you might be unsure about paying for their varicose veins or their sticking out ears to be remedied.
Private health insurance usually extended to the employees family. Many self-employed individuals were able to write off healthcare insurance as a business expense and saw it as a good investment.
The other element to my thesis is that America also enjoys socialized medicine. The largest plank in this is the VA service. Some commentators have suggested that this is the most efficient part of American healthcare. In addition there is Medicare and Medicaid and a separate provision for children. It is also true that there are government subsidies to the private insurance industry in the form of tax breaks. Finally, there are the county hospital ERs that provide free healthcare to the indigenous poor.
The UK currently spends about 7.4% of GDP on the NHS. Surprisingly, the American government spends a staggering 11% of a much larger GDP on healthcare. The healthcare purchased by insurance is on top of this.
There is no doubt in my mind that the very best healthcare is provided by doctors working in private practise. Isn't that what you would expect? The more you pay for something the more you are likely to receive for you money. After all, Honda makes very good cars, but Rolls Royce make better ones. In any business transaction you largely get what you pay for. It is also true that among the best paid doctors there are some flim flam men who are taking money under false pretenses, but that's the market for you.
The problem with the market is that we can't all afford Rolls Royces and some of us have to settle for a Ford. But even a Ford is expected to get us from A to B on time.
There was a time that the Ford provided by the NHS was a beat-up Edsel, but at that time only about 4% of GDP was being spent on it. I remember when I started as a hospital consultant I was single handed in haematology; now there are 5 people doing the job I was doing and 5 junior doctors being trained in the department where there were none before. There were 3 general physicians in my hospital; now there are 33. I have seen improvements in the quality of medicine that are almost unbelievable. Nonetheless, there are still blackspots in the system that need remedy.
The reason that private medicine has never been purchased by more than 20% of the population in the UK is that the NHS is so good. It is so good because it is very efficient, avoiding buying things that are unnecessary, using the power of central purchasing in the way that the Supermarkets do to drive down prices, yet at the same time allowing a high degree of local autonomy to take advantage of local situations.
I suspect that the reason that so many buy medical insurance in America is because the alternative is so awful.
Let's take some of the specific criticisms of the NHS. How about those long waiting times? Our own hospital has been at the forefront of getting these down. No-one has to wait more than two weeks to see a consultant about a suspected cancer. Hip replacement waiting times are down to six weeks. No-one in the country waits for more than 18 weeks for any procedure.
The NHS won't pay for expensive cancer drugs. There is some truth in this. But until recently the only way you could get rituximab for CLL in America was by terminological inexactitude. If you called your CLL a type of lymphoma then you could get the insurance companies to pay for it. You could do the same in the UK until the authorities got wise to the fact that there was no evidence that rituximab showed benefit in CLL. It was not until the German CLL8 trial reported that we were sure that rituximab improved the length of remissions in CLL. It is the pharmaceutical companies who are to blame for this. They could have conducted the relevant trials a decade earlier if they had had the will.
Doctors all round the world are still performing procedures for which there is no evidence of benefit. NICE has addressed this problem and is reducing the pressures on doctors to continue in their bad old ways. A good example would be the use of protein-pump inhibitors like omeprazole for indigestion. The bill for this is greater than the bill for all cancer chemotherapy put together. Even switching to ranitidine would make lost cancer chemotherapy affordable, but most indigestion responds perfectly well to antacids from the drugstore. If it doesn't then suspect peptic ulcer which can be cured by two weeks omeprazole and some cheap antibiotics.
The other criticism of socialised medicine is that it reduces doctors' incomes. The frightening example of Cuba is often brought up. And it is true. For my few private patients I was paid at 10 times the rate that the NHS paid me. On the other hand the NHS was paying me roughly the same as the Prime Minister was getting, so I shouldn't complain. Lots of people on salaries earn plenty - as we are finding out in the banking crisis.
There is a real problem with bureaucracy in anything run by the government and it is very important that the government is kept at arms length from anything to do with medicine. In the NHS every family doctor is an independent contractor, not a slaried employee. Nor is it necessary for a national health service to come from taxes; most European schemes are insurance-based. But with such a large number of Americans getting such poor healthcare, change is inevitable.
Thursday, February 26, 2009
Wednesday, February 25, 2009
The magic of numbers
I remember the last time I had an accident in my car. I say an accident, but I was entirely culpable. I was late. It was dark and wet and I was driving too fast for the conditions. As I rounded a bend in the road, doing 43.2 mph I was confronted by the red tail lights of a stack of traffic held up in front of me. I ploughed into the back of a 4X4. No-one was hurt, but my car was damaged enough for me to have to abandon my journey.
The odd thing was that when I looked at the odometer it read 70,000.0 miles.
Of course, that number is no more significant than 72,865.7 but we want to attach significance to round numbers. That old car limped on to 131,875.3 miles, about which I have absolutely nothing to say. Perhaps it would have been more perfect had I scrapped it after the accident. Superstition would have forced me to.
Of course the realy significant number was the 43.2 mph and if you go to this website you will see why.
The odd thing was that when I looked at the odometer it read 70,000.0 miles.
Of course, that number is no more significant than 72,865.7 but we want to attach significance to round numbers. That old car limped on to 131,875.3 miles, about which I have absolutely nothing to say. Perhaps it would have been more perfect had I scrapped it after the accident. Superstition would have forced me to.
Of course the realy significant number was the 43.2 mph and if you go to this website you will see why.
Sunday, February 22, 2009
Religious Refugees
The UNHCR defines a refugee as a person who has fled his country owing to well founded fear of being persecuted for reasons of race, religion, nationality, membership of a particular social group or political opinion, is outside the country of his nationality, is unable or owing to such fear is unwilling to avail himself of the protection of that country. (In every case the male pronoun includes the female). Free countries have a duty to offer asylum to those in such danger.
There is a special problem with converts from Islam. According to Sharia law, leaving Islam is a crime on a par with treason that is punishable by death (or life imprisonment if it is a woman according to some readings). Not every Muslim takes this view, but many countries that operate according to Sharia law do. Even when the government of a country takes an enlightened view, family members and certain rural communities do not. Even enlightened governments are reluctant to interfere in the workings of families and local communities. In Pakistan, for instance, there have been many Christian converts from Islam who have been unmolested, but if you happen to live near the Afghan border, your father or brothers might kill you if you convert.
Recently, a Libyan asylum seeker who had converted to Christianity was beaten almost to death while in the West Drayton Removal Centre in the UK, by Somali and Yemeni detainees, as he left the makeshift church in the centre.
There is a great ignorance on behalf of officials of national immigration services (I am speaking in particular about the UK, Germany and New Zealand) about the danger that Christian converts from Islam are in, and a lack of cultural sensitivity. The UNHCR takes the view that converts are in no danger in Iran - a view that most in the West would regard as laughable were it not so serious. Then take the questions asked of converts to establish the genuineness of their conversions. "How do you prepare a turkey for Christmas?" "Recite the Roman Catholic Mass." "What were the names of the thieves crucified with Jesus on the Cross?"
Some immigrants have been offered Muslim interpreters. Do they not realise the risk of this. Although some interpreters may be scrupulously honest they will hardly be able to present the asylum seekers problems with any insight, and there may be an incentive to mistranslate so that the person is sent home for 'reconversion'.
However, it is not all bad news. In September last year an asylum seeker "George" a Syrian who had previously seen his application for asylum refused because the Inspector could not believe that George's father would truly hurt his son, finally won the right to stay in Britain.
There is a special problem with converts from Islam. According to Sharia law, leaving Islam is a crime on a par with treason that is punishable by death (or life imprisonment if it is a woman according to some readings). Not every Muslim takes this view, but many countries that operate according to Sharia law do. Even when the government of a country takes an enlightened view, family members and certain rural communities do not. Even enlightened governments are reluctant to interfere in the workings of families and local communities. In Pakistan, for instance, there have been many Christian converts from Islam who have been unmolested, but if you happen to live near the Afghan border, your father or brothers might kill you if you convert.
Recently, a Libyan asylum seeker who had converted to Christianity was beaten almost to death while in the West Drayton Removal Centre in the UK, by Somali and Yemeni detainees, as he left the makeshift church in the centre.
There is a great ignorance on behalf of officials of national immigration services (I am speaking in particular about the UK, Germany and New Zealand) about the danger that Christian converts from Islam are in, and a lack of cultural sensitivity. The UNHCR takes the view that converts are in no danger in Iran - a view that most in the West would regard as laughable were it not so serious. Then take the questions asked of converts to establish the genuineness of their conversions. "How do you prepare a turkey for Christmas?" "Recite the Roman Catholic Mass." "What were the names of the thieves crucified with Jesus on the Cross?"
Some immigrants have been offered Muslim interpreters. Do they not realise the risk of this. Although some interpreters may be scrupulously honest they will hardly be able to present the asylum seekers problems with any insight, and there may be an incentive to mistranslate so that the person is sent home for 'reconversion'.
However, it is not all bad news. In September last year an asylum seeker "George" a Syrian who had previously seen his application for asylum refused because the Inspector could not believe that George's father would truly hurt his son, finally won the right to stay in Britain.
Saturday, February 21, 2009
Cataloguing films
I am still cataloguing my movies on DVD and VHS. I now have about 900, including 90 children's films (mostly on VHS).
The directors who now mostly feature are Alfred Hitchcock with 19, David Lean with 14, Steven Spielberg, Billy Wilder and Peter Weir, each with 10, Clint Eastwood and Ingmar Bergman with 8 each, the Coen brothers and Douglas Sirk with 7 and on 6 come James Ivory, John Huston, Martin Scorsese, Michael Powell and Stephen Frears.
As far as male actors are concerned, Humphrey Bogart leads with 18, Anthony Hopkins is next with 14, then Clive Owen with 12 and John Mills with 9. Then tied with 8 films each are Al Pacino, Alec Guinness, Daniel Day Lewis, Morgan Freeman, Robert De Niro, Tom Cruise, William Holden and Alan Rickman.
For Female actors the order is Cate Blanchett and Judi Dench with 10, Helen Mirren and Nicole Kidman with 9, Ingrid Bergman, Kate Winslett, Julia Roberts and Diane Keaton with 8 and Helena Bonham-Carter and Meryl Streep with 7.
I'm not sure what this says about me. I suppose it says I like old war films (John Mills) and I tend to collect everything by certain directors; that I like Film Noir and good actors. Perhaps someone could suggest from these lists which films you think I don't have in my collection and those I ought to have.
Incidentally, I still haven't watched more than 200 of the films.
