When I attend a committee that awards grants to researchers, I am of course sworn to secrecy about what goes on there, but I can blog about the general themes that researchers are pursuing without referring to specific grant proposals. On Thursday it was clear CLL is very much a focus for new research.
Following the German trial that everyone knows will be reported at ASH, that will show FCR to be superior to FC, there seems no doubt that FCR is the treatment of choice for patients under the age of 70 and possibly those under 65. Even so, around 5% will be resistant to this regime and what to do for them is still a difficult decision. Alemtuzumab (Campath) is clearly one of the drugs that should be used, but it penetrates large tumor masses poorly and needs to be combined with something else. Most is known about teh high dose steroid + Campath combination, but workers are taking a close look at Fludarabine and Campath. This combination seems to work in patients with del 17p and large nodes. There are several ways of using this drug combination and trials are being conducted with several different schedules.
Revlimid is another drug that works in del 17p patients, though it does not seem to be as effective as either Campath or high dose steroids. There are several trials and proposed trials which are seeking to further evaluate this drug. One possible way of using it is in poor risk symptomless early stage disease. The aim here is to avoid chemotherapy which would damage normal bone marrow and possible select for more malignant clones or even trigger disease progression. Revlimid seems to have no direct effect on the tumor, but works in CLL by limiting the help to tumor growth provided by the stroma in bone marrow and lymph nodes. It may be that this is the best way to use the drug.
Other experimental drugs that I have already written about are also reaching clinical trials. A correspondent let it be known that he was the second patient to start on a Nutlin trial. Nutlin is an MDM-2 inhibitor that allows p53 to accumulate. The PARP-1 inhibitor AZD2281 is also close to clinical trial in CLL. AZD2281 is an inhibitor of DNA repair. It is effective in vitro in cells that have a defect of homologous recombination, such as breast cancer cells that lack BRCA-1 or CLL cells that lack ATM. Trials in breast cancer have already begun.
Means of enhancing immunity to tumors is very much a current interest. Stem cell allograft is the principle current means of such immunotherapy, but it is hard to separate GVHL from GVHD. One means of lessening the GVHD effect without reducing the GVL effect is the infusion of regulatory T cells. This is ready to be scaled up from mice to men. The same effect might also be achieved by depleting donor lymphocyte infusions of CD8 positive T cells.
Vaccination of the donor before harvest of donor lymphocyte infusion is another approach, making use of donor altruism. HA-1 is a minor histocompatability antigen which is lacking in 30% of donors, but present on 70% of tumors. There are lots of new ways of vaccinating, one of which, DNA vaccination is very much a thing of the moment. With my GTAC hat on, I frequently see DNA vaccines against HIV, TB and malaria. One of the most effective methods is so called prime boost, where the immune system is primed by a DNA vaccine and then boosted by a genetic vaccine, where the foreign gene is contained within a virus. Modified vaccinia Ankara is the safest choice.
Another potential antigen for DNA vaccines is WT-1, a tumor antigen represented on myeloid malignancies. Electroporation (passing a small electric shock through the vaccination site) enhances the effect of DNA vaccines and was recently successfully employed in a prostate cancer trial.
Sunday, September 28, 2008
The election on healthcare
The BMJ has reviewed the respective health care plans of the two American Presidential candidates.
As summarized by the medical journal McCain's plan proposes to eliminate the tax benefits of employer sponsored insurance. Currently those who benefit from employer based insurance receive a substantial tax subsidy since the dollar value of their benefit is not counted as taxable income. They also enjoy other benefits since employers buy insurance in group markets, which are cheaper and do not subject individual employees to medical underwriting - in other words you don't get a loaded premium and exclusion clauses because you have some pre-existing medical condition or a propensity to such. These employer-based plans are often top of the market products with extras that most people would not be able to afford (though many of these benefits would come as standard in Britain's NHS). If you have to purchase your own plan you generally have fewer benefits, aggressive medical underwriting and higher premiums (sometimes five times as high). And you don't get a tax exemption for the money you spend on it.
The McCain idea is that eliminating the tax benefit for everyone would wean people off these gold-plated policies (which cost the employer an average of $12,000 a year for a family). Instead of this tax benefit, everyone would receive a a flat rate tax credit of $2,500 for an individual and $5,000 for a family. Of course, the employed would expect a pay rise from their employer since they would no longer be paying for health insurance. McCain also thinks that elimination of employer insurance will invigorate the individual health insurance market which currently only covers 6.5% of Americans. To free up this market, McCain proposes the elimination of state based regulation, and to allow companies to operate across state lines. Although medical underwriting would continue, he proposes expanded state-sponsored high risk pools to pay for their insurance.
The Obama plan proposes to maintain the tax subsidies for employer sponsored insurance and to convert the individual and small business market into a group market so as to enjoy similar privileges as the large employer market. He wants a group market under the auspices of the Federal Government which would mirror the benefits available to Federal employees. As an alternative to this Insurance Exchange, people would be free to enter a public plan similar to Medicare. Large Employers would be obligated to cover their employees, while smaller employers would receive a subsidy to do the same. Individuals would receive a sliding scale subsidy based on income. Medical underwriting would be eliminated as everyone would be in one of these large pools. All children would be required to have insurance but adults might elect to 'go bare'.
Will either of these plans solve the problem? I rather doubt it. Currently half of US bankruptcies result from medical expenses, despite the fact that America spends far more on healthcare than any other nation. What I am sure of is that whatever system is introduced, the players will find ways to game the system.
As summarized by the medical journal McCain's plan proposes to eliminate the tax benefits of employer sponsored insurance. Currently those who benefit from employer based insurance receive a substantial tax subsidy since the dollar value of their benefit is not counted as taxable income. They also enjoy other benefits since employers buy insurance in group markets, which are cheaper and do not subject individual employees to medical underwriting - in other words you don't get a loaded premium and exclusion clauses because you have some pre-existing medical condition or a propensity to such. These employer-based plans are often top of the market products with extras that most people would not be able to afford (though many of these benefits would come as standard in Britain's NHS). If you have to purchase your own plan you generally have fewer benefits, aggressive medical underwriting and higher premiums (sometimes five times as high). And you don't get a tax exemption for the money you spend on it.
The McCain idea is that eliminating the tax benefit for everyone would wean people off these gold-plated policies (which cost the employer an average of $12,000 a year for a family). Instead of this tax benefit, everyone would receive a a flat rate tax credit of $2,500 for an individual and $5,000 for a family. Of course, the employed would expect a pay rise from their employer since they would no longer be paying for health insurance. McCain also thinks that elimination of employer insurance will invigorate the individual health insurance market which currently only covers 6.5% of Americans. To free up this market, McCain proposes the elimination of state based regulation, and to allow companies to operate across state lines. Although medical underwriting would continue, he proposes expanded state-sponsored high risk pools to pay for their insurance.
The Obama plan proposes to maintain the tax subsidies for employer sponsored insurance and to convert the individual and small business market into a group market so as to enjoy similar privileges as the large employer market. He wants a group market under the auspices of the Federal Government which would mirror the benefits available to Federal employees. As an alternative to this Insurance Exchange, people would be free to enter a public plan similar to Medicare. Large Employers would be obligated to cover their employees, while smaller employers would receive a subsidy to do the same. Individuals would receive a sliding scale subsidy based on income. Medical underwriting would be eliminated as everyone would be in one of these large pools. All children would be required to have insurance but adults might elect to 'go bare'.
