This was before John was put in prison
Imprisoned for their faith:
Biplob Marandi sentenced to one year in prison in Bangladesh for selling Christian books. Released on March 29th when charges thrown out. Praise the Lord!
Three leaders of the Shouwang church in Beijing are still held in custody after meeting in the open air to worship following the closing of their church building by the Chinese authorities.
Pastor Omar Gude Perez granted conditional release from his six and a half year prison sentence in Cuba. He was originally arrested on false charges of 'human trafficking and then convicted on trumped up charges of falsification of documents.
Irene Wiens, a Geman mother of four, has been jailed in Germany for keeping her children out of mandatory sex education classes.
Two new Christian believers were conditionally released from prison in Iran after their arrest for alleged national security crimes.
Qamar David was found dead in his prison cell in Pakistan. He had been imprisoned in 2002 following a charge of 'blasphemy' against Muhammed. His appeal was due to be heard.
This is a small snapshot of people who are or have been in prison for their faith around the world. Readers can get up-to-date information from here or here.
Saturday, May 21, 2011
Friday, May 20, 2011
Freedom of religion
I gather Barry O'Bama is about to visit Ireland. I wonder how his visit will compare with that of the Queen who completes a four day visit today? It's a hundred years since a British monarch has visited and by all accounts the visit was a great success.
Of course we have had nearly a century of troubles between the two largest islands of the British Isles, troubles of a largely religious nature. Although many of the early Irish nationalists were protestants what kept the two nations apart was the aggressive Roman Catholicism of Eamon Devalera. Ireland was a severely priest-ridden country which oppressed its people in an unacceptable way. No wonder the North wanted to have nothing to do with it. The pedophilia scandals that have since come out proves that they were right.
Freedom of religion is something we should all aspire to. No country that favors one particular religion over another is behaving honorably. I would favor the disestablishment of the Church of England. Disestablishment of the Anglican church in Wales certainly has not harmed the Christian church there. As for the so called Islamic states that forbid people from changing their religion, what are they afraid of? If Islam is so great who would want to depart from it?
Of course we have had nearly a century of troubles between the two largest islands of the British Isles, troubles of a largely religious nature. Although many of the early Irish nationalists were protestants what kept the two nations apart was the aggressive Roman Catholicism of Eamon Devalera. Ireland was a severely priest-ridden country which oppressed its people in an unacceptable way. No wonder the North wanted to have nothing to do with it. The pedophilia scandals that have since come out proves that they were right.
Freedom of religion is something we should all aspire to. No country that favors one particular religion over another is behaving honorably. I would favor the disestablishment of the Church of England. Disestablishment of the Anglican church in Wales certainly has not harmed the Christian church there. As for the so called Islamic states that forbid people from changing their religion, what are they afraid of? If Islam is so great who would want to depart from it?
John 3:23
Now John also was baptizing at Aenon near Salim, because there was plenty of water, and people were constantly coming to be baptized.
This is a proof text for Baptists. The point about there being plenty of water demonstrates that baptism was about immersion. When discussions were being held by King James with the Bishops and the Puritans about the 1611 translation of the Bible, one of the stipulations that James made was that Baptidso should not be translated, merely transliterated. He didn't want it realized that this was a technical term of the dyeing industry. You don't just sprinkle dye on cloth; you have to dip the cloth in the dye.
just think, John the Baptist might have been called the Big Dipper.
This is a proof text for Baptists. The point about there being plenty of water demonstrates that baptism was about immersion. When discussions were being held by King James with the Bishops and the Puritans about the 1611 translation of the Bible, one of the stipulations that James made was that Baptidso should not be translated, merely transliterated. He didn't want it realized that this was a technical term of the dyeing industry. You don't just sprinkle dye on cloth; you have to dip the cloth in the dye.
just think, John the Baptist might have been called the Big Dipper.
Do we need different trials for the elderly?
One of the bugbears of clinical trials is that they are usually conducted in younger patients. This is especially relevant in CLL where the median age of presentation is 70. The question has been asked as to whether we should have specific trials for older patients and would they give different answers to the trials that we have now.
There has been an attempt to answer these questions published in today's Lancet, not in CLL but in colorectal cancer in which I have more than a passing interest.
Colorectal cancer is the most common tumour worldwide and the second leading cause of cancer death in European countries and the USA, with about 800 000 new cases yearly. Although most clinical trials have not specifically excluded older or frail patients, as long as they have been suitable for the investigated treatment, there is always a strong selection process for patients who will be entered into clinical trials, especially if more toxic or somewhat innovative treatments are investigated. The median age at disease onset ranges between about 65–70 years and at death 72–77 years. 60% of deaths occur in patients older than 75 years and about 40% in those older than 80 years. The median age of a typical trial population for advanced disease is 60–65 years, with a maximum age mostly of 75 years. Retrospective analysis of randomised trials has shown that elderly patients have more or less the same response to chemotherapy as do younger patients.
The MRC FOCUS2 trial is the first randomised trial specifically tailored for this group of patients—elderly, frail, or both—in advanced colorectal cancer, thus representing a major part of the typical population of patients in routine practice. They compared single-agent fluorouracil with an upfront FOLFOX-type combination for overall and progression-free survival, and compared (in a factorial design) the value of the oral fluorouracil prodrug capecitabine with intravenous fluorouracil/levofolinate infusion.
The study showed that the upfront combination with oxaliplatin achieved a significantly increased response rate and made a limited, but not statistically significant, contribution to progression-free survival; overall survival was not improved. However, there was clear evidence of an overall benefit by addition of oxaliplatin defined by a composite index (overall treatment utility [OTU]) which had been developed and which was able to define the overall clinical utility depending on simple clinical variables that represent the biology of the disease and the patients' general characteristics, as well as the subjective opinion of the doctor and patient regarding the real value of the chosen treatment.
This trial supports what has been derived as “standard” from retrospective subgroup analyses of the older population of patients from previous trials, and the clinical experience which led to the definition of a treatment selection according to the treatment aim, the clinical disease characteristics, and co morbidity. Commonly, these patients are considered only for single-agent fluorouracil. FOCUS2 supports the addition of a new measure, OTU, to the selection process, and furthermore supports the use of upfront fluorouracil/oxaliplatin combination in this patient population—but in reduced doses and without capecitabine. Probably the other relevant result of FOCUS2 was that most patients do well with an a-priori dose reduction of fluorouracil or capecitabine and oxaliplatin, with a dose increase only if toxicity allowed (only 30% of the patients), indicating that an initial 20% dose reduction could be the standard of care for these patients.
As an aside I should say that after a few treatments that I found too toxic, they reduced my doses by 20%.
This trial needs confirmation. In addition, it does not represent the typical treatment scenario in most European countries. For example, in Europe many oncologists give fluorouracil/bevacizumab as first-line treatment, or at least as second-line treatment, and try at least to use oxaliplatin and irinotecan and (if the tumour is KRAS wild-type) cetuximab/panitumumab as salvage treatment, even in this population of patients with relatively poor outlook. This relative lack of use of salvage treatment, beyond the generally poorer prognosis in this elderly and frail population, might have relevantly contributed to the short overall survival of only 10–12 months in FOCUS2, rather than just the fact that the patients selected for inclusion were elderly, frail or both.
What this trial does is to emphasize that it is the biology of the disease that determines response and the robustness of the patient that determines whether he or she can survive the treatment. It is not a different disease in the elderly, but co-morbidities will affect the way the drugs are handled and regimes may need to be tailor-made for the elderly and infirm. For example we know that people with impaired renal function need a smaller dose of fludarabine for the same effect.
There has been an attempt to answer these questions published in today's Lancet, not in CLL but in colorectal cancer in which I have more than a passing interest.
Colorectal cancer is the most common tumour worldwide and the second leading cause of cancer death in European countries and the USA, with about 800 000 new cases yearly. Although most clinical trials have not specifically excluded older or frail patients, as long as they have been suitable for the investigated treatment, there is always a strong selection process for patients who will be entered into clinical trials, especially if more toxic or somewhat innovative treatments are investigated. The median age at disease onset ranges between about 65–70 years and at death 72–77 years. 60% of deaths occur in patients older than 75 years and about 40% in those older than 80 years. The median age of a typical trial population for advanced disease is 60–65 years, with a maximum age mostly of 75 years. Retrospective analysis of randomised trials has shown that elderly patients have more or less the same response to chemotherapy as do younger patients.
The MRC FOCUS2 trial is the first randomised trial specifically tailored for this group of patients—elderly, frail, or both—in advanced colorectal cancer, thus representing a major part of the typical population of patients in routine practice. They compared single-agent fluorouracil with an upfront FOLFOX-type combination for overall and progression-free survival, and compared (in a factorial design) the value of the oral fluorouracil prodrug capecitabine with intravenous fluorouracil/levofolinate infusion.
The study showed that the upfront combination with oxaliplatin achieved a significantly increased response rate and made a limited, but not statistically significant, contribution to progression-free survival; overall survival was not improved. However, there was clear evidence of an overall benefit by addition of oxaliplatin defined by a composite index (overall treatment utility [OTU]) which had been developed and which was able to define the overall clinical utility depending on simple clinical variables that represent the biology of the disease and the patients' general characteristics, as well as the subjective opinion of the doctor and patient regarding the real value of the chosen treatment.