The directors who now mostly feature are Alfred Hitchcock with 19, David Lean with 14, Steven Spielberg, Billy Wilder and Peter Weir, each with 10, Clint Eastwood and Ingmar Bergman with 8 each, the Coen brothers and Douglas Sirk with 7 and on 6 come James Ivory, John Huston, Martin Scorsese, Michael Powell and Stephen Frears.
As far as male actors are concerned, Humphrey Bogart leads with 18, Anthony Hopkins is next with 14, then Clive Owen with 12 and John Mills with 9. Then tied with 8 films each are Al Pacino, Alec Guinness, Daniel Day Lewis, Morgan Freeman, Robert De Niro, Tom Cruise, William Holden and Alan Rickman.
For Female actors the order is Cate Blanchett and Judi Dench with 10, Helen Mirren and Nicole Kidman with 9, Ingrid Bergman, Kate Winslett, Julia Roberts and Diane Keaton with 8 and Helena Bonham-Carter and Meryl Streep with 7.
I'm not sure what this says about me. I suppose it says I like old war films (John Mills) and I tend to collect everything by certain directors; that I like Film Noir and good actors. Perhaps someone could suggest from these lists which films you think I don't have in my collection and those I ought to have.
Incidentally, I still haven't watched more than 200 of the films.
Friday, February 20, 2009
Cancer Screening
When the CT scanner first appeared people dreamed of everyone having a scan at regular intervals to detect early cancer. We have become used to the mantra that in cancer "Early diagnosis means early treatment means more cures and fewer cancer deaths". Screening has been so heavily backed by government information that we have all bought into it. In today's BMJ is a paper from Peter Gotzsche and his colleagues in Denmark which questions the value of mammography. They produce the following figures: If 2000 women are screened regularly for 10 years, one will avoid dying from breast cancer, but 10 healthy women will as a consequence become cancer patients and be treated unnecessarily. These women will have whole or part of their breast removed and some will also receive unnecessary radiotherapy or chemotherapy. Some will develop a secondary leukemia because of the therapy. Furthermore another 200 healthy women will experience a false alarm and suffer psychological trauma.
All this sounds counter-intuitive. Surely it is better to know what is going on?
The problem with breast screening is not that cancers are missed, but that they are over-diagnosed. It is becoming clear that cancer may be diagnosed when the tumor is very small and despite its grim reputation, many cancers do not progress during the lifetime of the individual. Those of us who work with CLL are well aware of this fact: the commonest treatment applied is watch and wait. I am reminded of an obituary of a man from Oklahoma who died in his eighties, 52 years after his untreated CLL was first diagnosed. If it is true for CLL, why would it not be true for cancers of other tissues. Since CT scanning has become so sensitive we have been recognizing very small lumps in the lungs. Do these represent lung cancer? Or perhaps marginal zone lymphomas? Biopsy is the only way of finding out, but isn't that a bit invasive for what may be a false alarm? So we tend to watch and wait there too.
With mammogram results it is relatively easy to do a biopsy and this leads to the possibility of over diagnosis. For a start there is carcinoma-in-situ, which constitutes 20% of the diagnoses made. We know that fewer than half such cases lead to invasive cancer, but 30% are treated with mastectomy. Then there are patients who really do have cancer, but such an indolent cancer that it would never have become noticeable in the patient's lifetime.
Screening does not lead to fewer mastectomies; indeed in randomized trials 20% more mastectomies are performed in screened patients. You would think that this would be offset by a reduced number of mastectomies in older women whose late-occurring cancer had been forestalled. Unfortunately, this is not so. Radiotherapy is applied to some women whose cancer would not have progressed. It is known that radiotherapy doubles teh rate of mortality from lung cancer and heart disease.
Breast cancer rates are apparently increasing because mammography finds more cases. The cure rate is also improving, but the absolute number of women dying from breast cancer has not changed.
Similar results are available for PSA screening for prostate cancer. The disease is not 10 times more common than it was in the 1990s, but the number of people dying from prostate cancer every year has not changed - it remains the same in countries which adopt both a restrictive and a liberal policy on the use of PSA as a screening test.
I speak with some feeling as someone whose screening colonoscopy has led to two further colonoscopies, and octreatide scan and two CT scans, and still no diagnosis.
To explain the problem it helps to look at the maths. Suppose that a screening test is almost completely accurate; that it misses no positive cases and is 99.99% accurate. That means that one test in 10,000 will be a false positive. Not many tests are as accurate as this, but suppose you are screening for a rare disease with an incidence of 4 in 100,000 in the general population. That means that for every 10 positive tests, 6 will be false positives. (4 in 100,000 is the approximate frequency of CLL).
We underestimate the harm done by worrying patients. Few there are who face impending doom with equanimity.
All this sounds counter-intuitive. Surely it is better to know what is going on?
The problem with breast screening is not that cancers are missed, but that they are over-diagnosed. It is becoming clear that cancer may be diagnosed when the tumor is very small and despite its grim reputation, many cancers do not progress during the lifetime of the individual. Those of us who work with CLL are well aware of this fact: the commonest treatment applied is watch and wait. I am reminded of an obituary of a man from Oklahoma who died in his eighties, 52 years after his untreated CLL was first diagnosed. If it is true for CLL, why would it not be true for cancers of other tissues. Since CT scanning has become so sensitive we have been recognizing very small lumps in the lungs. Do these represent lung cancer? Or perhaps marginal zone lymphomas? Biopsy is the only way of finding out, but isn't that a bit invasive for what may be a false alarm? So we tend to watch and wait there too.
With mammogram results it is relatively easy to do a biopsy and this leads to the possibility of over diagnosis. For a start there is carcinoma-in-situ, which constitutes 20% of the diagnoses made. We know that fewer than half such cases lead to invasive cancer, but 30% are treated with mastectomy. Then there are patients who really do have cancer, but such an indolent cancer that it would never have become noticeable in the patient's lifetime.
Screening does not lead to fewer mastectomies; indeed in randomized trials 20% more mastectomies are performed in screened patients. You would think that this would be offset by a reduced number of mastectomies in older women whose late-occurring cancer had been forestalled. Unfortunately, this is not so. Radiotherapy is applied to some women whose cancer would not have progressed. It is known that radiotherapy doubles teh rate of mortality from lung cancer and heart disease.
Breast cancer rates are apparently increasing because mammography finds more cases. The cure rate is also improving, but the absolute number of women dying from breast cancer has not changed.
Similar results are available for PSA screening for prostate cancer. The disease is not 10 times more common than it was in the 1990s, but the number of people dying from prostate cancer every year has not changed - it remains the same in countries which adopt both a restrictive and a liberal policy on the use of PSA as a screening test.
I speak with some feeling as someone whose screening colonoscopy has led to two further colonoscopies, and octreatide scan and two CT scans, and still no diagnosis.
To explain the problem it helps to look at the maths. Suppose that a screening test is almost completely accurate; that it misses no positive cases and is 99.99% accurate. That means that one test in 10,000 will be a false positive. Not many tests are as accurate as this, but suppose you are screening for a rare disease with an incidence of 4 in 100,000 in the general population. That means that for every 10 positive tests, 6 will be false positives. (4 in 100,000 is the approximate frequency of CLL).
We underestimate the harm done by worrying patients. Few there are who face impending doom with equanimity.
Tuesday, February 17, 2009
Vitamin B
The B Vitamins are a group of water-soluble substances which are not otherwise related to each other. There are eight of them, but claims for vitamin status are made for another 23. A vitamin is a substance that is essential for healthy living that cannot be synthesized by teh body. The other 23 eithercan be synthesized by teh human body or are not essential for health. I will deal with teh eight true vitamins and then explain why some of the others are not true vitamins.
Vitamin B1 or thiamine is the substance that is necessary in the diet to prevent beriberi. Chinese medical texts referred to beriberi as early as 2700 BC. Symptoms of beriberi include severe lethargy and fatigue, together with complications affecting the cardiovascular, nervous, muscular, and gastrointestinal systems. The origin of the word is from a Sinhalese phrase meaning "I cannot, I cannot", the word being doubled for emphasis. Two types of beriberi are recognized: the 'wet-type' affects the heart; through a combination of heart failure and weakening of the capillary walls, it causes the peripheral tissues to become edematous. Dry beriberi causes wasting and partial paralysis resulting from damaged peripheral nerves.
In 1884, Takaki Kanehiro, a British-trained Japanese doctor of the Japanese Navy, observed that beriberi was endemic among low-ranking crew who often ate nothing but rice, but not among crews of Western navies and officers who consumed a Western-style diet. Kanehiro initially believed that lack of protein was the chief cause of beriberi. He conducted one of the first cliical trials using the crews of two battleships; one crew was fed only white rice, while the other was fed a diet of meat, fish, barley, rice, and beans. The group that ate only white rice reported 161 crew with beriberi and 25 deaths, while the latter group had only 14 cases of beriberi and no deaths. This convinced Kanehiro and the Japanese Navy that diet was the cause of beriberi. But Kanehiro wrongly thought that protein was the missing element in the diet (Kwashiorkor, which is caused by protein deficiency also causes heart failure).
In 1897 Christian Eijkman, a military doctor in the Dutch Indies, discovered that chickens fed on a diet of cooked, polished rice developed paralysis, which could be reversed by discontinuing rice polishing (he mistakenly attributed that to a nerve poison in the endosperm of rice, from which the outer layers of the grain gave protection to the body. In 1897, Christiaan Eijkman in the Dutch East Indies, discovered that feeding unpolished rice instead of the polished variety to chickens prevented paralysis in the chickens. In 1898, Sir Frederick Hopkins postulated that some foods contained "accessory factors" — in addition to proteins, carbohydrates and fats, — that were necessary for the functions of the human body.
Eijkman was awarded a Nobel Price in Psysiology and Medicine in 1929, because his observations led to the discovery of vitamins). An associate, Gerrit Grijns, correctly interpreted the connection between excessive consumption of polished rice and beriberi in 1901: he concluded that rice contained an essential nutrient in the outer layers of the grain that was removed in polishing. In 1911 Casimir Funk isolated an antineuritic substance from rice bran that he called a “vitamine” (on account of its containing an amino group). Dutch chemists, Jansen and Donath, went on to isolate and crystallize the active agent in 1926, whose structure was determined by R.R.Williams, a US chemist, in 1934. Thiamin (“sulfur-containing vitamin”) was synthesized in 1936 by the same group. It was first named “aneurin” (for anti-neuritic vitamin).
Thiamine occurs naturally in unrefined cereals and fresh foods, particularly whole grain bread, fresh meat, legumes, green vegetables, fruit, and milk. Beriberi is therefore common in people whose diet excludes these particular types of nutrition.