Will either of these plans solve the problem? I rather doubt it. Currently half of US bankruptcies result from medical expenses, despite the fact that America spends far more on healthcare than any other nation. What I am sure of is that whatever system is introduced, the players will find ways to game the system.
Friday, September 26, 2008
CLL - MBL - IWCLL
Earlier this year new guidelines on CLL were published by the IWCLL. I have to admit that despite being consulted about the paper before publication a change has slipped through that I did not notice – and it is a very controversial change. Previously the threshold for diagnosis was a lymphocyte count of 5000 per cu mm. This has been changed to a B lymphocyte count of 5000. The proportion of lymphocytes that are B cells is extremely variable, so in order to reach a B cell count of 5000 a person might need to have an absolute lymphocyte count of greater than 10,000.
This needs to be seen in the context of the diagnosis of monoclonal B lymphocytosis (MBL) in which the individual has circulating lymphocytes exactly like CLL cells, but the absolute lymphocyte count is less than 5000. Under the new definition what would previously have been called CLL would now be called MBL unless that total B-lymphocyte count is greater than 5000. A lot of patients who have been told that they have been told that they have CLL would suddenly have their diagnosis corrected to MBL. It has been estimated that 40% of patients with stage 0 CLL in fact have MBL.
There are real problems with this. First, it means that flow cytometry becomes essential for diagnosis and also for follow up. This is much more expensive than a simple cbc. Second, patients will fluctuate between MBL and CLL on successive visits to their doctor. Third, MBL turns into CLL at the rate of1% per year, so it does not mean that follow-up can be omitted. Fourth, a paper from Andy Rawstron in the NEJM earlier this year suggested that a threshold of 2000 B cells was necessary for MBL to progress – patients with lower levels were very unlikely to do so.
To some extent this new definition satisfies the problem that Victor Hoffbrand and I raised earlier this year, namely that patients were being told that they had leukemia, yet they would never need treatment for it, though even with the new definition that will still be the case for some patients (though for fewer than before).
I guess the major problem that I have with this change is that it has been made without the benefit of evidence to guide it, merely on the gut-instinct of the authors.
This needs to be seen in the context of the diagnosis of monoclonal B lymphocytosis (MBL) in which the individual has circulating lymphocytes exactly like CLL cells, but the absolute lymphocyte count is less than 5000. Under the new definition what would previously have been called CLL would now be called MBL unless that total B-lymphocyte count is greater than 5000. A lot of patients who have been told that they have been told that they have CLL would suddenly have their diagnosis corrected to MBL. It has been estimated that 40% of patients with stage 0 CLL in fact have MBL.
There are real problems with this. First, it means that flow cytometry becomes essential for diagnosis and also for follow up. This is much more expensive than a simple cbc. Second, patients will fluctuate between MBL and CLL on successive visits to their doctor. Third, MBL turns into CLL at the rate of1% per year, so it does not mean that follow-up can be omitted. Fourth, a paper from Andy Rawstron in the NEJM earlier this year suggested that a threshold of 2000 B cells was necessary for MBL to progress – patients with lower levels were very unlikely to do so.
To some extent this new definition satisfies the problem that Victor Hoffbrand and I raised earlier this year, namely that patients were being told that they had leukemia, yet they would never need treatment for it, though even with the new definition that will still be the case for some patients (though for fewer than before).
I guess the major problem that I have with this change is that it has been made without the benefit of evidence to guide it, merely on the gut-instinct of the authors.
Ivy League
West College, Princeton.I am always hungry for silly little anecdotes, especially ones about the derivation of words, and I was told one yesterday by a colleague. Where does "Ivy league" come from? I had always assumed it described the ivy covered buildings of the New England colleges, but no, I was told that it referred to a football (not proper football but that strange American version of Rugby where you wear body armor and are allowed to pass the ball forwards) league started by Harvard, Yale, Princeton and Columbia. The league of four was known by the Roman numerals IV (hence Ivy).
Sounds nice, but probably not true. The term "ivy colleges" was coined by the New York Tribune sports journalist, Stanley Woodward thus "A proportion of our eastern ivy colleges are meeting little fellows another Saturday before plunging into the strife and the turmoil. ” October 14, 1933, describing the football season and the first use of "Ivy League was in the Christian Science Monitor two years later.
The eight Ivy League Colleges are Harvard, Yale, University of Pennsylvania, Princeton, Columbia, Cornell, Browns and Dartmouth.
Monday, September 22, 2008
Agatha Christie
Last night I watched an episode of Poirot. David Suchet is far and away the best impersonator of Agatha Christie's famous Belgian detective and his performance has improved over the years. Coincidentally last week saw an investigation into Suchet's ancestors. Although Jewish, David is now an evangelical Christian; that never stops him being Jewish, of course. He ancestors came from an area of central Europe that has been Russian and Prussia in its history. The persecution was the same whatever the nation.
Suchet surpasses both Ustinov and Finney. Three new 2-hour episodes are currently being shown on ITV. 'Cat among the pigeons' which was aired last night has a fairly silly plot, but just watching Suchet's performance and soaking in the period brought me a great deal of pleasure.
However, it reminded me of my childhood. Agatha Christie was banned from our house, not on grounds of taste, but because she was ajudged too frightening. Today we regard these films as light entertainment; when I was a child she was for adults only. People were murdered! How things have changed.
In the 1940s and 1950s in Britain murder was very rare and a thing of horror.
Suchet surpasses both Ustinov and Finney. Three new 2-hour episodes are currently being shown on ITV. 'Cat among the pigeons' which was aired last night has a fairly silly plot, but just watching Suchet's performance and soaking in the period brought me a great deal of pleasure.
However, it reminded me of my childhood. Agatha Christie was banned from our house, not on grounds of taste, but because she was ajudged too frightening. Today we regard these films as light entertainment; when I was a child she was for adults only. People were murdered! How things have changed.
In the 1940s and 1950s in Britain murder was very rare and a thing of horror.
Friday, September 19, 2008
Mid-term blues
It is a constant rule that every ruler becomes unpopular in his or her mid-term. It was obviously true of Prime Minister Harold Wilson in 1968, and I tried to combine this with an anti-smoking message.
House
Since clearing the loft for the electrician to come I have been sorting through what I should keep and what I should throw away. I came across this sketch I made of the view from the bedroom window of our first apartment just after we were married.
Wednesday, September 17, 2008
Prolymphocytes
There has been quite a lot of discussion lately about prolymphocytes. A prolymphocyte is a lymphocyte that looks different down the microscope. It is larger than the average lymphocyte, the nucleus tends to be a bit eccentric in the cytoplasm (as in off-center not as in crazy). The nucleus has a single prominent nucleolus and the cytoplasm may stain a bit bluish. These are not blast cells; they are probably lymphocytes that have been activated, but not very much. There are a couple of types of leukemia that consist entirely of prolymphocytes (T-PLL and B-PLL) and I have written about them before here .