This trial supports what has been derived as “standard” from retrospective subgroup analyses of the older population of patients from previous trials, and the clinical experience which led to the definition of a treatment selection according to the treatment aim, the clinical disease characteristics, and co morbidity. Commonly, these patients are considered only for single-agent fluorouracil. FOCUS2 supports the addition of a new measure, OTU, to the selection process, and furthermore supports the use of upfront fluorouracil/oxaliplatin combination in this patient population—but in reduced doses and without capecitabine. Probably the other relevant result of FOCUS2 was that most patients do well with an a-priori dose reduction of fluorouracil or capecitabine and oxaliplatin, with a dose increase only if toxicity allowed (only 30% of the patients), indicating that an initial 20% dose reduction could be the standard of care for these patients.
As an aside I should say that after a few treatments that I found too toxic, they reduced my doses by 20%.
This trial needs confirmation. In addition, it does not represent the typical treatment scenario in most European countries. For example, in Europe many oncologists give fluorouracil/bevacizumab as first-line treatment, or at least as second-line treatment, and try at least to use oxaliplatin and irinotecan and (if the tumour is KRAS wild-type) cetuximab/panitumumab as salvage treatment, even in this population of patients with relatively poor outlook. This relative lack of use of salvage treatment, beyond the generally poorer prognosis in this elderly and frail population, might have relevantly contributed to the short overall survival of only 10–12 months in FOCUS2, rather than just the fact that the patients selected for inclusion were elderly, frail or both.
What this trial does is to emphasize that it is the biology of the disease that determines response and the robustness of the patient that determines whether he or she can survive the treatment. It is not a different disease in the elderly, but co-morbidities will affect the way the drugs are handled and regimes may need to be tailor-made for the elderly and infirm. For example we know that people with impaired renal function need a smaller dose of fludarabine for the same effect.
Thursday, May 19, 2011
Aphorisms 14
God says, “If anyone is in Hell it will be over my dead body.” – Rico Tice
On Norman Vincent Peale Adlai Stevenson’s quipped: I find Paul appealing and Peale appalling.
“The free man owns himself. He can damage himself with either eating or drinking; he can ruin himself with gambling. If he does he is certainly a damn fool, and he might possibly be a damned soul; but if he may not, he is not a free man any more than a dog.” G. K. Chesterton
"Ninety percent of the politicians give the other ten percent a bad reputation." Henry Kissinger
Scepticism is integral to the scientific process, because most claims turn out to be false
“If today you can take a thing like xxxxxxxx and make it a crime to teach it in the public schools, tomorrow you can make it a crime to teach it in the private schools, and next year you can make it a crime to teach it in the church. At the next session you can ban books and the newspapers. Ignorance and fanaticism are ever busy… After a while it is the setting of man against man, creed against creed, until the flying banners and beating drums are marching backwards to the glorious ages of the 16th century when bigots lighted fagots to burn the man who dared to bring any intelligence and enlightenment and culture to the human mind.” - Clarence Darrow
DNA makes RNA, RNA makes protein, and proteins make us."
Francis Crick (1916-2004)
Nobody makes me; I take full responsibility.
I have always asked stupid questions and never been satisfied with easy answers. When I got to college I found this was called “Philosophy”. Keith Ward.
On Norman Vincent Peale Adlai Stevenson’s quipped: I find Paul appealing and Peale appalling.
“The free man owns himself. He can damage himself with either eating or drinking; he can ruin himself with gambling. If he does he is certainly a damn fool, and he might possibly be a damned soul; but if he may not, he is not a free man any more than a dog.” G. K. Chesterton
"Ninety percent of the politicians give the other ten percent a bad reputation." Henry Kissinger
Scepticism is integral to the scientific process, because most claims turn out to be false
“If today you can take a thing like xxxxxxxx and make it a crime to teach it in the public schools, tomorrow you can make it a crime to teach it in the private schools, and next year you can make it a crime to teach it in the church. At the next session you can ban books and the newspapers. Ignorance and fanaticism are ever busy… After a while it is the setting of man against man, creed against creed, until the flying banners and beating drums are marching backwards to the glorious ages of the 16th century when bigots lighted fagots to burn the man who dared to bring any intelligence and enlightenment and culture to the human mind.” - Clarence Darrow
DNA makes RNA, RNA makes protein, and proteins make us."
Francis Crick (1916-2004)
Nobody makes me; I take full responsibility.
I have always asked stupid questions and never been satisfied with easy answers. When I got to college I found this was called “Philosophy”. Keith Ward.
John 3:22
After this, Jesus and his disciples went out into the Judean, where he spent some time with them, and baptised.
It seems here to be clear that part of the ministry of Jesus was baptism. Was this the same baptism as John's or a different one? We Baptists hold a high view of baptism. We see it first as an act of symbolic cleansing. This is a fresh start; our old sins are washed away, but that would by itself be of no use because we would get dirty again. The Emperor Constantine only got baptized on his death bed so that he would commit no more sins afterwards. No for us Baptists there is a second symbol to do with total immersion. It is like going down into a grave and re-emerging newborn, symbolising the new birth of the Holy Spirit. With the Holy Spirit in control sin is constrained.
It seems here to be clear that part of the ministry of Jesus was baptism. Was this the same baptism as John's or a different one? We Baptists hold a high view of baptism. We see it first as an act of symbolic cleansing. This is a fresh start; our old sins are washed away, but that would by itself be of no use because we would get dirty again. The Emperor Constantine only got baptized on his death bed so that he would commit no more sins afterwards. No for us Baptists there is a second symbol to do with total immersion. It is like going down into a grave and re-emerging newborn, symbolising the new birth of the Holy Spirit. With the Holy Spirit in control sin is constrained.
Rape in the headlines.
Girl, 13, dragged into bushes and raped as she walked home from school in broad daylight
This was the headline in the Daily Mail today. On the same day the Justice Secretary was in trouble for appearing to suggest that some rapes are not as serious as others, and suggesting that some rapists might have their prison sentence halved if they pleaded guilty and so avoided the trauma of a court appearance for the victim. At the same time news comes of the resignation of the head of the IMF following his unhappy predicament in New York.
We continue to see very low conviction rates for alleged rapists and indeed prison sentences for those who falsely cry rape. There is controversy over anonymity for alleged rape victims but none for alleged rapists.
In my view sex outside marriage is wrong, but one has to admit that it goes on. Around 20% of married men admit to having had an affair. Hardly anyone would admit to being a virgin when they married these days. Sex outside marriage is not unlawful nor is adultery. The law has great difficulty in proving that sex is rape and not consensual. The circumstance being what they are it is usually one person's word against another's. Unless there is evidence of violence the case is likely to be unprovable.
This is not to diminish the offence, simply to say that is difficult to prove an allegation in a court of law. Furthermore, the gathering of evidence is distasteful and often in the past the police have not been helpful, though I believe it is better these days. Many women do not want to go through the trauma of evidence collection.
The Justice Secretary has a reputation for being forthright and no doubt he spoke out of turn. What he should have said is that we have a problem with rape. It is an offence that is difficult to prove in many cases and a crime supercharged with emotion. For a man to force himself on a woman is a very great crime which should always attract a prison sentence. Some forms of rape are even more severe than this and might be regarded as aggravated rape. For example a man who breaks into a house as a burglar and rapes or someone who attacks a young girl walking home from school are especially severe forms of rape and should attract the most severe sentences up to ad including life-imprisonment. Another, vile practice is to make the rape-victim relive the whole assault again in a court of law. Rapists who do this should expect to be treated by the judge more severely than those who plead guilty and spare the woman this sort of trauma.
Speaking for myself now and not for the Justice secretary, it is clear to me that because of its nature rape will always attract those who like to read about murky goings on, but it is also a feminist issue about centuries of oppression of women by men. From a man's point of view, I have no doubt that the greater openness about sex since the 1960s has left men in a more confused position than before and many men are really not sure how to interpret signals from women.
That being so, men must learn to live in the new circumstances. Best to save sex for marriage as God intended.
This was the headline in the Daily Mail today. On the same day the Justice Secretary was in trouble for appearing to suggest that some rapes are not as serious as others, and suggesting that some rapists might have their prison sentence halved if they pleaded guilty and so avoided the trauma of a court appearance for the victim. At the same time news comes of the resignation of the head of the IMF following his unhappy predicament in New York.
We continue to see very low conviction rates for alleged rapists and indeed prison sentences for those who falsely cry rape. There is controversy over anonymity for alleged rape victims but none for alleged rapists.
In my view sex outside marriage is wrong, but one has to admit that it goes on. Around 20% of married men admit to having had an affair. Hardly anyone would admit to being a virgin when they married these days. Sex outside marriage is not unlawful nor is adultery. The law has great difficulty in proving that sex is rape and not consensual. The circumstance being what they are it is usually one person's word against another's. Unless there is evidence of violence the case is likely to be unprovable.
This is not to diminish the offence, simply to say that is difficult to prove an allegation in a court of law. Furthermore, the gathering of evidence is distasteful and often in the past the police have not been helpful, though I believe it is better these days. Many women do not want to go through the trauma of evidence collection.