Beriberi may be found in people whose diet consists mainly of polished white rice, which is very low in thiamine because the thiamine-bearing husk has been removed. It can also be seen in chronic alcoholics with an inadequate diet (Wernicke-Korsakoff syndrome), as well as being a rare side effect of gastric bypass surgery. If a baby is mainly fed on the milk of a mother who suffers from thiamine deficiency then that child may develop beriberi as well.
Wernicke’s encephalopathy (WE) is the type of thiaqmine deficiency most frequently seen in Western society. Although it may also occur in patients with impaired nutrition from other causes, it is usually seen in alcoholics. It is a striking neuro-psychiatric disorder characterized by paralysis of eye movements, abnormal stance and gait, and markedly deranged mental function.
Alcoholics may have thiamin deficiency because of the following: 1) inadequate nutritional intake: alcoholics tend to intake less than the recommended amount of thiamin. 2) decreased uptake of thiamin from the GI tract: active transport of thiamin into enterocytes is disturbed during acute alcohol exposure. 3) liver thiamin stores are reduced due to hepatic steatosis or fibrosis. 4) impaired thiamin utilization: magnesium, which is required for the binding of thiamin to thiamin-using enzymes within the cell, is also deficient due to chronic alcohol consumption. The inefficient utilization of any thiamin that does reach the cells will further exacerbate the thiamin deficiency. 5) Ethanol per se inhibits thiamin transport in the gastrointestinal system and blocks phosphorylation of thiamin to its cofactor form, TDP.
Korsakoff Psychosis is generally considered to occur with deterioration of brain function in patients initially diagnosed with WE. This is an amnestic-confabulatory syndrome characterized by retrograde and anterograde amnesia, impairment of conceptual functions, and decreased spontaneity and initiative. Because of their loss of memory they invent the most fantastic explanations for their circumstances.
However, most people on normal diets do not require vitamin B1 supplements.
Vitamin B1 or thiamine is the substance that is necessary in the diet to prevent beriberi. Chinese medical texts referred to beriberi as early as 2700 BC. Symptoms of beriberi include severe lethargy and fatigue, together with complications affecting the cardiovascular, nervous, muscular, and gastrointestinal systems. The origin of the word is from a Sinhalese phrase meaning "I cannot, I cannot", the word being doubled for emphasis. Two types of beriberi are recognized: the 'wet-type' affects the heart; through a combination of heart failure and weakening of the capillary walls, it causes the peripheral tissues to become edematous. Dry beriberi causes wasting and partial paralysis resulting from damaged peripheral nerves.
In 1884, Takaki Kanehiro, a British-trained Japanese doctor of the Japanese Navy, observed that beriberi was endemic among low-ranking crew who often ate nothing but rice, but not among crews of Western navies and officers who consumed a Western-style diet. Kanehiro initially believed that lack of protein was the chief cause of beriberi. He conducted one of the first cliical trials using the crews of two battleships; one crew was fed only white rice, while the other was fed a diet of meat, fish, barley, rice, and beans. The group that ate only white rice reported 161 crew with beriberi and 25 deaths, while the latter group had only 14 cases of beriberi and no deaths. This convinced Kanehiro and the Japanese Navy that diet was the cause of beriberi. But Kanehiro wrongly thought that protein was the missing element in the diet (Kwashiorkor, which is caused by protein deficiency also causes heart failure).
In 1897 Christian Eijkman, a military doctor in the Dutch Indies, discovered that chickens fed on a diet of cooked, polished rice developed paralysis, which could be reversed by discontinuing rice polishing (he mistakenly attributed that to a nerve poison in the endosperm of rice, from which the outer layers of the grain gave protection to the body. In 1897, Christiaan Eijkman in the Dutch East Indies, discovered that feeding unpolished rice instead of the polished variety to chickens prevented paralysis in the chickens. In 1898, Sir Frederick Hopkins postulated that some foods contained "accessory factors" — in addition to proteins, carbohydrates and fats, — that were necessary for the functions of the human body.
Eijkman was awarded a Nobel Price in Psysiology and Medicine in 1929, because his observations led to the discovery of vitamins). An associate, Gerrit Grijns, correctly interpreted the connection between excessive consumption of polished rice and beriberi in 1901: he concluded that rice contained an essential nutrient in the outer layers of the grain that was removed in polishing. In 1911 Casimir Funk isolated an antineuritic substance from rice bran that he called a “vitamine” (on account of its containing an amino group). Dutch chemists, Jansen and Donath, went on to isolate and crystallize the active agent in 1926, whose structure was determined by R.R.Williams, a US chemist, in 1934. Thiamin (“sulfur-containing vitamin”) was synthesized in 1936 by the same group. It was first named “aneurin” (for anti-neuritic vitamin).
Thiamine occurs naturally in unrefined cereals and fresh foods, particularly whole grain bread, fresh meat, legumes, green vegetables, fruit, and milk. Beriberi is therefore common in people whose diet excludes these particular types of nutrition.
Beriberi may be found in people whose diet consists mainly of polished white rice, which is very low in thiamine because the thiamine-bearing husk has been removed. It can also be seen in chronic alcoholics with an inadequate diet (Wernicke-Korsakoff syndrome), as well as being a rare side effect of gastric bypass surgery. If a baby is mainly fed on the milk of a mother who suffers from thiamine deficiency then that child may develop beriberi as well.
Wernicke’s encephalopathy (WE) is the type of thiaqmine deficiency most frequently seen in Western society. Although it may also occur in patients with impaired nutrition from other causes, it is usually seen in alcoholics. It is a striking neuro-psychiatric disorder characterized by paralysis of eye movements, abnormal stance and gait, and markedly deranged mental function.
Alcoholics may have thiamin deficiency because of the following: 1) inadequate nutritional intake: alcoholics tend to intake less than the recommended amount of thiamin. 2) decreased uptake of thiamin from the GI tract: active transport of thiamin into enterocytes is disturbed during acute alcohol exposure. 3) liver thiamin stores are reduced due to hepatic steatosis or fibrosis. 4) impaired thiamin utilization: magnesium, which is required for the binding of thiamin to thiamin-using enzymes within the cell, is also deficient due to chronic alcohol consumption. The inefficient utilization of any thiamin that does reach the cells will further exacerbate the thiamin deficiency. 5) Ethanol per se inhibits thiamin transport in the gastrointestinal system and blocks phosphorylation of thiamin to its cofactor form, TDP.
Korsakoff Psychosis is generally considered to occur with deterioration of brain function in patients initially diagnosed with WE. This is an amnestic-confabulatory syndrome characterized by retrograde and anterograde amnesia, impairment of conceptual functions, and decreased spontaneity and initiative. Because of their loss of memory they invent the most fantastic explanations for their circumstances.
However, most people on normal diets do not require vitamin B1 supplements.
Sunday, February 15, 2009
Current affairs
politicsNo blogging for week because I have been busy preparing a sermon for this evening and for leading a Bible study last Thursday. So a few comments on what has been in the news this week.
Gert Wilders, the Dutch MEP was denied entry to Britain to show his film 'Fitner' to parliamentarians in the House of Lords. Readers of this blog will know that I have seen this film and provided a link to it on the internet. It is a short film that juxtaposes scenes of atrocities committed by Muslims (9/11, 7/7, Madrid and a hostage beheading) with the parts of the Koran that certain Muslims use to justify their actions. Banning Wilders did not stop anyone watching it. Indeed the added publicity ensured that many more people went to the various websites that feature it.
It is obviously true that not all Muslims ascribe to these views any more than Christians and Jews any longer feel the need to totally wipe out the Amalekites. The problems is that some Muslims do, and many of them live in the Western democracies. People over here are frightened by them. Free speech is not an optional extra to protect people who agree with you. The Muslim member of the House of Lords was out of order when he persuaded the Home Secretary to ban Wilders and the Home Secretary was both wimpish and authoritarian.
Jade Goody was treated for metastatic cervical cancer and it was announced that the disease is untreatable and that she has little time left. She is the ultimate in the 'famous for 15 minutes' syndrome. She first came to fame for her outrageous behavior on 'Big Brother' and then was cast off 'I'm a Celebrity Get Me Out of Here' for racist speech. She was held up as an example of the colossal ignorance of the 'underclass'. Then on the Indian version of 'Big Brother' she was told on camera that she had advanced cancer. While the TV world looked on she lost her hair to chemotherapy. She has expressed a desire to die on camera as a warning to the world. Since cervical cancer is mostly caused by Human Papilloma Virus, which is a sexually transmitted infection one wonders whether her display will reduce promiscuity.
And as if outrageous behavior had yet to reach its limit, we now have a 12 year-old apparently fathering a child on a 15 year old girl. The boy is clearly pre-pubertal and the claim is probably untrue, but exactly what do the parents think they are doing? Trying to make money from their children's misfortune is the obvious answer. The welfare state will provide the children with somewhere to live and £30,000 a year in benefits, apparently. then there is what the newspapers and TV will pay for the stories. It may all come to nothing since two older boys are now claiming to be the father. It seems to me that the teenagers should be taken into care and the parents prosecuted - and the baby adopted.
But adoption itself in hazardous. One couple have had their three children adopted against there will because social workers thought they had been abusing their middle child. Doubts have now arisen as to the justice of the claim. It seems that the child failed to thrive on formula milk and was switched to a soya substitute that lacked vitamin C. Experts have claimed that the apparent injuries were due to scurvy. Nonetheless, the Appeal Court has ruled that the adoptions are irreversible. As the father said, "If our children had been kidnapped and then recovered, would the children have had to stay with the kidnappers because they had got used to them?"
The financial crisis deepens with Gordon Brown catching most of the stick. He got the plaudits in the good times and must expect criticism in the bad ones. They latest suggest is 'quantitative easing', a euphemism for printing money. The Retail Price Index of inflation was 0.1% this month. This was mainly due to a fall in mortgage interest rates and a cut of 2.5% in VAT. However the Consumer Prices Index, which is the government's favored measure was 3.1%, still way above the 2% target. So have we got inflation or deflation?
The real problem in the economy is the failure of the banks to lend money to people needing cash to keep their businesses active, or to replace their car or to improve their house. The government has given the banks billions of taxpayers money so that they can lend, but it seems that that money is being used to replenish their own financial reserves and pay their employees huge bonuses. Since several of the banks are now nationalized, the government has it in its power to remedy that behavior. However, so many of the bankers are advising the government that I doubt it will happen. The Bank of England thinks 2010 will be better. Presumably because we will by then be shot of the Labor Party.
ADDED LATER 26/5/09. The 12 year old was not the father.