When prolymphocytes appear in the blood of patients with CLL, people get worried that the disease is transforming. If you follow the link you will find that this is usually not so. For one thing, prolymphocytes are often missed on the blood film if the spreading is not good enough or the staining poor. If you have trisomy 12 then to have 10-15% prolymphocytes is quite normal. They appear after you flu jab and if you have an infection. Furthermore, CLL does not transform into PLL as some of the older specialists thought. B-PLL is a quite separate (and very rare) disease.
Another important point is about calculating the absolute lymphocyte count. The prolymphocytes should be counted in with the lymphocytes (so should the atypical lymphocytes). I have been asked by worried patients about a change in their absolute lymphocyte count because the first lab did not include them and the second one did.
Calamities continue.
As if we didn't have enough problems my wife fell backwards out of the loft to land on her back ten feet below. Although concussed by the fall no bones seemed to be broken. However she was unable to weight bear on her right leg and her ribs seemed to be very bruised. She has been confined to bed.
Fortunately both my sons have been to help me clear out the loft in time for the builders to come and assess the job of re-insulating the loft, and putting in a new stairwell to make access safer. However, she was in so much pain by 1 am Tuesday morning that we had to call an ambulance to take her to hospital for an X-ray. There were no fractures, but they put her on stronger pain-killers and gave her a walking aid to enable her to get to the bathroom.
In the meantime I am learning how to be a housewife. I first attempted a casserole, which went very well, and encouraged, I thought I would make an apple crumble. I picked half a dozen apples from the tree, peeled and stewed them and then made up the topping with flour, sugar and butter. Because the oven was in use with the casserole, I had to use the top oven, which doubles as a grill. Somewhat confused on how one switches from one to the other, I ended up grilling the crumble instead of baking it. It immediately caught fire. Smoke began issuing from the grill chimney, and when I looked through the oven door I saw flames dancing on the surface of my dish. I pulled it out and threw a cloth over it to extinguish the fire and then had to scrape the charred surface from the pudding. I quickly manufactured some more crumble (quantities by rule of eye this time rather than exact measurements on the scales -and I threw in some cinnamon) and it turned out an excellent pudding.
Since then I have managed fish and chips and a cheese pie, not to mention runner beans, mushrooms and fried tomatoes. This evening I will attempt bangers and mash.
But the cooking is only half of it. I have been vacuuming, I've done three loads of washing and I've cleaned the toilets. Truly, a woman's work is never done.
Fortunately both my sons have been to help me clear out the loft in time for the builders to come and assess the job of re-insulating the loft, and putting in a new stairwell to make access safer. However, she was in so much pain by 1 am Tuesday morning that we had to call an ambulance to take her to hospital for an X-ray. There were no fractures, but they put her on stronger pain-killers and gave her a walking aid to enable her to get to the bathroom.
In the meantime I am learning how to be a housewife. I first attempted a casserole, which went very well, and encouraged, I thought I would make an apple crumble. I picked half a dozen apples from the tree, peeled and stewed them and then made up the topping with flour, sugar and butter. Because the oven was in use with the casserole, I had to use the top oven, which doubles as a grill. Somewhat confused on how one switches from one to the other, I ended up grilling the crumble instead of baking it. It immediately caught fire. Smoke began issuing from the grill chimney, and when I looked through the oven door I saw flames dancing on the surface of my dish. I pulled it out and threw a cloth over it to extinguish the fire and then had to scrape the charred surface from the pudding. I quickly manufactured some more crumble (quantities by rule of eye this time rather than exact measurements on the scales -and I threw in some cinnamon) and it turned out an excellent pudding.
Since then I have managed fish and chips and a cheese pie, not to mention runner beans, mushrooms and fried tomatoes. This evening I will attempt bangers and mash.
But the cooking is only half of it. I have been vacuuming, I've done three loads of washing and I've cleaned the toilets. Truly, a woman's work is never done.
Friday, September 12, 2008
Calamities
Not much blogging this week, but it's been a week of calamities. It began with a light bulb blowing in the bathroom. The light fitting there is pretty but old and very difficult to take apart to fit a new light bulb. After spending half an hour doing so and finally reassembling it, the other bulb blew. This was too much, so I contacted an electrician to come and replace it with a more user-friendly version.
When he eventually came he had bad news. He brought down from the attic a sample of the electrical wiring. Our attic/loft is insulated with very small polystyrene chips, and where the wiring had passed through them they had melted so that the wires were coated with a brittle sticky mess. "This is a house fire waiting to happen," he said. He was so concerned that he rushed back the next day to give us a quote for rewiring the house.
Well, we knew we had to have the house rewired. It's 30+ years since the wiring was looked at, and if you try and sell a house without an electrical safety certificate, the government prevents you. So he comes back and the first thing he says is, "You'll have to empty out the loft.
Our loft contains the gathered detritus of 41 years of marriage. Children's toys, unfinished jigsaw puzzles, discarded suitcases, wedding dresses, hundreds of books, '78' records, school reports, old photographs, VHS tapes and recorders, sleeping bags, unused pieces if furniture, old Christmas cards, musical instruments, prams and pushchairs and baby's cots, old radios, notes from every examination my daughter ever took, jeans to fit everybody from size 6 to 16, rubber boots, baseball caps from various holiday destinations, souvenirs, unwanted presents, presents we couldn't think who to give to, old carpets and vinyl floor coverings, odd bits of wood, last year's Christmas decorations, vinyl 33s and 45s, indoor TV aerials and boosters, broken tape recorders, SCART leads, old rolls of wallpaper, disused galvanized water tanks, dozens of pairs of women's shoes, old kettles and toasters, crockery and cutlery, 5 guitars, inflatable mattresses, and old bedclothes.
We began to remove it but where should we put it? Some was easily identifiable as fit only for the dump and I have taken five carloads over there. Some could go to Charity shops, and some to homeless depots. Nonetheless, some would have to be retained and this has been distributed through the house and garage. It was in transferring what was already in the garage into the garage loft that I came a cropper. The step ladder gave way while I was levering myself up into the loft and I was left hanging by my right shoulder. This has stretched my brachial plexus and left me with a numb thumb.
As a result we have decided to invest in proper loft ladders to gain access to both our lofts and moreover to replace that leaky, eighty-year old skylight, and while the loft is clear we will have the insulation removed and replaced and a new floor put down.
Then the flat roof over the bay window in out bedroom started leaking causing the ceiling paper to bulge until it eventually tore and a bucketfull or rain water fell on top of me.
Oh the joys of owing a house!
When he eventually came he had bad news. He brought down from the attic a sample of the electrical wiring. Our attic/loft is insulated with very small polystyrene chips, and where the wiring had passed through them they had melted so that the wires were coated with a brittle sticky mess. "This is a house fire waiting to happen," he said. He was so concerned that he rushed back the next day to give us a quote for rewiring the house.
Well, we knew we had to have the house rewired. It's 30+ years since the wiring was looked at, and if you try and sell a house without an electrical safety certificate, the government prevents you. So he comes back and the first thing he says is, "You'll have to empty out the loft.