The Justice Secretary has a reputation for being forthright and no doubt he spoke out of turn. What he should have said is that we have a problem with rape. It is an offence that is difficult to prove in many cases and a crime supercharged with emotion. For a man to force himself on a woman is a very great crime which should always attract a prison sentence. Some forms of rape are even more severe than this and might be regarded as aggravated rape. For example a man who breaks into a house as a burglar and rapes or someone who attacks a young girl walking home from school are especially severe forms of rape and should attract the most severe sentences up to ad including life-imprisonment. Another, vile practice is to make the rape-victim relive the whole assault again in a court of law. Rapists who do this should expect to be treated by the judge more severely than those who plead guilty and spare the woman this sort of trauma.
Speaking for myself now and not for the Justice secretary, it is clear to me that because of its nature rape will always attract those who like to read about murky goings on, but it is also a feminist issue about centuries of oppression of women by men. From a man's point of view, I have no doubt that the greater openness about sex since the 1960s has left men in a more confused position than before and many men are really not sure how to interpret signals from women.
That being so, men must learn to live in the new circumstances. Best to save sex for marriage as God intended.
Wednesday, May 18, 2011
What is going on in the lymph nodes in CLL?
A couple of articles recently have described what is going on in the lymph nodes in CLL. I think it is pretty clear by now that the business end of CLL is in the lymph nodes and to a lesser extent the liver, spleen and bone marrow. Normally a lymph node is about the size of a split pea, so if you can feel them at all they are enormously enlarged. Most people with CLL don't have palpably enlarged lymph nodes or if they do, only one or two are enlarged. However, in some people the nodes are huge, bigger than a hen's egg, and this is generally an indication that treatment is indicated.
Lymph nodes are there to respond to infections. They are organs where B lymphocytes are brought into contact with the antigens that they have been designed for (every lymphocyte has a pre-designed pattern of immunoglobulin structure so that there is one for every antigen possible) and undergo a maturation process so that they can learn to produce the antibody that fits best to the antigen. This process is facilitated by the presence of T lymphocytes which help and control the maturation. Recognition of the driving antigen is through the BCR, a special arrangement of the lymphocyte's immunoglobulin molecule on the cell surface so that it can receive and transmit a signal through the cell's second messenger service. B lymphocytes leaving the lymph nodes are either memory cells that circulate, waiting to meet the infective agent again or turning into plasma cells which end up as antibody factories that reside mainly in the bone marrow.
In CLL this process has been circumvented. Instead of reactive follicles in the lymph nodes training the lymphocytes to make antibodies, there are what are known as pseudofollicular proliferation centers. These centers are geared up to make the B lymphocytes reproduce themselves and avoid death. Perhaps 30% of all CLL cases have a very restricted set of antibodies on their cell surfaces (so-called stereotyped BCRs) that seems to react with certain autoantigens that are exposed when cells enter apoptosis (programmed cell death). Most of these stereotyped BCRs comprise unmutated Ig and it is mainly the unmutated CLLs that produce proliferation center-laden lymph nodes.
Although the whole process of proliferation seems to be driven via the BCR it is not necessarily antigen dependent. It seems that inflammation can also be stimulatory, acting through what are known as Toll-like receptors (TLR). Stimulation of TLR by so called 'danger signals' sets in train events that keep CLL cells alive and makes them home in on lymph nodes. In any case many CLL cells express functional chemokine receptors CXCR3, CXCR4 and CXCR5. Within proliferation centers are many CD4+ T cells which express CD40L. These support the growth of CLL cells through CD40 ligation. Stromal cells and nurse-like cells interact with CLL cells to prevent apoptosis and the interaction of CD38 on the cell surface and its natural ligand CD31 also favors the twin effects of anti-apoptosis and proliferation. Cytokines such as IL-4 and chemokines like CXCL13/SDF-1 produced in proliferation centers promote the up-regulation of anti-apoptotic genes like BCL2, SURVIVIN and MCL1.
The whole effect can be summarized like this: First you need a BCR that will take messages and transmit them. This will usually,but not exclusively, be one with unmutated IgHV genes. Such CLL cells will circulate to the lymph nodes and may even be attracted there by chemokines responding to either antigenic signaling or TLR signaling. Once in the lymph node the presence of T helper cells has an effect on the CLL cell to keep it alive and cause it to divide. This effect is mediated through cell-to-cell contact and through cytokines and specific ligands. One of the effects is to up-regulate CD38. When we see CD38+ cells in the peripheral blood it is a sure sig that cell has recently visited a lymph node. Other stromal cells and nurse-like cells also participate in this dance, chuck in in their two-penneth into the cytokine soup.
So CLL cells survive and divide. and this proliferation is what is necessary for further genetic mistakes to be made, particularly ones that disable the TP53 pathway. This pathway is necessary to maintain the genetic integrity of the cell. Its function is to recognize genetic mistakes when they occur and to put the cell into stasis while a repair is made. If the cell is irreparable the TP53 is supposed to kill it off. It is a feature of cells in which the TP53 pathway is disabled that they accumulate further irreparable genetic damage and behave very wildly indeed. Clinically such disabling presages prolymphocytoid transformation or Richter's syndrome and in any case renders the cell unkillable by conventional cytotoxic drug combinations like FCR.
How can what's going on in the lymph nodes be stopped? Agents that specifically disable the CLL second messenger system, like CAL-101 and PCI32765, seem to be the best hope, but revlimid may also be useful. What the great danger is, is leaving the patient too long untreated so that TP53 pathway events occur.
Lymph nodes are there to respond to infections. They are organs where B lymphocytes are brought into contact with the antigens that they have been designed for (every lymphocyte has a pre-designed pattern of immunoglobulin structure so that there is one for every antigen possible) and undergo a maturation process so that they can learn to produce the antibody that fits best to the antigen. This process is facilitated by the presence of T lymphocytes which help and control the maturation. Recognition of the driving antigen is through the BCR, a special arrangement of the lymphocyte's immunoglobulin molecule on the cell surface so that it can receive and transmit a signal through the cell's second messenger service. B lymphocytes leaving the lymph nodes are either memory cells that circulate, waiting to meet the infective agent again or turning into plasma cells which end up as antibody factories that reside mainly in the bone marrow.
In CLL this process has been circumvented. Instead of reactive follicles in the lymph nodes training the lymphocytes to make antibodies, there are what are known as pseudofollicular proliferation centers. These centers are geared up to make the B lymphocytes reproduce themselves and avoid death. Perhaps 30% of all CLL cases have a very restricted set of antibodies on their cell surfaces (so-called stereotyped BCRs) that seems to react with certain autoantigens that are exposed when cells enter apoptosis (programmed cell death). Most of these stereotyped BCRs comprise unmutated Ig and it is mainly the unmutated CLLs that produce proliferation center-laden lymph nodes.
Although the whole process of proliferation seems to be driven via the BCR it is not necessarily antigen dependent. It seems that inflammation can also be stimulatory, acting through what are known as Toll-like receptors (TLR). Stimulation of TLR by so called 'danger signals' sets in train events that keep CLL cells alive and makes them home in on lymph nodes. In any case many CLL cells express functional chemokine receptors CXCR3, CXCR4 and CXCR5. Within proliferation centers are many CD4+ T cells which express CD40L. These support the growth of CLL cells through CD40 ligation. Stromal cells and nurse-like cells interact with CLL cells to prevent apoptosis and the interaction of CD38 on the cell surface and its natural ligand CD31 also favors the twin effects of anti-apoptosis and proliferation. Cytokines such as IL-4 and chemokines like CXCL13/SDF-1 produced in proliferation centers promote the up-regulation of anti-apoptotic genes like BCL2, SURVIVIN and MCL1.
The whole effect can be summarized like this: First you need a BCR that will take messages and transmit them. This will usually,but not exclusively, be one with unmutated IgHV genes. Such CLL cells will circulate to the lymph nodes and may even be attracted there by chemokines responding to either antigenic signaling or TLR signaling. Once in the lymph node the presence of T helper cells has an effect on the CLL cell to keep it alive and cause it to divide. This effect is mediated through cell-to-cell contact and through cytokines and specific ligands. One of the effects is to up-regulate CD38. When we see CD38+ cells in the peripheral blood it is a sure sig that cell has recently visited a lymph node. Other stromal cells and nurse-like cells also participate in this dance, chuck in in their two-penneth into the cytokine soup.
So CLL cells survive and divide. and this proliferation is what is necessary for further genetic mistakes to be made, particularly ones that disable the TP53 pathway. This pathway is necessary to maintain the genetic integrity of the cell. Its function is to recognize genetic mistakes when they occur and to put the cell into stasis while a repair is made. If the cell is irreparable the TP53 is supposed to kill it off. It is a feature of cells in which the TP53 pathway is disabled that they accumulate further irreparable genetic damage and behave very wildly indeed. Clinically such disabling presages prolymphocytoid transformation or Richter's syndrome and in any case renders the cell unkillable by conventional cytotoxic drug combinations like FCR.
How can what's going on in the lymph nodes be stopped? Agents that specifically disable the CLL second messenger system, like CAL-101 and PCI32765, seem to be the best hope, but revlimid may also be useful. What the great danger is, is leaving the patient too long untreated so that TP53 pathway events occur.