Gert Wilders, the Dutch MEP was denied entry to Britain to show his film 'Fitner' to parliamentarians in the House of Lords. Readers of this blog will know that I have seen this film and provided a link to it on the internet. It is a short film that juxtaposes scenes of atrocities committed by Muslims (9/11, 7/7, Madrid and a hostage beheading) with the parts of the Koran that certain Muslims use to justify their actions. Banning Wilders did not stop anyone watching it. Indeed the added publicity ensured that many more people went to the various websites that feature it.
It is obviously true that not all Muslims ascribe to these views any more than Christians and Jews any longer feel the need to totally wipe out the Amalekites. The problems is that some Muslims do, and many of them live in the Western democracies. People over here are frightened by them. Free speech is not an optional extra to protect people who agree with you. The Muslim member of the House of Lords was out of order when he persuaded the Home Secretary to ban Wilders and the Home Secretary was both wimpish and authoritarian.
Jade Goody was treated for metastatic cervical cancer and it was announced that the disease is untreatable and that she has little time left. She is the ultimate in the 'famous for 15 minutes' syndrome. She first came to fame for her outrageous behavior on 'Big Brother' and then was cast off 'I'm a Celebrity Get Me Out of Here' for racist speech. She was held up as an example of the colossal ignorance of the 'underclass'. Then on the Indian version of 'Big Brother' she was told on camera that she had advanced cancer. While the TV world looked on she lost her hair to chemotherapy. She has expressed a desire to die on camera as a warning to the world. Since cervical cancer is mostly caused by Human Papilloma Virus, which is a sexually transmitted infection one wonders whether her display will reduce promiscuity.
And as if outrageous behavior had yet to reach its limit, we now have a 12 year-old apparently fathering a child on a 15 year old girl. The boy is clearly pre-pubertal and the claim is probably untrue, but exactly what do the parents think they are doing? Trying to make money from their children's misfortune is the obvious answer. The welfare state will provide the children with somewhere to live and £30,000 a year in benefits, apparently. then there is what the newspapers and TV will pay for the stories. It may all come to nothing since two older boys are now claiming to be the father. It seems to me that the teenagers should be taken into care and the parents prosecuted - and the baby adopted.
But adoption itself in hazardous. One couple have had their three children adopted against there will because social workers thought they had been abusing their middle child. Doubts have now arisen as to the justice of the claim. It seems that the child failed to thrive on formula milk and was switched to a soya substitute that lacked vitamin C. Experts have claimed that the apparent injuries were due to scurvy. Nonetheless, the Appeal Court has ruled that the adoptions are irreversible. As the father said, "If our children had been kidnapped and then recovered, would the children have had to stay with the kidnappers because they had got used to them?"
The financial crisis deepens with Gordon Brown catching most of the stick. He got the plaudits in the good times and must expect criticism in the bad ones. They latest suggest is 'quantitative easing', a euphemism for printing money. The Retail Price Index of inflation was 0.1% this month. This was mainly due to a fall in mortgage interest rates and a cut of 2.5% in VAT. However the Consumer Prices Index, which is the government's favored measure was 3.1%, still way above the 2% target. So have we got inflation or deflation?
The real problem in the economy is the failure of the banks to lend money to people needing cash to keep their businesses active, or to replace their car or to improve their house. The government has given the banks billions of taxpayers money so that they can lend, but it seems that that money is being used to replenish their own financial reserves and pay their employees huge bonuses. Since several of the banks are now nationalized, the government has it in its power to remedy that behavior. However, so many of the bankers are advising the government that I doubt it will happen. The Bank of England thinks 2010 will be better. Presumably because we will by then be shot of the Labor Party.
ADDED LATER 26/5/09. The 12 year old was not the father.
Sunday, February 08, 2009
The Prodigal Son
I guess this story and the one about the Good Samaritan are the best known of Jesus' parables. Most people think they know it well. A young man, as young men do, gets fed up with his straight-laced family and wants to see the world. He asks his dad for the money that is coming to him when his father dies and he takes it and splits. He spends the next few years in riotous living. You can imagine him doing a Paris Hilton, getting into all kinds of scrapes and having enough money to bail himself out of them. He would have been a popular chap; lots of fair-weather friends.
You can see where it's heading. All good things come to an end. His money runs out, his friends desert him. There's famine in the land. He tries to get a job but the only work he can get is looking after pigs, which for a Jew would have been especially degrading. In the end he comes to his senses, realizes how much better he would have been had he not left home and goes back to mum and dad, who, as parents do, take him back. They may seem a bit soft, but that's what parents are like, a mother’s love has no limits. After all, he is their flesh and blood.
So, it's a cautionary tale about keeping to the straight and narrow, telling us that we ought to obey our parents and warning us about the sort of life that the young man embarked on.
I guess that's how many people see it, but it is a profound misunderstanding of the text.
To understand a text, we have to look at the context - otherwise it becomes a pretext. This is one of three parables in Luke 15 about losing things: a lost coin, a lost sheep and a lost son. It tells us about the concern the owner has about losing things.
I guess most of us have lost something vital. My son was due to fly to Switzerland on Friday, but his girlfriend lost her passport. They searched high and low for it. They tore her place apart, but it was nowhere to be found and the holiday had to be postponed. Most of us have lost our keys. Do you have one of those devices that causes your key ring to emit an electronic noise when you blow a whistle or clap your hands? I wish I did. I'm always putting my keys down somewhere and not remembering where. When I've lost something like that I can't settle at anything else. I must find it. It plays on my mind.
The lady who lost her coin, the shepherd who lost a sheep - these stories are telling us that our Father's concern for a sinner who goes astray is no less.
To simply say that the returning prodigal was accepted, because that's what parents do, misses the point. The German Poet, Heinrich Heine, who had converted from Judaism to Christianity in order to preserve his German citizenship, was asked on his deathbed by a priest whether he thought that God would forgive his sins. He replied, "Dieu me pardonnera; c'est son metier" - God will forgive me; that's His job.
To assume that we are going to get forgiven so perfunctorily, misreads the younger son's heartfelt repentance. The Bible tells us that he ‘came to his senses’. It reminds us of Legion, the man from whom Jesus cast many Demons. The people came out and found the man sitting at Jesus’ feet, ‘dressed and in his right mind’. Repentance is not a formula for getting forgiven – it literally means ‘think again’. It involves starting with a different premise. In all three parables it is repentance that is stressed. In Luke 15:7, the parable of the lost sheep, Jesus says, “I tell you that in the same way there will be more rejoicing in heaven over one sinner who repents than over ninety-nine righteous persons who do not need to repent.” and in Luke 15:10, the parable of the lost coin, He says, “In the same way, I tell you, there is rejoicing in the presence of the angels of God over one sinner who repents."
Is the young man truly repentant? These days we see many people who swap sides when the going gets tough. Footballers who are proud to pull on the shirt of Portsmouth (or Tottenham or West Ham) and talk about the history of the club and how proud they are to be thought of in the same lineage as Jimmy Dickinson (or Danny Blanchflower of Bobby Moore). Then Real Madrid or Liverpool or Chelsea flash their check books and loyalty is easily bought. Was this prodigal just seeing which side his bread was buttered on? I don’t think so. He accepted that he had forfeited his sonhood and was eager to be a slave in his father’s house.
And if this attitude belittles the son’s repentance, it also diminishes the hurt done to the father. To ask for your inheritance while your father still lives, is tantamount to saying, "I wish you were dead." To take that amount of capital out of the business must have seriously affected how it was run. Presumably the father would have had to borrow to realize the cash. That would have been an added burden on the revenues of the farm.
We have to remember that this parable would have been shocking to his hearers. They would know all about unreasonable love. They would remember what Isaiah had said in chapter 49 v 15: "Can a mother forget the baby at her breast and have no compassion on the child she has borne? Though she may forget, I will not forget you!” In illustrating God’s extreme grace, Isaiah turns to a mother’s nature. Ask a mother, “If your son were making false returns on his Income Tax declaration, would you shop him?” or “Supposing your son was a murderer, would you hand him over to the police?” Time and again mothers help their sons to get away – and who would blame a mother?
Notwithstanding, a mother’s love, the Jew’s life was defined by the Law. In Jewish eyes a woman was weak. A Jewish man would thank God everyday that he was not born a woman. In a court of law a woman’s word was worth much less than a man’s. A man was not sentimental. This young man had broken the Fifth Commandment and the Tenth Commandment and probably the Seventh as well. The Jews believed in forgiveness. The young man could have taken an animal to the Temple and made a sin-offering, but no, he traipses back to his father and his father in his weakness rushes out to meet him with open arms like a mere woman.
I imagine a Jew of the day would have found this depiction of God offensive. And in a way I agree with them. It really won’t do to brush away sin as if it didn’t matter. Two weeks ago the Manchester United midfielder, Michael Carrick, burst into the penalty area and was tripped by the Everton center half. United had already scored from a penalty awarded when the same player had been tripped earlier, and this time the referee waved away the claim. When questioned afterwards, Sir Alex Fergusson, the United manager said, “Of course it was a penalty, even more blatant that the first one. But you can’t expect to get two penalties in a match like this.”
Like many fans I was outraged. Surely we have a right to expect the referee to be fair. No matter how much of an advantage United might have had, fouls can’t simply be ignored. I would be very worried by a God who simply ignored sin as if it had never happened. Winking at my indiscretions is one thing, but if my enemy harms me I want him punished. It’s not fair!
It is interesting to note the actions of the father. As well as putting shoes on his feet, a cloak on his back and a ring on his finger, he has the fattened calf slaughtered. Is it special pleading to see the killing of an animal as having a special meaning? The Jews knew all about animal sacrifices. They knew about the nature of surrogacy. The sacrifice on the Day of Atonement was, as here, a young bull.
Looking backwards we can see that it was the very teller of the story who was to be sacrificed as a surrogate for the prodigal son and for all prodigals since. We can see him as the atoning sacrifice for our sins. God doesn’t wink at our sin, but he doesn’t hold them against us. He has taken the punishment for them on himself in the body of the Son.
So, it’s not just a warning for the young; it’s a description of God’s amazing grace; of how the lost can be saved and the damned redeemed. It’s a message that tells us that no-one is too bad to save; that no-one is so far gone that they cannot be rescued and that God in his great love is not willing that any should perish, but that all should turn from their wicked ways and live. And when we look at the context – that Jesus was sitting down with Tax-collectors and sinners – we see that it is a point well made.
But I don’t think that is the main point of the story. The main point concerns the older brother.
When I was younger I had a lot of sympathy for the older brother. After all, he was the sensible one. He’d kept his nose clean, slaved away at home, been a good example, always been there to help around the house, obeyed the rules and now he felt he was being taken for granted. On the other hand his brother had been an absolute wastrel, spent the family money of wicked things, gone missing when his father had to take out a bigger loan to keep the farm going – not only had he been the cause of the loan in the first place, but he’d not been around to help about the farm to pay off the interest – and now his big plans had all collapsed he had come scurrying back to Papa with his tail between his legs. No wonder he felt hard done by.