Our loft contains the gathered detritus of 41 years of marriage. Children's toys, unfinished jigsaw puzzles, discarded suitcases, wedding dresses, hundreds of books, '78' records, school reports, old photographs, VHS tapes and recorders, sleeping bags, unused pieces if furniture, old Christmas cards, musical instruments, prams and pushchairs and baby's cots, old radios, notes from every examination my daughter ever took, jeans to fit everybody from size 6 to 16, rubber boots, baseball caps from various holiday destinations, souvenirs, unwanted presents, presents we couldn't think who to give to, old carpets and vinyl floor coverings, odd bits of wood, last year's Christmas decorations, vinyl 33s and 45s, indoor TV aerials and boosters, broken tape recorders, SCART leads, old rolls of wallpaper, disused galvanized water tanks, dozens of pairs of women's shoes, old kettles and toasters, crockery and cutlery, 5 guitars, inflatable mattresses, and old bedclothes.
We began to remove it but where should we put it? Some was easily identifiable as fit only for the dump and I have taken five carloads over there. Some could go to Charity shops, and some to homeless depots. Nonetheless, some would have to be retained and this has been distributed through the house and garage. It was in transferring what was already in the garage into the garage loft that I came a cropper. The step ladder gave way while I was levering myself up into the loft and I was left hanging by my right shoulder. This has stretched my brachial plexus and left me with a numb thumb.
As a result we have decided to invest in proper loft ladders to gain access to both our lofts and moreover to replace that leaky, eighty-year old skylight, and while the loft is clear we will have the insulation removed and replaced and a new floor put down.
Then the flat roof over the bay window in out bedroom started leaking causing the ceiling paper to bulge until it eventually tore and a bucketfull or rain water fell on top of me.
Oh the joys of owing a house!
Monday, September 08, 2008
Non Hemic Autoimmunity in CLL
Although everyone is familiar with the autoimmune complications of chronic lymphocytic leukemia (CLL), a clear understanding of their pathogenesis is still wanting. More than twenty years ago Hamblin et al established that the overwhelming majority of such complications involved the formed elements of the blood, and especially red cells[1]. Autoimmune haemolytic anemia (AIHA) occurs in around 15% of patients with CLL, and, conversely, CLL causes 14% of all cases of AIHA[2]. More recently workers in Aberdeen have produced a plausible hypothesis to explain this, suggesting that CLL cells act as atypical antigen presenting cells for the Rh protein[3, 4]. Two other hypotheses have been put forward to explain the high prevalence of autoimmunity in CLL.
One possibility is that the immunoglobulin produced by the CLL has autoantibody activity. However, most cases of CLL produce very little immunoglobulin. It is possible that this mechanism applies in the very rare cases of cold agglutination syndrome and acquired angioedema[5], but most autoimmune complications result from the immune response to the tumor rather than from the tumor itself.
The strikingly high incidence of AIHA after treatment with fludarabine, a drug known for its suppression of T lymphocytes, led Myint et al to suggest that suppression of regulatory T cells might be responsible for AIHA in CLL[6] and it was subsequently confirmed that regulatory T cells are increased in the peripheral blood in CLL especially in advanced disease, but they are exquisitely sensitive to treatment with fludarabine[7]. Regulatory T cells were recognized from the study of mice thymectomized at three days of age, which developed various autoimmune diseases when reconstituted with cells from syngeneic spleen or bone marrow[8]. In humans they can be recognized by their CD4+, CD25+, FoxP3+ immunophenotype. In CLL they are thought to play a part in both the global immunodeficiency[9] and in the suppression of any immune attack on the leukemia[10].
Non-hemic autoimmunity in CLL is very rare, but at least two syndromes, glomerulonephritis and paraneoplastic pemphigus, have been clearly identified[2]. Interestingly, both have been triggered by treatment with fludarabine[11-17]. In this issue of Leukemia Research Qian et al[18] describe a patient with CLL who developed both ANCA-positive glomerulonephritis and paraneoplastic pemphigus after treatment with the combination of fludarabine, cyclophosphamide and mitoxantrone. These conditions have not been seen together previously in a single patient. Subsequently, after treatment with prednisolone, cyclophosphamide and rituximab the patient developed neurological symptoms with dizziness and weakness in his left arm and leg without changes in tendon reflexes, and later status epilepticus and coma which was eventually fatal. Magnetic resonance imaging revealed a lesion in the right parietal lobe which could not be identified further.
The authors have attributed the cerebral lesion to a third paraneoplastic syndrome, namely paraneoplastic neurological syndrome (PNS), and have suggested a vasculitic mechanism on rather indirect evidence. PNS has recently been defined to distinguish it from neurological syndromes that are merely coincidental with a cancer[19]. Since the abnormality in this patient is not a classical neurological syndrome (such as Lambert-Eaton syndrome, Guillain-Barré syndrome or stiff person syndrome etc), did not occur within two years of the diagnosis of cancer and onconeural antibodies were not detected, this case does not meet the diagnostic criteria of PNS. Although described in association with a wide variety of neoplastic conditions, PNS has not previously been described in association with CLL. Apart from those attributable to Herpes Zoster infections, neurological syndromes are indeed rare in CLL and most have been attributed to leukemic infiltration of the CNS[20] or progressive multifocal leukoencephalopathy[21-23].
References
1. Hamblin TJ, Oscier DG, Young BJ. Autoimmunity in chronic lymphocytic leukaemia. Journal of Clinical Pathology 1986; 39:713 716.
2. Hamblin TJ, Autoimmune complications of chronic lymphocytic leukemia. Seminars in Oncology. 2006; 33:230-239.
3. Barker RN, Hall AM, Standen GR, Jones J, Elson CJ. Identification of T-cell epitopes on the Rhesus polypeptides in autoimmune hemolytic anemia. Blood. 1997; 90:2701-2715.
4. Hall AM, Vickers MA, McLeod E, Barker RN. Rh autoantigen presentation to helper T cells in chronic lymphocytic leukemia by malignant B cells. Blood. 2005; 105:2007-2015.
5. Hamblin TJ. Autoimmune disease and its management in chronic lymphocytic leukemia In: Chronic Lymphoid Leukemias ed BD Cheson 2nd edition New York : Marcel Dekker; 2001, pp. 435-458.
6. Myint H, Copplestone JA, Orchard J et al. Fludarabine-related AIHA in patients with chronic lymphocytic leukaemia. Br J Haematol 1995; 91:341-344.
7. Beyer M, Kochanek M, Darabi-K et al. Reduced frequencies and suppressive function of CD4+ CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood 2005; 106:2018-2025.
8. Shevak EM. Regulatory T cells in autoimmunity. Annual Reviews of Immunology 2000; 18:423-449.
9. Giannopoulos K, Schmitt M, Kowal M et al. Characterization of regulatory T cells in patients with B-cell chronic lymphocytic leukemia. Oncol Rep. 2008; 20:677-682.
10. Hus J, Schmitt M, Tabarkiewicz J et al. Vaccination of B-CLL patients with autologous dendritic cells can change the frequency of leukemia antigen-specific CD8+ T cells as well as CD4+CD25+FocP3+ regulatory T cells toward an antileukemia response. Leukemia 2008; 22:1007-1017.