John 3:19-21
This is the verdict: Light has come into the world, but people loved darkness instead of light because their deeds were evil. Everyone who does evil hates the light, and will not come into the light for fear that their deeds will be exposed. But whoever lives by the truth comes into the light, so that it may be seen plainly that what they have done has been done in the sight of God.
There are people who believe that mankind is basically good. The evidence of our ears and eyes lays siege to such an idea. Currently in the news we read of Dominique Strauss Kahn, the leader of the IMF, who has been charged with a serious sexual assault on a chamber maid in a New York hotel. Of course, he has only been charged, but his defence appears to be that he was only fornicating not raping. His reputation precedes him. Apparently he was well known as a serial sexual predator. He is not alone. French politicians seem to have made a practice of outrageous sexual exploits and in Italy things are hardly better. Also in today's paper the former Governor of California is in sexual trouble.
In England, the problem seems to be not sex but money, with several MPs in prison and others in disgrace. There also seems to be a raft of actors and footballers in the public eye who have been going to law to save their sordid affairs from being exposed. We need not mention the preachers and bishops who have fallen from grace. I can assert that few would welcome the light being shone on their lives. Men indeed love darkness.
There are people who believe that mankind is basically good. The evidence of our ears and eyes lays siege to such an idea. Currently in the news we read of Dominique Strauss Kahn, the leader of the IMF, who has been charged with a serious sexual assault on a chamber maid in a New York hotel. Of course, he has only been charged, but his defence appears to be that he was only fornicating not raping. His reputation precedes him. Apparently he was well known as a serial sexual predator. He is not alone. French politicians seem to have made a practice of outrageous sexual exploits and in Italy things are hardly better. Also in today's paper the former Governor of California is in sexual trouble.
In England, the problem seems to be not sex but money, with several MPs in prison and others in disgrace. There also seems to be a raft of actors and footballers in the public eye who have been going to law to save their sordid affairs from being exposed. We need not mention the preachers and bishops who have fallen from grace. I can assert that few would welcome the light being shone on their lives. Men indeed love darkness.
Tuesday, May 17, 2011
Statistics
Google have added a statistics package to Blogger which means I can see whether anybody reads this blog. I am pleased to be able to tell you that most days I get over 500 page views and the maximum is 744. The most popular article is the one on how rituximab works.
John 3:18
Whoever believes in him is not condemned, but whoever does not believe stands condemned already because he has not believed in the name of God's one and only Son.
It could hardly be put more plainly. All have sinned and fallen short of the required standard. All are therefore condemned. There is one way out take it and you are free; fail to take it and you will perish. That way is belief in the Lord Jesus Christ. Those who rejecthim will surely perish.
Today Stephen Hawking said that heaven is for those who are afraid of the dark. He's right. There are those who are too stupid or willful to be afraid of the dark. The Bible tells of the outer darkness where there is wailing and gnashing of teeth. Be afraid; be very afraid.
It could hardly be put more plainly. All have sinned and fallen short of the required standard. All are therefore condemned. There is one way out take it and you are free; fail to take it and you will perish. That way is belief in the Lord Jesus Christ. Those who rejecthim will surely perish.
Today Stephen Hawking said that heaven is for those who are afraid of the dark. He's right. There are those who are too stupid or willful to be afraid of the dark. The Bible tells of the outer darkness where there is wailing and gnashing of teeth. Be afraid; be very afraid.
Telling stories.
We like stories. We like a beginning, a middle and an end. It's the way we're made. The greatest Teacher ever used stories to teach. Listen, a farmer went out to sow his seed... A man was going down from Jerusalem to Jericho when he fell among thieves... There was a man who had two sons...
As patients we like a narrative. Rather than have a series of blood tests we want to put together a story about our condition. Sometimes it is a wrong story, but it is more satisfying than the truth. I remember a young 35-year old man who worked on the railway. He had an accident and broke his leg. X-rays showed that it was a pathological fracture. He had been developing myeloma at the site and this had weakened the bone at the point where it had fractured. For him and his Union representative the story was that the industrial accident had caused the myeloma. This story was so compelling (it ended with a nice compensation package) that they wouldn't be swayed. This was the satisfying story.
I have a little story of my own to try out. A couple of days ago I developed swelling of my ankles. I have had it before and though it is largely unexplained I accounted for it by postulating a rare condition known as RS3PO. As I usually do, I took a furosamide tablet.
Yesterday I noticed a fine maculo-papular rash on my forehead. It didn't itch or cause me any bother; it was just there. It seems that such a rash can be an allergy to furosamide. Last night I was particularly bothered by abdominal bloating. This has been a problem since my surgery last year. I have been left with a blind loop of bowel which easily fills with air. I have got used to putting up with it. Last night it was particularly troublesome.
Here is how I put the story together. RS3PO is known to be associated with men in their sixties with malignant disease. The mechanism is unknown but s thought to be autoimmune. This perhaps makes an allergic reaction to furosamide more likely. The type of rash is associated with immune complexes.
rashes are seldom just on the surface and it is reasonable to assume that it is also on the peritoneum where it can cause edema. this could cause more problems with intestinal motility and therefore with bloating. The remedy for all this is likely to be steroids so I have increased my steroid dose for the next week.
Ths story is satisfying in that it predicts a remedy. The hypothesis can be tested.
As patients we like a narrative. Rather than have a series of blood tests we want to put together a story about our condition. Sometimes it is a wrong story, but it is more satisfying than the truth. I remember a young 35-year old man who worked on the railway. He had an accident and broke his leg. X-rays showed that it was a pathological fracture. He had been developing myeloma at the site and this had weakened the bone at the point where it had fractured. For him and his Union representative the story was that the industrial accident had caused the myeloma. This story was so compelling (it ended with a nice compensation package) that they wouldn't be swayed. This was the satisfying story.
I have a little story of my own to try out. A couple of days ago I developed swelling of my ankles. I have had it before and though it is largely unexplained I accounted for it by postulating a rare condition known as RS3PO. As I usually do, I took a furosamide tablet.
Yesterday I noticed a fine maculo-papular rash on my forehead. It didn't itch or cause me any bother; it was just there. It seems that such a rash can be an allergy to furosamide. Last night I was particularly bothered by abdominal bloating. This has been a problem since my surgery last year. I have been left with a blind loop of bowel which easily fills with air. I have got used to putting up with it. Last night it was particularly troublesome.
Here is how I put the story together. RS3PO is known to be associated with men in their sixties with malignant disease. The mechanism is unknown but s thought to be autoimmune. This perhaps makes an allergic reaction to furosamide more likely. The type of rash is associated with immune complexes.
rashes are seldom just on the surface and it is reasonable to assume that it is also on the peritoneum where it can cause edema. this could cause more problems with intestinal motility and therefore with bloating. The remedy for all this is likely to be steroids so I have increased my steroid dose for the next week.
Ths story is satisfying in that it predicts a remedy. The hypothesis can be tested.
Monday, May 16, 2011
Bendamustine as second line. An Italian look-back
Most people are agreed that FCR is the best first line therapy if you are fit enough. CAL-101 and PCI32765 both look promising as disease modifying agents that act a bit like Gleevec for CLL, though the jury is still out on long-term effects. What about second-line in patients who have responded well to FCR?
It seems that repeating FCR in patients who have had a 2-year remission and not suffered major problems with it first time around is probably the right idea. However, few people will be able to get six course in a second time and the older patient and one with co-morbidities might be better advise not to try.
Is there a place for bedamustine plus rituximab as second line in patients declared unfit for a second FCR? An Italian atudy has addressed this issue. They evaluated bendamustine plus or minus rituximab in a group of heavily pretreated patients.
109 patients of median age 66 (39-85) were included. There were 80 males. 20 had B symptoms. Median prior therapies was 3 (1-8). 38% had received previous fludarabine and 39% had had previous rituximab. 62 were resistant to their last treatment. 22 received bendamustine alone and 87 the combination of bendamustine + rituximab. There was no attempt to randomize between them and I can't really see the point of lumping the together. This was the B J Haem. In Leukemia Research we would have been a bit more stringent about how the trial was reported. In fact it wasn't a trial at all, but a retropective look back at how bendamustine had been used in 24 Italian centers. I am afraid I would have rejected the paper for Leukemia Research.
105 patients were evaluable for response. 30 obtained CR, 43 a PR and 32 obtained no response. The CR rate for B+R was 32.5% and only 13.6% for B alone. Responsive patients had a better response (84.8%) than resistant patients (57.6%) (p=0.004). The median duration of response was 13 months.
Only 36% of patients received the intended 6 courses. 7% received 5 courses, 21% 4 courses and 34% 1-3 courses. Four patients were stopped early because of toxicity (1 herpetic encephalitis, 1 relapse of a melanoma, 1 myocardial infarction and 1 grade 4 neutropenia. 16.5% had grade 4 neutropenia and 17.5% thrombocytopenia, 15.5% anemia and 4.5% infection. Three of the 34 deaths were thought to be treatment-related.
What to make of this study? In view of my previous posting, not much. This was not a trial with an independent review panel. Responses were assessed by the patients' individual doctors and bias easily creeps in. The median duration of response was just over a year - not very long. All we can say is that Bendamustine is a drug that has some response in previously treated patients. A year later roughly a third of those treated were dead. I'm not sure what was gained by publishing this report. I am not impressed.