There is a story of Elizabeth Elliot’s that I have stolen from Chris Kelly. It’s not a Biblical story, but it is a parable. One day Jesus asked his disciples to carry a stone for him. They each picked up a stone from the ground. Clever old Peter picked up a tiny pebble that slipped easily into his pocket. No burden at all to carry that around. After they had been walking around the Galilean countryside all morning they stopped for lunch. Jesus asked them all to brink their stones to him and we waved his hand over them and turned them into bread. “That’s your lunch,” he said. Poor old Peter had less than a mouthful. After lunch Jesus asked the disciples to do the same again. Peter was not going to be fooled a second time. This time he picked up a boulder. As they walked over the hills of Judea, Peter struggled with his load. Shifting it from one shoulder to the other and then holding it next to his chest, then on his head, he fell further and further behind. Eventually, he caught them up. They had been sitting by the side of the lake for half an hour or so. “Ah, Peter,” said the Lord, “You’ve finally got here. You can chuck the rock in the lake now.”
“What? Aren’t you going to turn it into bread?”
“Peter, were you carrying that stone for me, as I asked, or were you carrying it for yourself?”
The older brother wasn’t being the dutiful son because he loved his father. He was doing it for the reward. He liked being thought of as ‘the good son’. He had the respect of the servants and the neighbors. He was a pillar of the community. He had a good image. And what is more he had expectations. Do you remember the oily character in Pride and Prejudice, Mr. William Collins, who was so nauseatingly obsequious to his patron, Lady Catherine de Bourgh? He too had expectations. The Bennet’s house at Longbourn was entailed to him – if Mr. Bennet were to die, Mrs. Bennet and her five daughters would be turfed out of home and hearth to make way for him. I think Jane Austen had the older brother in mind when she drew Mr. Collins.
The contrast between the two brothers turns on the word ‘slave’. The older brother complains that he has been slaving for his father for years without reward; the younger son regards becoming a slave in his father’s household as the source of his future joy.
Context is all important. Jesus told these three parables because the Pharisees were muttering. Their complaint was that “This man welcomes sinners.” The point Jesus is making is that not only does God welcome sinners, but the Pharisees are like the older brother who doesn’t welcome sinners.
Remember the Pharisee’s prayer, “God, I thank you that I am not like other men – robbers, evildoers, adulterers – or even like this tax collector.”
It is certainly a fine thing not to be a robber, evildoer or an adulterer. But if he thought he was not like other men, he was certainly mistaken.
The Apostle John writing in his old age says, “If we claim to be without sin, we deceive ourselves and the truth is not in us…If we claim we have not sinned we make Him out to be a liar.”
The truth is that even good people need a Savior. Even religious people need salvation. I am afraid that our churches are full of people who think they are safe and are not. They have lived good lives. Everybody thinks well of them. They could stand as MPs and be scrutinized by the scandal sheets and no-one would find anything to make a story about. No hidden mistress, their income tax returns are spotless, no unfortunate ‘perks’ they would be embarrassed by; they go to church twice on Sundays, they tithe religiously, they are always at Holy Communion. They are politically correct, watching their words carefully; “Paki” and “Golliwog” are not even in their vocabulary; they turn their TV off at the mains every night; they drive a hybrid car; their houses have roof insulation nine inches thick and their walls are insulated with polyurethane foam.
Yet these very good people still fall short of the standards Jesus has set. President Carter was a very good man. He may not have been a good President, but his lifestyle was exemplary. He was mocked about the story in Playboy. “Have you ever committed adultery?” he was asked.
“I have committed adultery in my heart,” he replied. He was just being honest. Applying to himself the interpretation of the Ten Commandments that Jesus had opened up in the Sermon on the Mount.
When the prodigal son was yet far off, his father, watching the road, perhaps standing on the roof of his house and scanning the horizon, spotted him. Was there something about the way he walked? Something about his gait or his body shape that he recognized. “I am the good shepherd,” said Jesus elsewhere, “I know my sheep.”
Can’t you feel the excitement, the anticipation, the overwhelming joy as the father ran to his son, threw his arms around him and kissed him? No wonder Jesus said there would be rejoicing in heaven.
What about the older brother? When he heard the music and the dancing he became angry. He skulked around outside and refused to go in. Not a lot of joy there. And it is a characteristic of the Pharisees. Would you not expect them to be pleased, for example, about the story of Zacchaeus, the reformed tax-collector? How about when they saw Lazarus raised from the dead? Or Blind Bartimaeus able to see again?
Supposing Joni Earickson suddenly got up from her wheelchair; would you rejoice? Or would you think it was a trick? When Jonathan Aitken was converted in prison did you suspect he was just trying to curry favor? To re-establish himself as a politician who was accepted in polite society. Did you feel the same about Chuck Colsen, the notorious Watergate plotter?
Have you met joyless Christians; people who are always picking holes in somebody else’s sweater? Oh, they are there. They don’t like the new hymn book. They don’t like the PowerPoint projector. The communion wine should be alcoholic/non-alcoholic (take your choice). They don’t like small groups. They find large meetings too impersonal. Church doesn’t do anything for me.
No wonder they are joyless. Without a Savior they never know whether the good they have done is enough. Is it enough to have double glazing? Should I perhaps get triple glazing? Should I set the house temperature at 68 rather than 70?
The prodigal son was humbled. He fell from a great height. One moment he was surrounded by rich friends, moving in the highest society. In today’s terms he would be lunching at the Savoy with merchant bankers, think it hilarious to send back a £500 bottle of wine because it was ‘corked’; then leave a £1000 tip. In the evening a little dinner party with Jude Law and a bevy of blondes and after the meal, a snort of cocaine. He would be pictured in ‘Hello’ in his Armani suit and Paul Smith shirt.
Just a blink later and he is wallowing with the pigs, his money gone, and he squabbles with the hogs to eat their food. Not difficult for him to be realistic about his situation. Humility comes easy to a man who has been brought down low.
Not so his brother. When you think you’re doing well, when you have a religious ritual to go by, when you’re good, it’s hard to see you need a savior. Did you see David Beckham in the England match on Wednesday? He’s done well to come back to international football hasn’t he? Except that he harassed the referee over what he thought was a wrong decision and got himself a yellow card. When you are convinced you are in the right humility is a hard currency to deal in. Pride keeps us from the kingdom.
Are they irredeemable, these joyless Christians? Listen to what the Apostle Paul says of himself. “If anyone else thinks he has reasons to put confidence in the flesh, I have more: circumcised on the eighth day, of the people of Israel, of the tribe of Benjamin, a Hebrew of Hebrews; in regard to the law, a Pharisee; as for zeal, persecuting the church; as for legalistic righteousness, faultless.”
Elsewhere, he describes himself as the ‘chief of sinners’.
Only the Holy Spirit could change Paul, but the Holy Spirit did just that.
As I examine my heart, I invite you to do the same. Am I an older brother? Do I lack joy? Do I lack humility? If any of these accusations stick then turn to the Savior now. Pray that the Holy Spirit will give you the joy of your salvation. For he is not only able to do so, he is more than willing.
You can see where it's heading. All good things come to an end. His money runs out, his friends desert him. There's famine in the land. He tries to get a job but the only work he can get is looking after pigs, which for a Jew would have been especially degrading. In the end he comes to his senses, realizes how much better he would have been had he not left home and goes back to mum and dad, who, as parents do, take him back. They may seem a bit soft, but that's what parents are like, a mother’s love has no limits. After all, he is their flesh and blood.
So, it's a cautionary tale about keeping to the straight and narrow, telling us that we ought to obey our parents and warning us about the sort of life that the young man embarked on.
I guess that's how many people see it, but it is a profound misunderstanding of the text.
To understand a text, we have to look at the context - otherwise it becomes a pretext. This is one of three parables in Luke 15 about losing things: a lost coin, a lost sheep and a lost son. It tells us about the concern the owner has about losing things.
I guess most of us have lost something vital. My son was due to fly to Switzerland on Friday, but his girlfriend lost her passport. They searched high and low for it. They tore her place apart, but it was nowhere to be found and the holiday had to be postponed. Most of us have lost our keys. Do you have one of those devices that causes your key ring to emit an electronic noise when you blow a whistle or clap your hands? I wish I did. I'm always putting my keys down somewhere and not remembering where. When I've lost something like that I can't settle at anything else. I must find it. It plays on my mind.
The lady who lost her coin, the shepherd who lost a sheep - these stories are telling us that our Father's concern for a sinner who goes astray is no less.
To simply say that the returning prodigal was accepted, because that's what parents do, misses the point. The German Poet, Heinrich Heine, who had converted from Judaism to Christianity in order to preserve his German citizenship, was asked on his deathbed by a priest whether he thought that God would forgive his sins. He replied, "Dieu me pardonnera; c'est son metier" - God will forgive me; that's His job.
To assume that we are going to get forgiven so perfunctorily, misreads the younger son's heartfelt repentance. The Bible tells us that he ‘came to his senses’. It reminds us of Legion, the man from whom Jesus cast many Demons. The people came out and found the man sitting at Jesus’ feet, ‘dressed and in his right mind’. Repentance is not a formula for getting forgiven – it literally means ‘think again’. It involves starting with a different premise. In all three parables it is repentance that is stressed. In Luke 15:7, the parable of the lost sheep, Jesus says, “I tell you that in the same way there will be more rejoicing in heaven over one sinner who repents than over ninety-nine righteous persons who do not need to repent.” and in Luke 15:10, the parable of the lost coin, He says, “In the same way, I tell you, there is rejoicing in the presence of the angels of God over one sinner who repents."
Is the young man truly repentant? These days we see many people who swap sides when the going gets tough. Footballers who are proud to pull on the shirt of Portsmouth (or Tottenham or West Ham) and talk about the history of the club and how proud they are to be thought of in the same lineage as Jimmy Dickinson (or Danny Blanchflower of Bobby Moore). Then Real Madrid or Liverpool or Chelsea flash their check books and loyalty is easily bought. Was this prodigal just seeing which side his bread was buttered on? I don’t think so. He accepted that he had forfeited his sonhood and was eager to be a slave in his father’s house.
And if this attitude belittles the son’s repentance, it also diminishes the hurt done to the father. To ask for your inheritance while your father still lives, is tantamount to saying, "I wish you were dead." To take that amount of capital out of the business must have seriously affected how it was run. Presumably the father would have had to borrow to realize the cash. That would have been an added burden on the revenues of the farm.