11. Bazarbachi A, Bachelez H, Dehen L, Delmer A, Zittoun R, Dubertret L. Lethal paraneoplastic pemphigus following treatment of chronic lymphocytic leukaemia with fludarabine Annals of Oncology 1995;6:730-731.
12. Braess J, Reich K, Willert S, Strutz F, Neumann C, Hiddemann W, Wormann B. Mucocutaneous autoimmune syndrome following fludarabine therapy for low-grade non-Hodgkin's lymphoma of B-cell type (B-NHL). Annals of Hematology 1997;75:227-230.
13. Gooplu C, Littlewood TJ, Frith P et al. Paraneoplastic pemphigus - an association with fludarabine. Br J Dermatol 2001;144:1102-1104
14. Powell AM, Albert S, Oyama N, Sakuma-Oyama Y, Bhogal B, Black MM. Paraneoplastic pemphigus secondary to fludarabine evolving into unusual oral pemphigus vegetans. J Eur Acad Dermatol Venereol. 2004;18:360-364
15. Yildiz O, Ozguroglu M, Yanmaz MT et al Paraneoplastic pemphigus associated with fludarabine use. Med Oncol. 2007; 24:115-118
16. Macheta MP, Parapia LA, Gouldesbrough DR Renal failure in a patient with chronic lymphocytic leukaemia treated with fludarabine Journal of Clinical Pathology 1995;48:181-182.
17. Tisler A, Pierratos A, Lipton JH. Crescentic glomerulonephritis with p-ANCA positivity in fludarabine-treated chronic lymphocytic leukaemia. Nephrology Dialysis Transplantation 1996;11:2306-2308.
18. Qian SX, Li JY, Hong M, Xu W, Qiu HX. Nonhematological autoimmunity (glomerulosclerosis, paraneoplastic pehigus and paraneoplastic neurological syndrome) in a patient with chronic lymphocytic leukemia: Diagnosis, prognosis and management. Leukemia Research 2008………
19. Graus F, Delattre JY, Antoine JC et al. Recpmmended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 2004; 75:1135-1140.
20. Bojsen-Mǿller M, Nielsen JL. CNS involvement in leukemia. An autopsy study of 100 consecutive patients. Acta Pathol Microbiol Immunol Scand [A} 1983; 91:209-216.
21. Shafran B, Roke ME, Barr RM, Caircross JG. Contrast enhancing lesions in progressive multifocal leukoencephalopathy: a clinicopathological correlation. Can J Neurol Sci 1987; 14:600-602.
22. Cid J, Revilla M, Cervera A et al. Progressive multifocal leukoencephalopathy following oral fludarabine treatment of chronic lymphocytic leukemia. Ann Hematol 200; 79:392-395.
23. Saumoy M, Castells G, Escoda L, Mares R, Richart C, Ugarriza A. Progressive multifocal leukoencephalopathy in chronic lymphocytic leukemia after treatment with fludarabine. Leuk Lymphoma 2002; 43:433-436.
One possibility is that the immunoglobulin produced by the CLL has autoantibody activity. However, most cases of CLL produce very little immunoglobulin. It is possible that this mechanism applies in the very rare cases of cold agglutination syndrome and acquired angioedema[5], but most autoimmune complications result from the immune response to the tumor rather than from the tumor itself.
The strikingly high incidence of AIHA after treatment with fludarabine, a drug known for its suppression of T lymphocytes, led Myint et al to suggest that suppression of regulatory T cells might be responsible for AIHA in CLL[6] and it was subsequently confirmed that regulatory T cells are increased in the peripheral blood in CLL especially in advanced disease, but they are exquisitely sensitive to treatment with fludarabine[7]. Regulatory T cells were recognized from the study of mice thymectomized at three days of age, which developed various autoimmune diseases when reconstituted with cells from syngeneic spleen or bone marrow[8]. In humans they can be recognized by their CD4+, CD25+, FoxP3+ immunophenotype. In CLL they are thought to play a part in both the global immunodeficiency[9] and in the suppression of any immune attack on the leukemia[10].
Non-hemic autoimmunity in CLL is very rare, but at least two syndromes, glomerulonephritis and paraneoplastic pemphigus, have been clearly identified[2]. Interestingly, both have been triggered by treatment with fludarabine[11-17]. In this issue of Leukemia Research Qian et al[18] describe a patient with CLL who developed both ANCA-positive glomerulonephritis and paraneoplastic pemphigus after treatment with the combination of fludarabine, cyclophosphamide and mitoxantrone. These conditions have not been seen together previously in a single patient. Subsequently, after treatment with prednisolone, cyclophosphamide and rituximab the patient developed neurological symptoms with dizziness and weakness in his left arm and leg without changes in tendon reflexes, and later status epilepticus and coma which was eventually fatal. Magnetic resonance imaging revealed a lesion in the right parietal lobe which could not be identified further.
The authors have attributed the cerebral lesion to a third paraneoplastic syndrome, namely paraneoplastic neurological syndrome (PNS), and have suggested a vasculitic mechanism on rather indirect evidence. PNS has recently been defined to distinguish it from neurological syndromes that are merely coincidental with a cancer[19]. Since the abnormality in this patient is not a classical neurological syndrome (such as Lambert-Eaton syndrome, Guillain-Barré syndrome or stiff person syndrome etc), did not occur within two years of the diagnosis of cancer and onconeural antibodies were not detected, this case does not meet the diagnostic criteria of PNS. Although described in association with a wide variety of neoplastic conditions, PNS has not previously been described in association with CLL. Apart from those attributable to Herpes Zoster infections, neurological syndromes are indeed rare in CLL and most have been attributed to leukemic infiltration of the CNS[20] or progressive multifocal leukoencephalopathy[21-23].
References
1. Hamblin TJ, Oscier DG, Young BJ. Autoimmunity in chronic lymphocytic leukaemia. Journal of Clinical Pathology 1986; 39:713 716.
2. Hamblin TJ, Autoimmune complications of chronic lymphocytic leukemia. Seminars in Oncology. 2006; 33:230-239.
3. Barker RN, Hall AM, Standen GR, Jones J, Elson CJ. Identification of T-cell epitopes on the Rhesus polypeptides in autoimmune hemolytic anemia. Blood. 1997; 90:2701-2715.
4. Hall AM, Vickers MA, McLeod E, Barker RN. Rh autoantigen presentation to helper T cells in chronic lymphocytic leukemia by malignant B cells. Blood. 2005; 105:2007-2015.
5. Hamblin TJ. Autoimmune disease and its management in chronic lymphocytic leukemia In: Chronic Lymphoid Leukemias ed BD Cheson 2nd edition New York : Marcel Dekker; 2001, pp. 435-458.
6. Myint H, Copplestone JA, Orchard J et al. Fludarabine-related AIHA in patients with chronic lymphocytic leukaemia. Br J Haematol 1995; 91:341-344.
7. Beyer M, Kochanek M, Darabi-K et al. Reduced frequencies and suppressive function of CD4+ CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood 2005; 106:2018-2025.
8. Shevak EM. Regulatory T cells in autoimmunity. Annual Reviews of Immunology 2000; 18:423-449.
9. Giannopoulos K, Schmitt M, Kowal M et al. Characterization of regulatory T cells in patients with B-cell chronic lymphocytic leukemia. Oncol Rep. 2008; 20:677-682.