It seems that repeating FCR in patients who have had a 2-year remission and not suffered major problems with it first time around is probably the right idea. However, few people will be able to get six course in a second time and the older patient and one with co-morbidities might be better advise not to try.
Is there a place for bedamustine plus rituximab as second line in patients declared unfit for a second FCR? An Italian atudy has addressed this issue. They evaluated bendamustine plus or minus rituximab in a group of heavily pretreated patients.
109 patients of median age 66 (39-85) were included. There were 80 males. 20 had B symptoms. Median prior therapies was 3 (1-8). 38% had received previous fludarabine and 39% had had previous rituximab. 62 were resistant to their last treatment. 22 received bendamustine alone and 87 the combination of bendamustine + rituximab. There was no attempt to randomize between them and I can't really see the point of lumping the together. This was the B J Haem. In Leukemia Research we would have been a bit more stringent about how the trial was reported. In fact it wasn't a trial at all, but a retropective look back at how bendamustine had been used in 24 Italian centers. I am afraid I would have rejected the paper for Leukemia Research.
105 patients were evaluable for response. 30 obtained CR, 43 a PR and 32 obtained no response. The CR rate for B+R was 32.5% and only 13.6% for B alone. Responsive patients had a better response (84.8%) than resistant patients (57.6%) (p=0.004). The median duration of response was 13 months.
Only 36% of patients received the intended 6 courses. 7% received 5 courses, 21% 4 courses and 34% 1-3 courses. Four patients were stopped early because of toxicity (1 herpetic encephalitis, 1 relapse of a melanoma, 1 myocardial infarction and 1 grade 4 neutropenia. 16.5% had grade 4 neutropenia and 17.5% thrombocytopenia, 15.5% anemia and 4.5% infection. Three of the 34 deaths were thought to be treatment-related.
What to make of this study? In view of my previous posting, not much. This was not a trial with an independent review panel. Responses were assessed by the patients' individual doctors and bias easily creeps in. The median duration of response was just over a year - not very long. All we can say is that Bendamustine is a drug that has some response in previously treated patients. A year later roughly a third of those treated were dead. I'm not sure what was gained by publishing this report. I am not impressed.
Public heath issues
Libertarians will not be pleased with the New Scottish government since their first declared act will be to introduce a minimum price for alcohol of 50p per unit. Of all places in the world, Scotland is one of the most addicted to alcohol. Life expectancy in Scotland is lower than in the rest of the UK and drinking certainly plays a part in this. Objections have been made that this punishes the poorer drinker, but that is precisely why it is being introduced; it is the poorer drinker who is suffering from alcoholism, liver disease and domestic abuse. My own view is that while you have a national health service, with someone else picking up the tab for your bad behavior, then the insurer of last resort is fully justified in limiting his outgoings by whatever means.
Exactly the opposite problem is happening in Germany. There is a Federal ban on smoking in Federal buildings, and most of the States have introduced bans on smoking in restaurants, bars and pubs. However, a recent survey found that four out of five restaurants and pubs use legal loopholes to get round the smoking ban.
In the UK cigarette manufacturers are using psychological ploys to keep people smoking. There are selling cigarettes in packets of 14. Although these packets cost more per cigarette than packets of 20, it means that poorer smokers will have a smaller capital outlay per packet purchased. They have also determined that 14 cigarettes a day is a reasonable target to aim for poor smokers.
From 2012 large stores will no longer be able to display cigarettes for sale and even small tobacconists will be unable to do so from 2015.
I imagine that most right wing Americans are appalled by the proposed new health plan in Vermont. It would abolish most insurance plans and introduce a single payer. Apparently one in five people in Vermont is without health insurance. It is claimed that the Vermont plan would result in cost savings of 25% over 10 years by administrative simplification, the introduction of no-fault malpractice,, the elimination of perverse incentives like fees for service and the insulation of major healthcare decisions from politics. All I can say is ,”Good luck!”
Another current issue is the contribution of pharmaceutical companies to medical associations.. Many medical societies and non-profit disease awareness organizations receive much of their funding from drug and device manufacturers. Millions of dollars are involved. Although not necessarily applied primarily to sell their wares, these monies can easily taint the continuing medical education that they supposedly support.
However, doctors and nurses are reluctant to pay for CME activities themselves. Although most doctors recognize the potential for bias that drug company funded CME introduces, most underestimate exactly how much money the drug companies are putting in and how biased they are. Recently regulations about drug company funding have become more stringent. Applicants for EHA tell me it is much more difficult to obtain funds from Big Pharma now.
In other areas there is news about excess winter deaths in cold weather. Studies have shown that excess winter deaths in the UK are three times higher in the coldest houses compared to the warmest houses. Fuel poverty is defined as having to spend 10% or more of a household’s net income on heating the house to an adequate level. In 2008 it was estimated that 18% of households suffered from fuel poverty. The most easy to influence factor is house insulation and the 2011 Energy Bill seeks to produce a strategy to insulate enough homes to tackle fuel poverty.
Fewer children in England and Wales are dying violently. Numbers have fallen substantially in the past 30 years. From 1974 to 2008 the numbers of infants who died from assault fell from 5.6 per 100,000 to o.7 per 100,000. During the same period the death rate in all children from assault fell from 0.6 to 0.2 per 100,000. However, the death rate for 15-19 year old boys from assault has risen. Presumably this reflects gang warfare in inner cities.
One of the great successes of British Public Heath has been the reduction of road accidents as a cause of death. I remember in the 1950s when there were fewer than a million cars on the roads that there were over 7000 deaths on the roads annually. Today with 20 million+ vehicles on the roads, there are just over 2000 road deaths. Road deaths have been truly terrible in the past. During the time that 48,000 American soldiers were killed in World War I, 14,000 civilians were killed on American roads. In France road deaths have fallen from 16,000 to 4000 in 40 years.
Worldwide, nearly 1.3 million people are killed annually on the roads. It is the commonest cause of death among young people aged 15-29.. A quarter of these deaths occur in India and China. Brazil and Russia are other countries with high death rates. The WHO is keen to introduce a raft of measures that have proved successful in Britain, France, Australia and Sweden, including enforcement of traffic regulations, the wearing of seat belts, speed limits, motor cycle helmets and avoiding drink driving.
Exactly the opposite problem is happening in Germany. There is a Federal ban on smoking in Federal buildings, and most of the States have introduced bans on smoking in restaurants, bars and pubs. However, a recent survey found that four out of five restaurants and pubs use legal loopholes to get round the smoking ban.
In the UK cigarette manufacturers are using psychological ploys to keep people smoking. There are selling cigarettes in packets of 14. Although these packets cost more per cigarette than packets of 20, it means that poorer smokers will have a smaller capital outlay per packet purchased. They have also determined that 14 cigarettes a day is a reasonable target to aim for poor smokers.
From 2012 large stores will no longer be able to display cigarettes for sale and even small tobacconists will be unable to do so from 2015.
I imagine that most right wing Americans are appalled by the proposed new health plan in Vermont. It would abolish most insurance plans and introduce a single payer. Apparently one in five people in Vermont is without health insurance. It is claimed that the Vermont plan would result in cost savings of 25% over 10 years by administrative simplification, the introduction of no-fault malpractice,, the elimination of perverse incentives like fees for service and the insulation of major healthcare decisions from politics. All I can say is ,”Good luck!”
Another current issue is the contribution of pharmaceutical companies to medical associations.. Many medical societies and non-profit disease awareness organizations receive much of their funding from drug and device manufacturers. Millions of dollars are involved. Although not necessarily applied primarily to sell their wares, these monies can easily taint the continuing medical education that they supposedly support.
However, doctors and nurses are reluctant to pay for CME activities themselves. Although most doctors recognize the potential for bias that drug company funded CME introduces, most underestimate exactly how much money the drug companies are putting in and how biased they are. Recently regulations about drug company funding have become more stringent. Applicants for EHA tell me it is much more difficult to obtain funds from Big Pharma now.
In other areas there is news about excess winter deaths in cold weather. Studies have shown that excess winter deaths in the UK are three times higher in the coldest houses compared to the warmest houses. Fuel poverty is defined as having to spend 10% or more of a household’s net income on heating the house to an adequate level. In 2008 it was estimated that 18% of households suffered from fuel poverty. The most easy to influence factor is house insulation and the 2011 Energy Bill seeks to produce a strategy to insulate enough homes to tackle fuel poverty.
Fewer children in England and Wales are dying violently. Numbers have fallen substantially in the past 30 years. From 1974 to 2008 the numbers of infants who died from assault fell from 5.6 per 100,000 to o.7 per 100,000. During the same period the death rate in all children from assault fell from 0.6 to 0.2 per 100,000. However, the death rate for 15-19 year old boys from assault has risen. Presumably this reflects gang warfare in inner cities.
One of the great successes of British Public Heath has been the reduction of road accidents as a cause of death. I remember in the 1950s when there were fewer than a million cars on the roads that there were over 7000 deaths on the roads annually. Today with 20 million+ vehicles on the roads, there are just over 2000 road deaths. Road deaths have been truly terrible in the past. During the time that 48,000 American soldiers were killed in World War I, 14,000 civilians were killed on American roads. In France road deaths have fallen from 16,000 to 4000 in 40 years.