We have to remember that this parable would have been shocking to his hearers. They would know all about unreasonable love. They would remember what Isaiah had said in chapter 49 v 15: "Can a mother forget the baby at her breast and have no compassion on the child she has borne? Though she may forget, I will not forget you!” In illustrating God’s extreme grace, Isaiah turns to a mother’s nature. Ask a mother, “If your son were making false returns on his Income Tax declaration, would you shop him?” or “Supposing your son was a murderer, would you hand him over to the police?” Time and again mothers help their sons to get away – and who would blame a mother?
Notwithstanding, a mother’s love, the Jew’s life was defined by the Law. In Jewish eyes a woman was weak. A Jewish man would thank God everyday that he was not born a woman. In a court of law a woman’s word was worth much less than a man’s. A man was not sentimental. This young man had broken the Fifth Commandment and the Tenth Commandment and probably the Seventh as well. The Jews believed in forgiveness. The young man could have taken an animal to the Temple and made a sin-offering, but no, he traipses back to his father and his father in his weakness rushes out to meet him with open arms like a mere woman.
I imagine a Jew of the day would have found this depiction of God offensive. And in a way I agree with them. It really won’t do to brush away sin as if it didn’t matter. Two weeks ago the Manchester United midfielder, Michael Carrick, burst into the penalty area and was tripped by the Everton center half. United had already scored from a penalty awarded when the same player had been tripped earlier, and this time the referee waved away the claim. When questioned afterwards, Sir Alex Fergusson, the United manager said, “Of course it was a penalty, even more blatant that the first one. But you can’t expect to get two penalties in a match like this.”
Like many fans I was outraged. Surely we have a right to expect the referee to be fair. No matter how much of an advantage United might have had, fouls can’t simply be ignored. I would be very worried by a God who simply ignored sin as if it had never happened. Winking at my indiscretions is one thing, but if my enemy harms me I want him punished. It’s not fair!
It is interesting to note the actions of the father. As well as putting shoes on his feet, a cloak on his back and a ring on his finger, he has the fattened calf slaughtered. Is it special pleading to see the killing of an animal as having a special meaning? The Jews knew all about animal sacrifices. They knew about the nature of surrogacy. The sacrifice on the Day of Atonement was, as here, a young bull.
Looking backwards we can see that it was the very teller of the story who was to be sacrificed as a surrogate for the prodigal son and for all prodigals since. We can see him as the atoning sacrifice for our sins. God doesn’t wink at our sin, but he doesn’t hold them against us. He has taken the punishment for them on himself in the body of the Son.
So, it’s not just a warning for the young; it’s a description of God’s amazing grace; of how the lost can be saved and the damned redeemed. It’s a message that tells us that no-one is too bad to save; that no-one is so far gone that they cannot be rescued and that God in his great love is not willing that any should perish, but that all should turn from their wicked ways and live. And when we look at the context – that Jesus was sitting down with Tax-collectors and sinners – we see that it is a point well made.
But I don’t think that is the main point of the story. The main point concerns the older brother.
When I was younger I had a lot of sympathy for the older brother. After all, he was the sensible one. He’d kept his nose clean, slaved away at home, been a good example, always been there to help around the house, obeyed the rules and now he felt he was being taken for granted. On the other hand his brother had been an absolute wastrel, spent the family money of wicked things, gone missing when his father had to take out a bigger loan to keep the farm going – not only had he been the cause of the loan in the first place, but he’d not been around to help about the farm to pay off the interest – and now his big plans had all collapsed he had come scurrying back to Papa with his tail between his legs. No wonder he felt hard done by.
There is a story of Elizabeth Elliot’s that I have stolen from Chris Kelly. It’s not a Biblical story, but it is a parable. One day Jesus asked his disciples to carry a stone for him. They each picked up a stone from the ground. Clever old Peter picked up a tiny pebble that slipped easily into his pocket. No burden at all to carry that around. After they had been walking around the Galilean countryside all morning they stopped for lunch. Jesus asked them all to brink their stones to him and we waved his hand over them and turned them into bread. “That’s your lunch,” he said. Poor old Peter had less than a mouthful. After lunch Jesus asked the disciples to do the same again. Peter was not going to be fooled a second time. This time he picked up a boulder. As they walked over the hills of Judea, Peter struggled with his load. Shifting it from one shoulder to the other and then holding it next to his chest, then on his head, he fell further and further behind. Eventually, he caught them up. They had been sitting by the side of the lake for half an hour or so. “Ah, Peter,” said the Lord, “You’ve finally got here. You can chuck the rock in the lake now.”
“What? Aren’t you going to turn it into bread?”
“Peter, were you carrying that stone for me, as I asked, or were you carrying it for yourself?”
The older brother wasn’t being the dutiful son because he loved his father. He was doing it for the reward. He liked being thought of as ‘the good son’. He had the respect of the servants and the neighbors. He was a pillar of the community. He had a good image. And what is more he had expectations. Do you remember the oily character in Pride and Prejudice, Mr. William Collins, who was so nauseatingly obsequious to his patron, Lady Catherine de Bourgh? He too had expectations. The Bennet’s house at Longbourn was entailed to him – if Mr. Bennet were to die, Mrs. Bennet and her five daughters would be turfed out of home and hearth to make way for him. I think Jane Austen had the older brother in mind when she drew Mr. Collins.
The contrast between the two brothers turns on the word ‘slave’. The older brother complains that he has been slaving for his father for years without reward; the younger son regards becoming a slave in his father’s household as the source of his future joy.
Context is all important. Jesus told these three parables because the Pharisees were muttering. Their complaint was that “This man welcomes sinners.” The point Jesus is making is that not only does God welcome sinners, but the Pharisees are like the older brother who doesn’t welcome sinners.
Remember the Pharisee’s prayer, “God, I thank you that I am not like other men – robbers, evildoers, adulterers – or even like this tax collector.”
It is certainly a fine thing not to be a robber, evildoer or an adulterer. But if he thought he was not like other men, he was certainly mistaken.
The Apostle John writing in his old age says, “If we claim to be without sin, we deceive ourselves and the truth is not in us…If we claim we have not sinned we make Him out to be a liar.”
The truth is that even good people need a Savior. Even religious people need salvation. I am afraid that our churches are full of people who think they are safe and are not. They have lived good lives. Everybody thinks well of them. They could stand as MPs and be scrutinized by the scandal sheets and no-one would find anything to make a story about. No hidden mistress, their income tax returns are spotless, no unfortunate ‘perks’ they would be embarrassed by; they go to church twice on Sundays, they tithe religiously, they are always at Holy Communion. They are politically correct, watching their words carefully; “Paki” and “Golliwog” are not even in their vocabulary; they turn their TV off at the mains every night; they drive a hybrid car; their houses have roof insulation nine inches thick and their walls are insulated with polyurethane foam.
Yet these very good people still fall short of the standards Jesus has set. President Carter was a very good man. He may not have been a good President, but his lifestyle was exemplary. He was mocked about the story in Playboy. “Have you ever committed adultery?” he was asked.
“I have committed adultery in my heart,” he replied. He was just being honest. Applying to himself the interpretation of the Ten Commandments that Jesus had opened up in the Sermon on the Mount.
When the prodigal son was yet far off, his father, watching the road, perhaps standing on the roof of his house and scanning the horizon, spotted him. Was there something about the way he walked? Something about his gait or his body shape that he recognized. “I am the good shepherd,” said Jesus elsewhere, “I know my sheep.”
Can’t you feel the excitement, the anticipation, the overwhelming joy as the father ran to his son, threw his arms around him and kissed him? No wonder Jesus said there would be rejoicing in heaven.
What about the older brother? When he heard the music and the dancing he became angry. He skulked around outside and refused to go in. Not a lot of joy there. And it is a characteristic of the Pharisees. Would you not expect them to be pleased, for example, about the story of Zacchaeus, the reformed tax-collector? How about when they saw Lazarus raised from the dead? Or Blind Bartimaeus able to see again?
Supposing Joni Earickson suddenly got up from her wheelchair; would you rejoice? Or would you think it was a trick? When Jonathan Aitken was converted in prison did you suspect he was just trying to curry favor? To re-establish himself as a politician who was accepted in polite society. Did you feel the same about Chuck Colsen, the notorious Watergate plotter?
Have you met joyless Christians; people who are always picking holes in somebody else’s sweater? Oh, they are there. They don’t like the new hymn book. They don’t like the PowerPoint projector. The communion wine should be alcoholic/non-alcoholic (take your choice). They don’t like small groups. They find large meetings too impersonal. Church doesn’t do anything for me.
No wonder they are joyless. Without a Savior they never know whether the good they have done is enough. Is it enough to have double glazing? Should I perhaps get triple glazing? Should I set the house temperature at 68 rather than 70?
The prodigal son was humbled. He fell from a great height. One moment he was surrounded by rich friends, moving in the highest society. In today’s terms he would be lunching at the Savoy with merchant bankers, think it hilarious to send back a £500 bottle of wine because it was ‘corked’; then leave a £1000 tip. In the evening a little dinner party with Jude Law and a bevy of blondes and after the meal, a snort of cocaine. He would be pictured in ‘Hello’ in his Armani suit and Paul Smith shirt.
Just a blink later and he is wallowing with the pigs, his money gone, and he squabbles with the hogs to eat their food. Not difficult for him to be realistic about his situation. Humility comes easy to a man who has been brought down low.
Not so his brother. When you think you’re doing well, when you have a religious ritual to go by, when you’re good, it’s hard to see you need a savior. Did you see David Beckham in the England match on Wednesday? He’s done well to come back to international football hasn’t he? Except that he harassed the referee over what he thought was a wrong decision and got himself a yellow card. When you are convinced you are in the right humility is a hard currency to deal in. Pride keeps us from the kingdom.
Are they irredeemable, these joyless Christians? Listen to what the Apostle Paul says of himself. “If anyone else thinks he has reasons to put confidence in the flesh, I have more: circumcised on the eighth day, of the people of Israel, of the tribe of Benjamin, a Hebrew of Hebrews; in regard to the law, a Pharisee; as for zeal, persecuting the church; as for legalistic righteousness, faultless.”
Elsewhere, he describes himself as the ‘chief of sinners’.
Only the Holy Spirit could change Paul, but the Holy Spirit did just that.
As I examine my heart, I invite you to do the same. Am I an older brother? Do I lack joy? Do I lack humility? If any of these accusations stick then turn to the Savior now. Pray that the Holy Spirit will give you the joy of your salvation. For he is not only able to do so, he is more than willing.
Friday, February 06, 2009
NICE picture
This morning in the post I received this remarkable picture. "What's remarkable about it?" you may ask, "Just an old couple cutting a cake." Edith and John are celebrating their Diamond Wedding anniversary.