10. Hus J, Schmitt M, Tabarkiewicz J et al. Vaccination of B-CLL patients with autologous dendritic cells can change the frequency of leukemia antigen-specific CD8+ T cells as well as CD4+CD25+FocP3+ regulatory T cells toward an antileukemia response. Leukemia 2008; 22:1007-1017.
11. Bazarbachi A, Bachelez H, Dehen L, Delmer A, Zittoun R, Dubertret L. Lethal paraneoplastic pemphigus following treatment of chronic lymphocytic leukaemia with fludarabine Annals of Oncology 1995;6:730-731.
12. Braess J, Reich K, Willert S, Strutz F, Neumann C, Hiddemann W, Wormann B. Mucocutaneous autoimmune syndrome following fludarabine therapy for low-grade non-Hodgkin's lymphoma of B-cell type (B-NHL). Annals of Hematology 1997;75:227-230.
13. Gooplu C, Littlewood TJ, Frith P et al. Paraneoplastic pemphigus - an association with fludarabine. Br J Dermatol 2001;144:1102-1104
14. Powell AM, Albert S, Oyama N, Sakuma-Oyama Y, Bhogal B, Black MM. Paraneoplastic pemphigus secondary to fludarabine evolving into unusual oral pemphigus vegetans. J Eur Acad Dermatol Venereol. 2004;18:360-364
15. Yildiz O, Ozguroglu M, Yanmaz MT et al Paraneoplastic pemphigus associated with fludarabine use. Med Oncol. 2007; 24:115-118
16. Macheta MP, Parapia LA, Gouldesbrough DR Renal failure in a patient with chronic lymphocytic leukaemia treated with fludarabine Journal of Clinical Pathology 1995;48:181-182.
17. Tisler A, Pierratos A, Lipton JH. Crescentic glomerulonephritis with p-ANCA positivity in fludarabine-treated chronic lymphocytic leukaemia. Nephrology Dialysis Transplantation 1996;11:2306-2308.
18. Qian SX, Li JY, Hong M, Xu W, Qiu HX. Nonhematological autoimmunity (glomerulosclerosis, paraneoplastic pehigus and paraneoplastic neurological syndrome) in a patient with chronic lymphocytic leukemia: Diagnosis, prognosis and management. Leukemia Research 2008………
19. Graus F, Delattre JY, Antoine JC et al. Recpmmended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry 2004; 75:1135-1140.
20. Bojsen-Mǿller M, Nielsen JL. CNS involvement in leukemia. An autopsy study of 100 consecutive patients. Acta Pathol Microbiol Immunol Scand [A} 1983; 91:209-216.
21. Shafran B, Roke ME, Barr RM, Caircross JG. Contrast enhancing lesions in progressive multifocal leukoencephalopathy: a clinicopathological correlation. Can J Neurol Sci 1987; 14:600-602.
22. Cid J, Revilla M, Cervera A et al. Progressive multifocal leukoencephalopathy following oral fludarabine treatment of chronic lymphocytic leukemia. Ann Hematol 200; 79:392-395.
23. Saumoy M, Castells G, Escoda L, Mares R, Richart C, Ugarriza A. Progressive multifocal leukoencephalopathy in chronic lymphocytic leukemia after treatment with fludarabine. Leuk Lymphoma 2002; 43:433-436.
Sunday, September 07, 2008
Rituxin and high white counts
Many people are confused over why some doctors recommend reducing the white count before starting rituximab. Remember that rituximab was originally introduced for the treatment of non-Hodgkin's lymphoma, a disease mainly confined to the lymph nodes in which substantial disease in the blood is rare. Even in this situation, though first pass reactions to rituximab infusions are common. usually they don't recur on second and subsequent infusions.
The usual reaction is of fever and shivering attacks, although some people also get rashes and swelling of the face and tongue. It is important to stress that these reactions are not allergic reactions. Although they often resemble anaphylaxis, they are different. Generally they can be aborted by slowing the drip down or stopping it for a while and then restarting it. Because you have had a reaction once, it doesn't mean that you are likely to have one next time as with allergy. In fact most people only have a reaction with their first experience of the drug.
Nor is this tumor lysis syndrome, which is caused by a destruction of the tumor that is so rapid that the body does not have time to clear the waste products from the destruction. Tumor lysis syndrome is most unlikely to be produced by rituximab and is anyway quite different. The problems with tumor lysis involve trying to get rid of excess potassium and uric acid quickly enough before the kidneys are damaged and the heart sent into an arrhythmia. The normal approach is to give plenty of fluids and to use allopurinol to prevent the formation of uric acid.
Still less does rituximab cause cytokine storm or cytokine release syndrome. This was what was responsible for the Northwick Park incident where six volunteers experienced severe problems including collapse, low blood pressure, shivering attacks and kidney failure after being given the Tegenero anti-CD28 antibody. It is also seen in kidney cancer patients who are treated with massive doses of interleukin-2.
No, rituximab reactions are anaphylactoid reactions, so-called because they resemble anaphylaxis, but they have a quite different cause. When antibody reacts with its antigen - eg rituximab reacts with the CD20 on the surface of the tumor cell - it attracts a protein known as complement. Actually complement is not a single protein but a series of more than a dozen proteins. They operate as a cascade - activation of one protein activates the next in the chain and so on down the line. If the chain is completed as far as C9 complement punches a hole in the cell to kill it, but often the chain is incomplete and the activation results in the deposition of C3 on the surface of the cells, which has the effect of making the tumor cell more appetizing to the 'big eater' cells (or macrophages). When the complement components are activated bits of the proteins break off and are released into the fluid around the cell. Some of these broken off bits have activities of their own. In particular, C3a and C5a are anaphylactoids that cause fever, shivering attacks and low blood pressure. If they end up in the fluid around the cells in the lymph nodes that one thing, but if they end up in the fluid surrounding the cells in the blood the effect is much more severe.
That's why most doctors are wary of using rituximab if the white count is more than 50K. So sometimes FC is given on the first course and FCR on the second and subsequent course. On the other hand, Ron Taylor has demonstrated that a very small dose - perhaps as little as 20 mg - of rituximab is all that is needed to clear the white cells from the circulation, and it does so without a reaction. It has yet to be shown that small doses like this are sufficient to treat the disease elsewhere in the body, so I prefer the Kanti Rai approach to this problem, namely to give 20% of the rituximab fairly slowly on day 1, and the remainder of the dose on day 2.
The usual reaction is of fever and shivering attacks, although some people also get rashes and swelling of the face and tongue. It is important to stress that these reactions are not allergic reactions. Although they often resemble anaphylaxis, they are different. Generally they can be aborted by slowing the drip down or stopping it for a while and then restarting it. Because you have had a reaction once, it doesn't mean that you are likely to have one next time as with allergy. In fact most people only have a reaction with their first experience of the drug.
Nor is this tumor lysis syndrome, which is caused by a destruction of the tumor that is so rapid that the body does not have time to clear the waste products from the destruction. Tumor lysis syndrome is most unlikely to be produced by rituximab and is anyway quite different. The problems with tumor lysis involve trying to get rid of excess potassium and uric acid quickly enough before the kidneys are damaged and the heart sent into an arrhythmia. The normal approach is to give plenty of fluids and to use allopurinol to prevent the formation of uric acid.