Worldwide, nearly 1.3 million people are killed annually on the roads. It is the commonest cause of death among young people aged 15-29.. A quarter of these deaths occur in India and China. Brazil and Russia are other countries with high death rates. The WHO is keen to introduce a raft of measures that have proved successful in Britain, France, Australia and Sweden, including enforcement of traffic regulations, the wearing of seat belts, speed limits, motor cycle helmets and avoiding drink driving.
John 3:17
For God did not send his Son into the world to condemn the world, but to save the world through him.
Too many see God as a present judge. The Law is there to reveal our sin and our need of a Savior. God has provided a remedy. He does not come to either condemn or condone, but to rescue. Imagine a number of people trapped in a forest fire. The fireman could bewail the fact that the forest is burning or could complain that those trapped by it must be arsonists. He could even pooh-pooh the whole idea of the fire and say it doesn't matter, but the real reason that he is a fireman is to rescue those who are perishing.
Too many see God as a present judge. The Law is there to reveal our sin and our need of a Savior. God has provided a remedy. He does not come to either condemn or condone, but to rescue. Imagine a number of people trapped in a forest fire. The fireman could bewail the fact that the forest is burning or could complain that those trapped by it must be arsonists. He could even pooh-pooh the whole idea of the fire and say it doesn't matter, but the real reason that he is a fireman is to rescue those who are perishing.
Sunday, May 15, 2011
The difficulties of assessing response in trials
One of the problems with clinical trials is that their interpretation is so subjective. Having spent a couple of years as part of an independent review panel looking at the outcome of a clinical trial I confess that I have found some of the decisions very difficult.
For example, to obtain a complete remission in CLL it is necessary for all evidence of the disease to disappear, but that is not enough. It is also necessary for the blood count to be restored to normal. It is not necessary to have the disappearance of the disease to be confirmed by CT or US scan, but it is necessary to demonstrate that there are fewer than 30% of lymphocytes in a bone marrow trephine. If for some reason there has been a CT scan or an US then far from making matters easier, they become more difficult.
If someone has simply been examined clinically then one has to feel the lymph nodes in neck, armpit and groin and note that none of them has a long diameter of greater than 1.5 cm - not easy to be sure if the patient is fat. Liver and spleen are measured in cm below the margin of the ribs. If, after treatment, no lymph nodes or liver or spleen can be felt then there is a chance of a complete remission. But if a scan is done we have to make a decision as to whether what we have imaged is normal tissue or abnormal and usually this is not possible. How large is a normal spleen? It is bigger for men than women and I take a longest diameter of 10 cm for women an 12 cm for men. But obviously it varies between individuals. Is 13 cms an enlarged spleen? If it has reduced from 19 cm is it a complete remission?
Livers are even more difficult. They can be enlarged in leukemia for other reasons than disease infiltration. Seldom do they return to a mid-axillary length of 12 cm after treatment. CT scans make things difficult. But if CT scans are not done there is a danger of missing important large retroperitoneal lymph nodes.
Bone marrow trephines post-chemotherapy are essential if there could be a CR. There has been a tendency to do bone marrow aspirates and look for minimal residual disease by flow cytometry, but this cuts no ice with those who are doing the assessing, even though it might be a more accurate and meaningful way of adjudicating on response. For a CR there must be fewer than 30% lymphocytes in the marrow trephine. Obviously we don't count every cell so someone makes an estimate. This is seldom done very accurately; someone just gives his best shot. Even if there are fewer than 30% the trephine must be free of nodules, since nodules are incalculable. If there are nodules then a CR becomes a nodular PR.
The bone marrow trephine must be normo- or hypercellular. If it is not, it must be repeated in 4 weeks. I can tell you that this is an instruction that is rarely fulfilled.
The net result is that when the rules are applied strictly there are few CRs and when they are not, the CRs that are declared cannot be trusted.
For example, to obtain a complete remission in CLL it is necessary for all evidence of the disease to disappear, but that is not enough. It is also necessary for the blood count to be restored to normal. It is not necessary to have the disappearance of the disease to be confirmed by CT or US scan, but it is necessary to demonstrate that there are fewer than 30% of lymphocytes in a bone marrow trephine. If for some reason there has been a CT scan or an US then far from making matters easier, they become more difficult.
If someone has simply been examined clinically then one has to feel the lymph nodes in neck, armpit and groin and note that none of them has a long diameter of greater than 1.5 cm - not easy to be sure if the patient is fat. Liver and spleen are measured in cm below the margin of the ribs. If, after treatment, no lymph nodes or liver or spleen can be felt then there is a chance of a complete remission. But if a scan is done we have to make a decision as to whether what we have imaged is normal tissue or abnormal and usually this is not possible. How large is a normal spleen? It is bigger for men than women and I take a longest diameter of 10 cm for women an 12 cm for men. But obviously it varies between individuals. Is 13 cms an enlarged spleen? If it has reduced from 19 cm is it a complete remission?
Livers are even more difficult. They can be enlarged in leukemia for other reasons than disease infiltration. Seldom do they return to a mid-axillary length of 12 cm after treatment. CT scans make things difficult. But if CT scans are not done there is a danger of missing important large retroperitoneal lymph nodes.
Bone marrow trephines post-chemotherapy are essential if there could be a CR. There has been a tendency to do bone marrow aspirates and look for minimal residual disease by flow cytometry, but this cuts no ice with those who are doing the assessing, even though it might be a more accurate and meaningful way of adjudicating on response. For a CR there must be fewer than 30% lymphocytes in the marrow trephine. Obviously we don't count every cell so someone makes an estimate. This is seldom done very accurately; someone just gives his best shot. Even if there are fewer than 30% the trephine must be free of nodules, since nodules are incalculable. If there are nodules then a CR becomes a nodular PR.
The bone marrow trephine must be normo- or hypercellular. If it is not, it must be repeated in 4 weeks. I can tell you that this is an instruction that is rarely fulfilled.
The net result is that when the rules are applied strictly there are few CRs and when they are not, the CRs that are declared cannot be trusted.
John 3:16
For God so loved the world that he gave his one and only Son, that whoever believes in him shall not perish but have eternal life.
Perhaps the most famous verse in the whole Bible. Hard to believe that God loved the world that much. Hard to believe that he gave his one and only Son. Hard to believe that anyone who believed. Hard to believe in eternal life. Yet it is true.
This is what the Gospel is about. If you reject this you reject everything. You may as well be a worm. The corrolary is that those who do not believe in him, shall perish.
Perhaps the most famous verse in the whole Bible. Hard to believe that God loved the world that much. Hard to believe that he gave his one and only Son. Hard to believe that anyone who believed. Hard to believe in eternal life. Yet it is true.
This is what the Gospel is about. If you reject this you reject everything. You may as well be a worm. The corrolary is that those who do not believe in him, shall perish.
Saturday, May 14, 2011
FCM v FCM-R
A randomized phase II trial is designed to discover whether one treatment has more responses than another one. This means that historical controls do not need to be used, but it tells us nothing about how long the responses last or whether the overall survival differs between the two treatments.
Some years ago the idea that mitoxantrone might be a good drug for CLL was floated and the British group have conducted at trial comparing FCM with FCM-R. The patient group looked at were those who required treatment according to the NCI guidelines, who had had at least one previous course of treatment. 52 patients were randomized between the two arms. The median age was 68 (32-79) with 79% male. 23/37 had a beta-2M >4. The median number of prior therapies was 2 (1-6). 63% had had prior fludarabine. 21% were either refractory to fludarabine or had relapsed within 6 months of having fludarabine. 26/45 had unmutated IGHV genes, 11 had del 11q, and one del 17p. The two groups were well balanced. 69% received at least 4 cycles of treatment but 50% failed to receive all 6 prescribed cycles. reasons for early discontinuation were: death (1), toxicity (7), chest infection (2), patient choice (1) and the other unknown.
The treatment arms were Fludarabine 24mg/sq m/d for 5 days orally, Cyclophosphamide 150 mg/sq m/d for 5 days orally, Mitoxantrone 6 mg/sq m iv on day 1 plus or minus rituximab 375 mg/sq m on day 1 of the first course and 500 mg/sq m on day 1 of subsequent courses.
The overall response rate was 58% for FCM and 65% for FCM-R (not significantly different). The CR + CRi rate was 15% for FCM and 42% for FCM-R (not significantly different). Similarly the MRD negative rates were similar at 12% and 19%.
Forty-one serious adverse events were reported, equally distributed between the two arms. Thirty-one were thought to be treatment related. The safety profile for both arms was found to be similar.
The authors conclude that these regimens should be tested in larger studies and in fact this is being done in the ARCTIC and ADMIRE trials.
Some years ago the idea that mitoxantrone might be a good drug for CLL was floated and the British group have conducted at trial comparing FCM with FCM-R. The patient group looked at were those who required treatment according to the NCI guidelines, who had had at least one previous course of treatment. 52 patients were randomized between the two arms. The median age was 68 (32-79) with 79% male. 23/37 had a beta-2M >4. The median number of prior therapies was 2 (1-6). 63% had had prior fludarabine. 21% were either refractory to fludarabine or had relapsed within 6 months of having fludarabine. 26/45 had unmutated IGHV genes, 11 had del 11q, and one del 17p. The two groups were well balanced. 69% received at least 4 cycles of treatment but 50% failed to receive all 6 prescribed cycles. reasons for early discontinuation were: death (1), toxicity (7), chest infection (2), patient choice (1) and the other unknown.