Eighteen years ago John had been given just a few weeks to live. He had been diagnosed with kidney cancer which was regarded as inoperable. His lungs were almost totally replaced by secondary cancer and he had very large lymph nodes in his abdomen. There was no effective chemotherapy for kidney cancer, and in fact the recommended treatment was the female sex hormone, progesterone. This did no good, but it was pretty harmless.
About that time there had been a television program about a new type of agent called interleukin-2 (IL-2). It was a terrible treatment. Patients suffered terrific shivering attacks, their blood pressures dropped, they went into kidney failure, some died of heart failure, some developed horrific rashes, but some got better.
John came to see me. I wasn't sure who mentioned IL-2 first, it may well have been him. Ar first I dismissed it out of hand. It was not a licensed product. It was impossibly expensive (£9000 then seemed an awful lot of money when you find it difficult to get the NHS to pay an extra £300 for mitoxantrone).
John offered to raise the £9000 but even then there was a rule that if you paid for your drugs privately your whole treatment had to be private. Had we gone down that route we would have been talking about £25,000+.
Instead I suggested that John make a contribution to our research fund so that we could start a clinical trial of interleukin-2 in kidney cancer. I wrote a protocol and got ethical approval even though I knew that without funding I would only be able to treat one patient.
We weren't really sure what to expect, but my team were up for it and we gave John the drug. The toxicity was bad, though not as bad as it had appeared on television. All the secondaries disappeared and the cancerous kidney shrunk to such a size that it could be removed.
When we took this result to the company that made it, they funded me to treat another 24 kidney cancer patients, 25 melanomas and 10 colon cancer patients. We had one other kidney cancer complete remission, and she also is still alive, and 5 complete remissions in melanoma patients, but they all relapsed within a year. One of the colon cancer patients had a partial remission.
Several points to learn from this. The median is not the message, as Stephen J Gould said. Despite a poor median survival, some patients do very well on strange treatments that have no apparent survival benefit. Patient drive and determination is sometimes the most important factor. The looser arrangements for clinical trials that used to obtain had their good points as well as their bad ones.
In 1991 I was at the peak of my powers. Everything I touched turned to gold. My confidence was high and I felt I had magic in my fingers. What a dangerous state for any man to aspire to! If I felt like that now I would seek absolution.
Tuesday, February 03, 2009
What is a CR?
I spent yesterday wrestling with the CLL Guidelines - both the 1996 and the 2008 versions - trying to evaluate a clinical trial results as part of a Review Panel. It used to be quite easy, though pretty meaningless. To say you had a complete remission (CR) in CLL you had to have disappearance of all disease that could be detected by physical examination, and restoration of the blood count to reasonable levels - neutrophils > 1500/cu mm, lymphocytes <4000/cu mm, platelets >100,000/cu mm and Hb >11 g/dL. This had to last for two months, and at the end of those two months a bone marrow biopsy had to contain fewer than 30% lymphocytes and to be of reasonably normal cellularity.
Of course, the 1996 guidelines were written before imaging became a routine practice, so hepatomegaly meant that you could feel the liver below the edge of the ribs and splenomegaly meant that you could feel the spleen below the edge of the ribs.
If the patient did not fulfill the criteria for a CR the next test was to see if the conditions for a partial remission (PR) were met. These required a >50% decrease in the lymphocyte count, a >50% reduction in the size of the lymph nodes and a >50% reduction in hepatosplenomegaly plus the restoration of (or considerable improvement in) one of the elements of the blood count (ie platelets over 100,000/cu mm, Hb over 11 g/dL and neutrophils over 1500, or if these are not achieved a >50% increase over the baseline levels).
Patients who fail treatment might have progressive disease (PD) which was defined as a >50% increase in the sum of the products of at least two lymph nodes on two consecutive determinations at least 2 weeks apart (at least one node must be > than 2cm) or the appearance of new nodes that could be felt. Or a >50% increase in the size of the liver or spleen below the ribs or the appearance of one of these which was not previously present, or a >50% in the absolute number of circulating lymphocytes (as long as the number is greater than 5000/cu mm.
(It should be noted that all the >50% signs in this essay mean greater or equal to 50%; I don’t know how to make the sign for greater or equal to.)
Those who don’t improve enough to be called a PR or who don’t deteriorate enough to be called PD were designated as having stable disease (SD).
Although this system was fairly easy to operate it was a bit of a joke. This wasn’t a CR like the CRs of acute leukemia where getting a CR is a prelude to a cure. Everybody knew that obtaining a CR in CLL (and that itself was pretty rare) didn’t mean a cure. It was possible that 30% of the cells in the bone marrow were still leukemia cells. And since lymph nodes in the belly couldn’t be felt there could be a couple of kilograms of cancer there undetected. In fat people it’s almost impossible to feel lymph nodes in the armpits and in very thin people you can often feel very small lymph nodes, which may be enlarged because of infection rather than CLL. A spleen has to enlarge threefold to be felt below the ribs, and measuring the liver by physical examination is fraught with difficulties; for example, if the lungs are over expanded, as in emphysema, a normal sized liver can be felt below the ribs.
The new guidelines were prompted by a number of things. It had long been recognized that some patients apparently achieved CR, but their marrow biopsies, while mainly being free of CLL, contained lymphoid nodules. Were these lymphoid nodules foci of CLL or just reactive nodules of normal tissue? They clearly needed to be studied separately and so such patients were designated nPR. We do know that such patients have a shorter time to progression than those with CR. Then there were some patients who seemed to be in CR but their blood counts did not return to normal. It seemed that their bone marrow had been damaged by the CLL. Of course, it could have been the case that residual CLL was suppressing their bone marrow and preventing normalization. The 1996 guidelines regarded this as a controversial issue, but decided that they should be called PR – except that if Hb was still <11 g/dL, neutrophils <1500/cu mm and platelets <100,000 /cu mm they had to be regarded as stable disease.
The other confusing thing about the guidelines was that despite stressing that size measurements are to be determined by physical examination, they add “and appropriate radiographic techniques” for lymph node sizing, and “or appropriate radiographic techniques if in a clinical trial” for liver and spleen measurement, as if physical examination and ‘appropriate radiological techniques’ were interchangeable. We know for certain that radiological techniques will detect disease that is undetectable to the examiner’s hand.
For evaluating clinical trials it turns out that measurements are not noted down in the notes, and investigations are forgotten. There may be ‘after’ CT scans but no ‘before’ or vice versa.
So do the new guidelines help?
Now CR needs all the following criteria as assessed at least three months after the completion of treatment:
1. No clonal lymphocytes. This is more stringent than before – all you needed then was fewer than 4000 lymphocytes.
2. No significantly enlarged lymph nodes. In clinical trials CT scanning is now positively encouraged. So we are talking about the largest diameter of lymph nodes anywhere in the body, not being greater than 1.5 cm.
3. No hepatomegaly or splenomegaly by physical examination. We have now reverted to physical examination even though a CT scan will have been done to look for enlarged lymph nodes. The guidelines advise that if liver or spleen were found to be abnormal before treatment then a scan should be performed at evaluation; this should also be done if the evaluation was inconclusive by physical examination.
4. No constitutional symptoms.
5. Neutrophils >1500 / cu mm, platelets >100,000 /. Cu mm Hb >11 g/dL (untransfused). For more than 20 years I have been protesting that to choose the same Hb level for men and women is insane.
6. If all these points have been achieved a bone marrow aspirate and trephine biopsy should be performed. The marrow should be examined by flow cytometry and immunohistochemistry to look for clonal B cells. If clonal cells are found then the case is demoted to PR. It must be stressed here that the flow cytometry is not the powerful 4-color flow used to detect MRD, but the simpler 2-color flow that detects one cell in 100.If lymphoid nodules are found in the trephine, then immunohistochemistry should distinguish between CLL and reactive nodules. The nPR category therefore disappears. If the marrow is hypercellular, then it should be repeated in 4-6 weeks, provided the blood counts have recovered. In some cases it is necessary to continue to postpone the marrow, but this time interval should not exceed 6 months.
7. The question of apparent CR with a failure to recover the bone marrow also seems to have been resolved. Those who fulfill all the criteria for a CR including the marrow examination, but who have a persistent anemia, thrombocytopenia or neutropenia unrelated to CLL but related to drug toxicity are designated CRi (‘i’ stands for incomplete marrow recovery). In view of the fact that a PR still requires recovery of at least one of the marrow lineages, I am not clear whether CRi can be applied to a patient with complete pancytopenia.
PR is similar to before – slightly confusing. There are four things that must be achieved:
1. A decrease in blood lymphocytes to fewer than 50% of the starting value.
2. A reduction in the size of the lymph nodes. This has to be assessed by CT in a clinical trial, and is defined as a decrease of 50% or more of the ‘sum products’ of up to six lymph nodes ‘Sum products’ are the figure you get when you multiply the perpendicular diameters of individual lymph nodes. It doesn’t say which six nodes, but most people would take the six biggest ones – of course if only three are enlarged you’d just do it with three. If there is just one big node then you can take a 50% reduction in its diameter. As far as lymph nodes are concerned there must be no increase in size in any of them, though in small nodes of less than 2cm diameter, an increase of less than 25% is not considered significant. There must also be no new enlarged node that wasn’t enlarged before.
3. A decrease in the size of the liver or spleen by 50% or more defined by CT in clinical trials. This is the one I take issue with. Enlarged spleens are often 18 cm long when measured by CT. A 50% reduction in size to 9cm would make it smaller than normal – up to 12 cm – and measurement of livers will have a similar drawback. We don’t want treatment that will make the liver shrink to the size of someone’s with cirrhosis. What they mean is a 50% reduction in the enlargement of either organ, but since we don’t know what the normal was for that patient, we are unable to calculate an answer. Livers and spleens vary with body size – they are certainly larger in men than women. Until this issue is resolved I recommend that any liver or spleen that can’t be felt by clinical examination should be regarded as normal.
4. One of the following should be present: neutrophils >1500 / cu mm, platelets >100,000 / cu mm, Hb >11 g/dL, or if not then at least one should show a 50% improvement over baseline.
A further proviso is that at least one of these parameters should persist for at least 2 months. It is not clear to me from the paper whether this refers to all the 4 measurements or just one of those in section 4. I’m assuming it means any of the four sections.
Systemic symptoms don’t come into it. Although CR requires these to remit, a PR does not, although they have to be noted.
PD is generally obvious from blood counts and therefore need not be looked for by CT scanning, though clearly from the instructions in the paper, it can be. So if any of the following occur PD is said to have occurred:
1. Any new lesions appearing such as an new lymph node enlarged to >1.5 cm diameter, splenomegaly, hepatomegaly or any other organ infiltration.