Still less does rituximab cause cytokine storm or cytokine release syndrome. This was what was responsible for the Northwick Park incident where six volunteers experienced severe problems including collapse, low blood pressure, shivering attacks and kidney failure after being given the Tegenero anti-CD28 antibody. It is also seen in kidney cancer patients who are treated with massive doses of interleukin-2.
No, rituximab reactions are anaphylactoid reactions, so-called because they resemble anaphylaxis, but they have a quite different cause. When antibody reacts with its antigen - eg rituximab reacts with the CD20 on the surface of the tumor cell - it attracts a protein known as complement. Actually complement is not a single protein but a series of more than a dozen proteins. They operate as a cascade - activation of one protein activates the next in the chain and so on down the line. If the chain is completed as far as C9 complement punches a hole in the cell to kill it, but often the chain is incomplete and the activation results in the deposition of C3 on the surface of the cells, which has the effect of making the tumor cell more appetizing to the 'big eater' cells (or macrophages). When the complement components are activated bits of the proteins break off and are released into the fluid around the cell. Some of these broken off bits have activities of their own. In particular, C3a and C5a are anaphylactoids that cause fever, shivering attacks and low blood pressure. If they end up in the fluid around the cells in the lymph nodes that one thing, but if they end up in the fluid surrounding the cells in the blood the effect is much more severe.
That's why most doctors are wary of using rituximab if the white count is more than 50K. So sometimes FC is given on the first course and FCR on the second and subsequent course. On the other hand, Ron Taylor has demonstrated that a very small dose - perhaps as little as 20 mg - of rituximab is all that is needed to clear the white cells from the circulation, and it does so without a reaction. It has yet to be shown that small doses like this are sufficient to treat the disease elsewhere in the body, so I prefer the Kanti Rai approach to this problem, namely to give 20% of the rituximab fairly slowly on day 1, and the remainder of the dose on day 2.
Wednesday, September 03, 2008
Palin
Even though everyone in the UK will be affected by the American election, we don't get to vote in it. That is probably a good thing because no-one over here understands American politics, and what we are watching is not designed to capture the European vote. That Obama's campaign was to a degree so directed may prove to have been an error. Nevertheless, comment is free and here is my two-penneth on what I see going on.
It was a masterstroke of timing to diminish the attention that was directed at the Democratic Convention by announcing such an unusual VP candidate. It's an unusual name - she is no relative of Michael, but the word association cannot do her anything but good. Didn't he have a song about lumberjacks?
If you go to this site you will find a picture of Sarah Palin in a stars and stripes bikini toting a machine gun, labelled "Trailer Trash never looked so good". Scroll down the comments and you will find the two pictures that this image has been Photoshopped from. I have written before about not believing what you read or even what you see. Pictures can so easily be faked these days. However, timely reminder that it is, I wanted to think about the motives of those posting it, and the motives behind McCain's choice.
Of course, there will be some for whom the image of a bikini-clad doll with a gun will have the effect of reinforcing their vote for McCain, but they were always going to vote for the old war hero anyway - if they are sober enough to remember to. The purpose of the image, though, was to diminish Palin in the eyes of women. Obama has to convince Hilary supporters to vote for him. McCain has to spoil that. Hilary supporters are not a single constituency. There are the hard-line feminists and Palin will be anathema to them, just as Margaret Thatcher was. Then there is the Spanish-speaking constituency. George W had some appeal for these, speaking Spanish himself, but I guess that Palin adds nothing to that ticket.
Then there is the female blue collar vote. Obama managed to antagonise that in the Primary campaign, but despite Hilary's speech at the convention, there will be a lot of her supporters willing Obama to fail this time in order to give Hilary a chance in 2012. Some of these would vote for Palin just because she is a woman, but Palin does have blue-collar credentials. She has five kids. That is the lot of a lot of working class women. She has a daughter who has gone off the rails and got pregnant - far from diminishing her in the eyes of women, they will see this as one of the things that the ordinary woman has to put up with. She has a child with Down syndrome. If she were part of the Washington crowd she would undoubtedly have had a quiet abortion. Many working class women would not consider that - either for financial or religious reasons. Having a handicapped child and coping marks her out as a role model.
Here in Europe and amongst the liberal coastal elite in America, Palin exhibits traits that are horrifying. She is an Evangelical - she attends an Assemblies of God church and at least over here that is seen a a way out type of evangelical (don't they speak in tongues?). She is a Creationist. She is against abortion. She doesn't believe in global warming. She is against protecting Polar Bears. She is in favor of guns. Her husband works for the oil industry.
This is where Europeans don't understand Americans. Whereas in Europe evangelicals comprise no more than 5% of voters, in America they are a much larger constituency and this constituency is against abortion and is largely Creationist. The Catholic Biden, on the other hand will have his church against him if he pleads a woman's right to choose. In the UK the BBC assumes that the world is warming up because of human activity and has brainwashed the majority of voters; there are many more doubters in America. As for Polar Bears, their status as a protected species is a consequence of a Green myth. Their numbers are not diminishing and Al Gore's picture of mother and child stranded on an ice flow was pure propaganda; they had only short swim to the solid ice.
There may be more to discover about her and certainly the Democrats will be digging deeply. She will not be vulnerable to charges of inexperience lest the charge rebounds on Obama. If she is found to be corrupt it will hurt McCain because part of her attraction lies in her anti-corruption stance.
Whether any of this matters only time will tell, but it sure beats those boring speeches.
It was a masterstroke of timing to diminish the attention that was directed at the Democratic Convention by announcing such an unusual VP candidate. It's an unusual name - she is no relative of Michael, but the word association cannot do her anything but good. Didn't he have a song about lumberjacks?
If you go to this site you will find a picture of Sarah Palin in a stars and stripes bikini toting a machine gun, labelled "Trailer Trash never looked so good". Scroll down the comments and you will find the two pictures that this image has been Photoshopped from. I have written before about not believing what you read or even what you see. Pictures can so easily be faked these days. However, timely reminder that it is, I wanted to think about the motives of those posting it, and the motives behind McCain's choice.
Of course, there will be some for whom the image of a bikini-clad doll with a gun will have the effect of reinforcing their vote for McCain, but they were always going to vote for the old war hero anyway - if they are sober enough to remember to. The purpose of the image, though, was to diminish Palin in the eyes of women. Obama has to convince Hilary supporters to vote for him. McCain has to spoil that. Hilary supporters are not a single constituency. There are the hard-line feminists and Palin will be anathema to them, just as Margaret Thatcher was. Then there is the Spanish-speaking constituency. George W had some appeal for these, speaking Spanish himself, but I guess that Palin adds nothing to that ticket.