The treatment arms were Fludarabine 24mg/sq m/d for 5 days orally, Cyclophosphamide 150 mg/sq m/d for 5 days orally, Mitoxantrone 6 mg/sq m iv on day 1 plus or minus rituximab 375 mg/sq m on day 1 of the first course and 500 mg/sq m on day 1 of subsequent courses.
The overall response rate was 58% for FCM and 65% for FCM-R (not significantly different). The CR + CRi rate was 15% for FCM and 42% for FCM-R (not significantly different). Similarly the MRD negative rates were similar at 12% and 19%.
Forty-one serious adverse events were reported, equally distributed between the two arms. Thirty-one were thought to be treatment related. The safety profile for both arms was found to be similar.
The authors conclude that these regimens should be tested in larger studies and in fact this is being done in the ARCTIC and ADMIRE trials.
The Sound Barrier
Last night we watched another David Lean film, The Sound Barrier. Again it starred his wife, Ann Todd, together with Ralph Richardson, Nigel Patrick and Denholm Elliot. Like Psycho, it dispensed with it's Box Office attractions half way through the film.
Although ostensibly a story about technical advances, with the early days of jet airplanes glorified, but became a male versus female thing. Men believed things were worth doing, because they were there; women caring more for preserving life and limb. We hear the same battle when men go to war. Men can justify being in Iraq and Afghanistan, but women see the body bags and coffins.
Again the film showed what a great artist David Lean was, even before Lawrence of Arabia.
Although ostensibly a story about technical advances, with the early days of jet airplanes glorified, but became a male versus female thing. Men believed things were worth doing, because they were there; women caring more for preserving life and limb. We hear the same battle when men go to war. Men can justify being in Iraq and Afghanistan, but women see the body bags and coffins.
Again the film showed what a great artist David Lean was, even before Lawrence of Arabia.
John 3:14-15
Just as Moses lifted up the snake in the wilderness, so the Son of Man must be lifted up, that everyone who believes may have eternal life in him.”
The reference is to Numbers 21:8-9; the story of the bronze snake made by Moses when the Israelites were bitten by the snakes in the wilderness. I suppose this is a reference to the snake in the garden of Eden whose curse condemned mankind. The only way to be free from the curse of sin is by looking to Jesus. Note that jesus must be lifted up. There is no point in his just being there. We must make him known.
The reference is to Numbers 21:8-9; the story of the bronze snake made by Moses when the Israelites were bitten by the snakes in the wilderness. I suppose this is a reference to the snake in the garden of Eden whose curse condemned mankind. The only way to be free from the curse of sin is by looking to Jesus. Note that jesus must be lifted up. There is no point in his just being there. We must make him known.
Friday, May 13, 2011
Madeleine
The other night we watched an old David Lean film, Madelaine. It starred his wife, Ann Todd, and was the story of the Glasgow alleged murderess, Madelaine Smith. The case was famous for the Scottish verdict of 'not-proven'.
From time to time the old murder mystery is revisited on TV and most experts today consider her guilty, but she got away with it. The story was set in the 1850s and it was beautifully filmed in black and white. The attention to detail and the careful atmosphere that was developed show that Lean was one of the great directors. If you get a chance to see this great film, don't miss it.
From time to time the old murder mystery is revisited on TV and most experts today consider her guilty, but she got away with it. The story was set in the 1850s and it was beautifully filmed in black and white. The attention to detail and the careful atmosphere that was developed show that Lean was one of the great directors. If you get a chance to see this great film, don't miss it.
John 3:13
No one has ever gone into heaven except the one who came from heaven—the Son of Man.
What is there to do except to accept this statement at face value? Jesus spoke as one who had authority and this was why. He had the authority of God because he is God.
When we encounter the Jesus of the gospels we think of him as a man; he calls himself the son of man. But we must never forget that he is also God. There is no disputing with him. We cannot treat him as an equal. Although he subjected himself to the same traumas of life that we suffer, although he died on the cross, although he was betrayed and spat upon and hurt in so many ways; he was still God. We would do well to humble ourselves before him.
What is there to do except to accept this statement at face value? Jesus spoke as one who had authority and this was why. He had the authority of God because he is God.
When we encounter the Jesus of the gospels we think of him as a man; he calls himself the son of man. But we must never forget that he is also God. There is no disputing with him. We cannot treat him as an equal. Although he subjected himself to the same traumas of life that we suffer, although he died on the cross, although he was betrayed and spat upon and hurt in so many ways; he was still God. We would do well to humble ourselves before him.
New health bulletin
I have had a good week healthwise. I have been able to work quite hard on an international review panel for a clinical trial of a CLL drug, which necessitated 4 hours on the telephone to America and another 10 hours studying documents. As well as that, yesterday I attended a small group meeting from our church, which lasted two and a half hours. I was quite ‘buzzy’ by bed time and woke up at 3 am. I shall have to reduce the steroid dose.
Also this week we managed to spend a couple of hours in the New Forest. Tuesday was a balmy Spring day and we walked for 45 minutes among the tall trees at Rhinefelt near where Richard Branson owns a restaurant. Giant redwoods and Douglas Firs are among the tallest trees in the UK. The plantation has been run by the Forestry Commission since 1829 and it is a splendid facility. We met four other old couples walking round in the opposite direction, so we had the place almost to ourselves. It was certainly superior to the facility we visited just outside San Francisco.
The very hot weather has passed and the climate has returned to normal for mid Spring in England. Bright days with occasional showers. The flowers are about two weeks ahead of normal, but the garden is looking well. We have a new young gardener, our old one having had to give up with a bad back. It’s good to see young men picking up the old skills.
Also this week we managed to spend a couple of hours in the New Forest. Tuesday was a balmy Spring day and we walked for 45 minutes among the tall trees at Rhinefelt near where Richard Branson owns a restaurant. Giant redwoods and Douglas Firs are among the tallest trees in the UK. The plantation has been run by the Forestry Commission since 1829 and it is a splendid facility. We met four other old couples walking round in the opposite direction, so we had the place almost to ourselves. It was certainly superior to the facility we visited just outside San Francisco.
The very hot weather has passed and the climate has returned to normal for mid Spring in England. Bright days with occasional showers. The flowers are about two weeks ahead of normal, but the garden is looking well. We have a new young gardener, our old one having had to give up with a bad back. It’s good to see young men picking up the old skills.
John 3:11-12
Blogger has been down all day and it looks as though yesterday's posting on John has been lost. I will try to reconstruct it.
Very truly I tell you, we speak of what we know, and we testify to what we have seen, but still you people do not accept our testimony. I have spoken to you of earthly things and you do not believe; how then will you believe if I speak of heavenly things?
Were ever two at more of a cross purpose? Nicodemus is down-to-earth, logical, practically minded but Jesus is speaking of heavenly things. Dawkins and his ilk believe that the physical is all that there is, but Christianity is predicated on there being a supernatural existence.
Do you have a supernatural life and do you water it with prayer?
Very truly I tell you, we speak of what we know, and we testify to what we have seen, but still you people do not accept our testimony. I have spoken to you of earthly things and you do not believe; how then will you believe if I speak of heavenly things?
Were ever two at more of a cross purpose? Nicodemus is down-to-earth, logical, practically minded but Jesus is speaking of heavenly things. Dawkins and his ilk believe that the physical is all that there is, but Christianity is predicated on there being a supernatural existence.
Do you have a supernatural life and do you water it with prayer?
Hsp-90 revisited
It is always nice to see one’s old research fellows doing well. A couple of years ago Giles Best was working in our lab on CLL and I see he is now in Australia, working with Stephen Mulligan in Sydney. He has just published a paper in the British Journal of Haematology on a novel Hsp-90 inhibitor, SNX7081.
Readers will remember that there was a lot of excitement about the Hsp90 inhibitor, 17-AAG, particularly since the up-regulation of ZAP-70 used Hsp-90 as a chaperon. Recently there are suggestions that Hsp-90 inhibitors have promise in targeting cells with mutations of ATM and TP53. However, because of its quinine moiety at its core, 17-AAG looks like proving too toxic for clinical use.
Consequently, novel synthetic inhibitors have been developed including a family of products by Serenex. One of these is studied here. They have looked at the activity of an inhibitor, SNX7801, against a panel of eight haematological cell lines and 23 CLL patient samples. They found that SNX7081 is significantly more potent than 17-AAG in reducing the number of viable tumour cells by causing dramatic cell-cycle arrest without necessitating the TP53 pathway to be intact and by significantly reducing the amount of ZAP-70 expressed.
SNX7081 is recommended for clinical trials
Readers will remember that there was a lot of excitement about the Hsp90 inhibitor, 17-AAG, particularly since the up-regulation of ZAP-70 used Hsp-90 as a chaperon. Recently there are suggestions that Hsp-90 inhibitors have promise in targeting cells with mutations of ATM and TP53. However, because of its quinine moiety at its core, 17-AAG looks like proving too toxic for clinical use.