2. An increase by 50% or more of the greatest diameter of any previous lymph node.
3. An increase of 50% or more of the sum of the product of diameters of multiple nodes.
4. An increase in the size of liver or spleen by 50% or more or the appearance of spleens or livers that can now be felt.
5. An increase of50% or more in the absolute lymphocyte count, as long as it is greater than 5000.
6. Transformation to aggressive histology (eg Richter’s syndrome). This should be confirmed by biopsy.
7. The appearance of cytopenia unrelated to treatment or autoimmunity. This can only be assessed after treatment and so is defined as a fall in Hb by 2g/dL or to less than 10g/dL or by a decrease in platelet count by more than 50% or to below 100,000 per cu mm, that occurs at least 3 months after treatment ends and associated with an infiltrate of clonal lymphoid cells in the marrow. Note, the guidelines say nothing about late neutropenia.
SD is anything between PR and PD.
The duration of a response is measured from the end of the last treatment, but, confusingly, progression-free survival is measured from the first day of treatment.
Trials that are designed to eradicate the CLL should include testing for minimal residual disease (MRD). Either 4-color flow cytometry or allele-specific oligonucleotide PCR should be used using a threshold of one cell in 10,000. It is permissible to use blood for this assay except within 3 months of completing therapy, especially when alemtuzumab, rituximab or other antibodies have been used, in which case, bone marrow should be used.
Although the new guidelines make sense, there are still some ambiguities and in places the application of common sense runs counter to the wording of the document.
Of course, the 1996 guidelines were written before imaging became a routine practice, so hepatomegaly meant that you could feel the liver below the edge of the ribs and splenomegaly meant that you could feel the spleen below the edge of the ribs.
If the patient did not fulfill the criteria for a CR the next test was to see if the conditions for a partial remission (PR) were met. These required a >50% decrease in the lymphocyte count, a >50% reduction in the size of the lymph nodes and a >50% reduction in hepatosplenomegaly plus the restoration of (or considerable improvement in) one of the elements of the blood count (ie platelets over 100,000/cu mm, Hb over 11 g/dL and neutrophils over 1500, or if these are not achieved a >50% increase over the baseline levels).
Patients who fail treatment might have progressive disease (PD) which was defined as a >50% increase in the sum of the products of at least two lymph nodes on two consecutive determinations at least 2 weeks apart (at least one node must be > than 2cm) or the appearance of new nodes that could be felt. Or a >50% increase in the size of the liver or spleen below the ribs or the appearance of one of these which was not previously present, or a >50% in the absolute number of circulating lymphocytes (as long as the number is greater than 5000/cu mm.
(It should be noted that all the >50% signs in this essay mean greater or equal to 50%; I don’t know how to make the sign for greater or equal to.)
Those who don’t improve enough to be called a PR or who don’t deteriorate enough to be called PD were designated as having stable disease (SD).
Although this system was fairly easy to operate it was a bit of a joke. This wasn’t a CR like the CRs of acute leukemia where getting a CR is a prelude to a cure. Everybody knew that obtaining a CR in CLL (and that itself was pretty rare) didn’t mean a cure. It was possible that 30% of the cells in the bone marrow were still leukemia cells. And since lymph nodes in the belly couldn’t be felt there could be a couple of kilograms of cancer there undetected. In fat people it’s almost impossible to feel lymph nodes in the armpits and in very thin people you can often feel very small lymph nodes, which may be enlarged because of infection rather than CLL. A spleen has to enlarge threefold to be felt below the ribs, and measuring the liver by physical examination is fraught with difficulties; for example, if the lungs are over expanded, as in emphysema, a normal sized liver can be felt below the ribs.
The new guidelines were prompted by a number of things. It had long been recognized that some patients apparently achieved CR, but their marrow biopsies, while mainly being free of CLL, contained lymphoid nodules. Were these lymphoid nodules foci of CLL or just reactive nodules of normal tissue? They clearly needed to be studied separately and so such patients were designated nPR. We do know that such patients have a shorter time to progression than those with CR. Then there were some patients who seemed to be in CR but their blood counts did not return to normal. It seemed that their bone marrow had been damaged by the CLL. Of course, it could have been the case that residual CLL was suppressing their bone marrow and preventing normalization. The 1996 guidelines regarded this as a controversial issue, but decided that they should be called PR – except that if Hb was still <11 g/dL, neutrophils <1500/cu mm and platelets <100,000 /cu mm they had to be regarded as stable disease.
The other confusing thing about the guidelines was that despite stressing that size measurements are to be determined by physical examination, they add “and appropriate radiographic techniques” for lymph node sizing, and “or appropriate radiographic techniques if in a clinical trial” for liver and spleen measurement, as if physical examination and ‘appropriate radiological techniques’ were interchangeable. We know for certain that radiological techniques will detect disease that is undetectable to the examiner’s hand.
For evaluating clinical trials it turns out that measurements are not noted down in the notes, and investigations are forgotten. There may be ‘after’ CT scans but no ‘before’ or vice versa.
So do the new guidelines help?
Now CR needs all the following criteria as assessed at least three months after the completion of treatment:
1. No clonal lymphocytes. This is more stringent than before – all you needed then was fewer than 4000 lymphocytes.
2. No significantly enlarged lymph nodes. In clinical trials CT scanning is now positively encouraged. So we are talking about the largest diameter of lymph nodes anywhere in the body, not being greater than 1.5 cm.
3. No hepatomegaly or splenomegaly by physical examination. We have now reverted to physical examination even though a CT scan will have been done to look for enlarged lymph nodes. The guidelines advise that if liver or spleen were found to be abnormal before treatment then a scan should be performed at evaluation; this should also be done if the evaluation was inconclusive by physical examination.
4. No constitutional symptoms.
5. Neutrophils >1500 / cu mm, platelets >100,000 /. Cu mm Hb >11 g/dL (untransfused). For more than 20 years I have been protesting that to choose the same Hb level for men and women is insane.
6. If all these points have been achieved a bone marrow aspirate and trephine biopsy should be performed. The marrow should be examined by flow cytometry and immunohistochemistry to look for clonal B cells. If clonal cells are found then the case is demoted to PR. It must be stressed here that the flow cytometry is not the powerful 4-color flow used to detect MRD, but the simpler 2-color flow that detects one cell in 100.If lymphoid nodules are found in the trephine, then immunohistochemistry should distinguish between CLL and reactive nodules. The nPR category therefore disappears. If the marrow is hypercellular, then it should be repeated in 4-6 weeks, provided the blood counts have recovered. In some cases it is necessary to continue to postpone the marrow, but this time interval should not exceed 6 months.
7. The question of apparent CR with a failure to recover the bone marrow also seems to have been resolved. Those who fulfill all the criteria for a CR including the marrow examination, but who have a persistent anemia, thrombocytopenia or neutropenia unrelated to CLL but related to drug toxicity are designated CRi (‘i’ stands for incomplete marrow recovery). In view of the fact that a PR still requires recovery of at least one of the marrow lineages, I am not clear whether CRi can be applied to a patient with complete pancytopenia.
PR is similar to before – slightly confusing. There are four things that must be achieved:
1. A decrease in blood lymphocytes to fewer than 50% of the starting value.
2. A reduction in the size of the lymph nodes. This has to be assessed by CT in a clinical trial, and is defined as a decrease of 50% or more of the ‘sum products’ of up to six lymph nodes ‘Sum products’ are the figure you get when you multiply the perpendicular diameters of individual lymph nodes. It doesn’t say which six nodes, but most people would take the six biggest ones – of course if only three are enlarged you’d just do it with three. If there is just one big node then you can take a 50% reduction in its diameter. As far as lymph nodes are concerned there must be no increase in size in any of them, though in small nodes of less than 2cm diameter, an increase of less than 25% is not considered significant. There must also be no new enlarged node that wasn’t enlarged before.
3. A decrease in the size of the liver or spleen by 50% or more defined by CT in clinical trials. This is the one I take issue with. Enlarged spleens are often 18 cm long when measured by CT. A 50% reduction in size to 9cm would make it smaller than normal – up to 12 cm – and measurement of livers will have a similar drawback. We don’t want treatment that will make the liver shrink to the size of someone’s with cirrhosis. What they mean is a 50% reduction in the enlargement of either organ, but since we don’t know what the normal was for that patient, we are unable to calculate an answer. Livers and spleens vary with body size – they are certainly larger in men than women. Until this issue is resolved I recommend that any liver or spleen that can’t be felt by clinical examination should be regarded as normal.
4. One of the following should be present: neutrophils >1500 / cu mm, platelets >100,000 / cu mm, Hb >11 g/dL, or if not then at least one should show a 50% improvement over baseline.
A further proviso is that at least one of these parameters should persist for at least 2 months. It is not clear to me from the paper whether this refers to all the 4 measurements or just one of those in section 4. I’m assuming it means any of the four sections.
Systemic symptoms don’t come into it. Although CR requires these to remit, a PR does not, although they have to be noted.
PD is generally obvious from blood counts and therefore need not be looked for by CT scanning, though clearly from the instructions in the paper, it can be. So if any of the following occur PD is said to have occurred:
1. Any new lesions appearing such as an new lymph node enlarged to >1.5 cm diameter, splenomegaly, hepatomegaly or any other organ infiltration.
2. An increase by 50% or more of the greatest diameter of any previous lymph node.
3. An increase of 50% or more of the sum of the product of diameters of multiple nodes.
4. An increase in the size of liver or spleen by 50% or more or the appearance of spleens or livers that can now be felt.
5. An increase of50% or more in the absolute lymphocyte count, as long as it is greater than 5000.
6. Transformation to aggressive histology (eg Richter’s syndrome). This should be confirmed by biopsy.
7. The appearance of cytopenia unrelated to treatment or autoimmunity. This can only be assessed after treatment and so is defined as a fall in Hb by 2g/dL or to less than 10g/dL or by a decrease in platelet count by more than 50% or to below 100,000 per cu mm, that occurs at least 3 months after treatment ends and associated with an infiltrate of clonal lymphoid cells in the marrow. Note, the guidelines say nothing about late neutropenia.
SD is anything between PR and PD.
The duration of a response is measured from the end of the last treatment, but, confusingly, progression-free survival is measured from the first day of treatment.
Trials that are designed to eradicate the CLL should include testing for minimal residual disease (MRD). Either 4-color flow cytometry or allele-specific oligonucleotide PCR should be used using a threshold of one cell in 10,000. It is permissible to use blood for this assay except within 3 months of completing therapy, especially when alemtuzumab, rituximab or other antibodies have been used, in which case, bone marrow should be used.
Although the new guidelines make sense, there are still some ambiguities and in places the application of common sense runs counter to the wording of the document.