Then there is the female blue collar vote. Obama managed to antagonise that in the Primary campaign, but despite Hilary's speech at the convention, there will be a lot of her supporters willing Obama to fail this time in order to give Hilary a chance in 2012. Some of these would vote for Palin just because she is a woman, but Palin does have blue-collar credentials. She has five kids. That is the lot of a lot of working class women. She has a daughter who has gone off the rails and got pregnant - far from diminishing her in the eyes of women, they will see this as one of the things that the ordinary woman has to put up with. She has a child with Down syndrome. If she were part of the Washington crowd she would undoubtedly have had a quiet abortion. Many working class women would not consider that - either for financial or religious reasons. Having a handicapped child and coping marks her out as a role model.
Here in Europe and amongst the liberal coastal elite in America, Palin exhibits traits that are horrifying. She is an Evangelical - she attends an Assemblies of God church and at least over here that is seen a a way out type of evangelical (don't they speak in tongues?). She is a Creationist. She is against abortion. She doesn't believe in global warming. She is against protecting Polar Bears. She is in favor of guns. Her husband works for the oil industry.
This is where Europeans don't understand Americans. Whereas in Europe evangelicals comprise no more than 5% of voters, in America they are a much larger constituency and this constituency is against abortion and is largely Creationist. The Catholic Biden, on the other hand will have his church against him if he pleads a woman's right to choose. In the UK the BBC assumes that the world is warming up because of human activity and has brainwashed the majority of voters; there are many more doubters in America. As for Polar Bears, their status as a protected species is a consequence of a Green myth. Their numbers are not diminishing and Al Gore's picture of mother and child stranded on an ice flow was pure propaganda; they had only short swim to the solid ice.
There may be more to discover about her and certainly the Democrats will be digging deeply. She will not be vulnerable to charges of inexperience lest the charge rebounds on Obama. If she is found to be corrupt it will hurt McCain because part of her attraction lies in her anti-corruption stance.
Whether any of this matters only time will tell, but it sure beats those boring speeches.
Monday, September 01, 2008
SNPs and CLL
This is the fourth time I have written about single nucleotide polymorphisms (SNPs) in relation to CLL and I do so in response to a paper from Richard Houlston and Daniel Catovsky about to be published in Nature Genetics. (Di Barnardo et al, Nature Genetics published on-line 31st August 2008; doi:10.1038/ng.219). SNPs are an extremely powerful tool to investigate genetic tendencies for diseases and that is what has been done here.
A SNP is where a single nucleotide (ie G, A, C or T) in the genetic code has been swapped from the usual pattern. The best known variation is in sickle cell anemia, where one change causes a major disease, but most changes have no apparent effect. However, many of these so-called silent changes can make a particular protein operate in a very slightly different way, and several such polymorphisms acting in a synergistic way might make a patient prone to a certain type of response. For this to become leukemia, might require the right sort of trigger, or even more than one trigger happening at the same time.
So far we really don’t have much evidence as to what causes CLL, even though we know it does occur in families. Last year workers at Ohio State did discover a polymorphism that occurred in one family which made the DAP kinase enzyme operate in an adverse way, but it clearly wasn’t the cause of other cases of familial CLL and only one sporadic case was found where the same polymorphism occurred.
This is a major study involving hundreds of patients with CLL. The large numbers make it possible to find SNPs that make a small difference. They found 7 different SNPs that did so.
The SNP that was most significantly different from the controls had an odds ratio of 1.59. Although this was very significant because of the very large number of samples, this is not a very large extra risk. People who have a particular one letter switch are one and a half times as likely to have CLL than the general population – the risk changes from 4 per 100,000 to 6 per 100,000. Unraveling this SNP leads us to MUM1, a gene that has shown up before in the related condition, myeloma, and is now known to be the same as IRF4 a gene necessary for the transformation of memory B cells to plasma cells. The presumption is that this SNP doesn't produce a nonsense protein but likely one that affects the smooth running of this process when stressed. So this abnormality is very believable as being involved in the genesis of CLL.
The second most significant difference leads us to the area near GRAMD1B which seems to have an unknown function, so that's not very helpful. The odds ratio for this is 1.45.
The third most significant leads to an area with no known genes. The fourth leads to SP140 which codes for a nuclear body protein present in lymphocytes. We know that interferon increases the number of nuclear bodies and that somehow they are involved in the response to viral infection. Since there is accumulating evidence that infections might be involved in triggering CLL and the CLL may result from an error in coping with infection, a link to SP140 is not out of the question.
The fifth strongest association leads very indirectly through linkage disequilibrium to BIM, a pro-apoptotic protein. Apoptosis is impaired in CLL cells, so, again, a link may well be there. The sixth strongest leads to PRKD2 which has been also linked to CLL.
The picture is emerging of a number of different polymorphisms that could disturb the way that B cells react to stimuli. I am surprised that there are not more.
I am afraid that we are no nearer to understanding why some people are more likely to get CLL than others, but it is clear that it a reaction between heredity and environment.
A SNP is where a single nucleotide (ie G, A, C or T) in the genetic code has been swapped from the usual pattern. The best known variation is in sickle cell anemia, where one change causes a major disease, but most changes have no apparent effect. However, many of these so-called silent changes can make a particular protein operate in a very slightly different way, and several such polymorphisms acting in a synergistic way might make a patient prone to a certain type of response. For this to become leukemia, might require the right sort of trigger, or even more than one trigger happening at the same time.
So far we really don’t have much evidence as to what causes CLL, even though we know it does occur in families. Last year workers at Ohio State did discover a polymorphism that occurred in one family which made the DAP kinase enzyme operate in an adverse way, but it clearly wasn’t the cause of other cases of familial CLL and only one sporadic case was found where the same polymorphism occurred.
This is a major study involving hundreds of patients with CLL. The large numbers make it possible to find SNPs that make a small difference. They found 7 different SNPs that did so.
The SNP that was most significantly different from the controls had an odds ratio of 1.59. Although this was very significant because of the very large number of samples, this is not a very large extra risk. People who have a particular one letter switch are one and a half times as likely to have CLL than the general population – the risk changes from 4 per 100,000 to 6 per 100,000. Unraveling this SNP leads us to MUM1, a gene that has shown up before in the related condition, myeloma, and is now known to be the same as IRF4 a gene necessary for the transformation of memory B cells to plasma cells. The presumption is that this SNP doesn't produce a nonsense protein but likely one that affects the smooth running of this process when stressed. So this abnormality is very believable as being involved in the genesis of CLL.
The second most significant difference leads us to the area near GRAMD1B which seems to have an unknown function, so that's not very helpful. The odds ratio for this is 1.45.
The third most significant leads to an area with no known genes. The fourth leads to SP140 which codes for a nuclear body protein present in lymphocytes. We know that interferon increases the number of nuclear bodies and that somehow they are involved in the response to viral infection. Since there is accumulating evidence that infections might be involved in triggering CLL and the CLL may result from an error in coping with infection, a link to SP140 is not out of the question.
The fifth strongest association leads very indirectly through linkage disequilibrium to BIM, a pro-apoptotic protein. Apoptosis is impaired in CLL cells, so, again, a link may well be there. The sixth strongest leads to PRKD2 which has been also linked to CLL.
The picture is emerging of a number of different polymorphisms that could disturb the way that B cells react to stimuli. I am surprised that there are not more.
I am afraid that we are no nearer to understanding why some people are more likely to get CLL than others, but it is clear that it a reaction between heredity and environment.