Consequently, novel synthetic inhibitors have been developed including a family of products by Serenex. One of these is studied here. They have looked at the activity of an inhibitor, SNX7801, against a panel of eight haematological cell lines and 23 CLL patient samples. They found that SNX7081 is significantly more potent than 17-AAG in reducing the number of viable tumour cells by causing dramatic cell-cycle arrest without necessitating the TP53 pathway to be intact and by significantly reducing the amount of ZAP-70 expressed.
SNX7081 is recommended for clinical trials
Thursday, May 12, 2011
John 3:11-12
Very truly I tell you, we speak of what we know, and we testify to what we have seen, but still you people do not accept our testimony. I have spoken to you of earthly things and you do not believe; how then will you believe if I speak of heavenly things?
If ever people were talking at cross purposes it was these two. Nicodemus, being logical, down-to-earth, matter-of-fact; Jesus speaking of heavenly things; the two had no point of contact.
What we have to convince people of is that the physical is not all there is. Dawkins and his cohort would insist that it is, but the whole idea of Christianity is predicated on that there is more than the physical.
Do you have a spiritual life? Do you appreciate the supernatural and do you relate to it in prayer?
If ever people were talking at cross purposes it was these two. Nicodemus, being logical, down-to-earth, matter-of-fact; Jesus speaking of heavenly things; the two had no point of contact.
What we have to convince people of is that the physical is not all there is. Dawkins and his cohort would insist that it is, but the whole idea of Christianity is predicated on that there is more than the physical.
Do you have a spiritual life? Do you appreciate the supernatural and do you relate to it in prayer?
Wednesday, May 11, 2011
What is wrong with the NHS
The NHS is being reorganized again - or is it. In the wake of the Liberal Democrats defeat at the polls they are stiffening up their opposition to Andrew Lansley's Health Bill in the hope that they will be seen by the electorate as still having some backbone.
The Health Bill was an attempt to make the NHS more accountable to its users by giving control of the budgets to consortia of local family doctors instead of administrators. The government has ring fenced the budget of the NHS, but since there is a built-in inflation in health spending due to demographic drift and scientific development, even a stand-still budget seems like cuts.
So what is wrong with the NHS and what needs fixing?
The last Labour government threw a lot of money at the NHS and brought average spending up to where it was in most of Europe - but of course during the same period Europe also increased its spending so that the NHS still lags behind Germany, Spain and France in its spending. The criticism was made that much of the money was wasted because productivity actually fell while the spending increased. I contend that this was because the government did not believe how hard doctors and nurses were working. The contracts were made more watertight so that people were actually paid for their work and discouraged from doing unpaid overtime by the European Working Time Directive. So it appeared that people were doing less for more. More jobs were created to fill in the gaps.
Another criticism of the NHS was that priorities for treatment had become distorted. Waiting lists had been shortened to no more than 18 weeks anywhere, but this had sometimes meant that things like cosmetic surgery were given priority over mental health services or even cancer surgery. Cancer referrals was supposed to take no more than 2 weeks, but there were built in delays waiting for scans and follow-up appointments. Again every breast lump was placed at the head of the queue even though many of them would be benign cysts.
By giving GPs the budget the idea would be that they could better decide on priorities and not make the same basic errors that administrators would make. On the other hand GPs are themselves providers to the NHS and might find it profitable to favor their own services at the expense of other providers. Near-patient testing or the use of 'factory laboratories' without pathologist's supervision, might be preferred to our conventional model. GPs certainly favored themselves when abandoning night duties to private services for a very small cut in income. The private night services have scored some spectacular own-goals.
One possible drive behind the Conservative reforms has been the possibility of private providers supplying some of the services. I have no problem with this as long as they are professionally scrutinized. We have private catering and waste disposal, and why not. The attempt by Blair's government to introduce private treatment centers for orthopedic operations was disastrous. They cherry-picked the easy options and left their complications to be picked up by the NHS.
The other drawback of private treatment centers is their lack of commitment to training and research which are an essential element of the NHS. One remedy for this would be to ensure that hospital specialists had a say in the purchasing of services, but Lansley is resisting this. Lansley has family members who are family doctors and his might not be an unjaundiced eye.
It seems to me that there some elements of health that have to be provided by the public sector. This is recognized even in America where the CDC and VA are both provided at public expense.
Another question is whether it is possible to restrain the costs of drugs. In any market any product can price itself out of contention. The very rich, like Steve Jobs, will be able to buy anything to keep himself alive; the indigenous poor will not. An insurance system, however provided, evens out the difference, but it will not be attractive to everybody. Attempts to arbitrarily control what is spent will fall foul of individual unfair exceptions. The UK government has set up a cancer fund to deal with these exceptions when NICE seems harsh. It has not been universally acceptable.
I suppose what is wrong with the NHS is what is wrong with modern medicine. It is not universally successful.
The Health Bill was an attempt to make the NHS more accountable to its users by giving control of the budgets to consortia of local family doctors instead of administrators. The government has ring fenced the budget of the NHS, but since there is a built-in inflation in health spending due to demographic drift and scientific development, even a stand-still budget seems like cuts.
So what is wrong with the NHS and what needs fixing?
The last Labour government threw a lot of money at the NHS and brought average spending up to where it was in most of Europe - but of course during the same period Europe also increased its spending so that the NHS still lags behind Germany, Spain and France in its spending. The criticism was made that much of the money was wasted because productivity actually fell while the spending increased. I contend that this was because the government did not believe how hard doctors and nurses were working. The contracts were made more watertight so that people were actually paid for their work and discouraged from doing unpaid overtime by the European Working Time Directive. So it appeared that people were doing less for more. More jobs were created to fill in the gaps.
Another criticism of the NHS was that priorities for treatment had become distorted. Waiting lists had been shortened to no more than 18 weeks anywhere, but this had sometimes meant that things like cosmetic surgery were given priority over mental health services or even cancer surgery. Cancer referrals was supposed to take no more than 2 weeks, but there were built in delays waiting for scans and follow-up appointments. Again every breast lump was placed at the head of the queue even though many of them would be benign cysts.
By giving GPs the budget the idea would be that they could better decide on priorities and not make the same basic errors that administrators would make. On the other hand GPs are themselves providers to the NHS and might find it profitable to favor their own services at the expense of other providers. Near-patient testing or the use of 'factory laboratories' without pathologist's supervision, might be preferred to our conventional model. GPs certainly favored themselves when abandoning night duties to private services for a very small cut in income. The private night services have scored some spectacular own-goals.
One possible drive behind the Conservative reforms has been the possibility of private providers supplying some of the services. I have no problem with this as long as they are professionally scrutinized. We have private catering and waste disposal, and why not. The attempt by Blair's government to introduce private treatment centers for orthopedic operations was disastrous. They cherry-picked the easy options and left their complications to be picked up by the NHS.
The other drawback of private treatment centers is their lack of commitment to training and research which are an essential element of the NHS. One remedy for this would be to ensure that hospital specialists had a say in the purchasing of services, but Lansley is resisting this. Lansley has family members who are family doctors and his might not be an unjaundiced eye.
It seems to me that there some elements of health that have to be provided by the public sector. This is recognized even in America where the CDC and VA are both provided at public expense.
Another question is whether it is possible to restrain the costs of drugs. In any market any product can price itself out of contention. The very rich, like Steve Jobs, will be able to buy anything to keep himself alive; the indigenous poor will not. An insurance system, however provided, evens out the difference, but it will not be attractive to everybody. Attempts to arbitrarily control what is spent will fall foul of individual unfair exceptions. The UK government has set up a cancer fund to deal with these exceptions when NICE seems harsh. It has not been universally acceptable.
I suppose what is wrong with the NHS is what is wrong with modern medicine. It is not universally successful.
John 3:9-10
“How can this be?” Nicodemus asked. “You are Israel’s teacher,” said Jesus, “and do you not understand these things?
Jesus gently mocks Nicodemus, but at the same time continues to undermine the Old religion. First the purification rituals, then the idea of Temple sacrifice, now the Rabbinical authority. The old has gone.
Jesus gently mocks Nicodemus, but at the same time continues to undermine the Old religion. First the purification rituals, then the idea of Temple sacrifice, now the Rabbinical authority. The old has gone.
Tuesday, May 10, 2011
John 3:5-8
Jesus answered, “Very truly I tell you, no one can enter the kingdom of God unless they are born of water and the Spirit. Flesh gives birth to flesh, but the Spirit gives birth to spirit. You should not be surprised at my saying, ‘You must be born again.’ The wind blows wherever it pleases. You hear its sound, but you cannot tell where it comes from or where it is going. So it is with everyone born of the Spirit.”
A lot of nonsense is talked about 'spirituality'. It is all about letting go of your body, letting your mind drift and surrendering to the 'forces of the Universe'. It goes with Green issues, Gaia, wind chimes, crystals, Nature, sustainability, vegetarianism, and macrobiotic diets, and it goes against anything to do with reason, logic, planning, chemicals, genetics, science or materials.
Not so with the Holy Spirit. The Spirit is purposeful, thoughtful, concerned and a person. He is there to point people to Jesus. He stands alongside, encouraging, controling, thinking, planning, guarding and protecting. That 'other' spirituality is just about being controled by your emotions.
A lot of nonsense is talked about 'spirituality'. It is all about letting go of your body, letting your mind drift and surrendering to the 'forces of the Universe'. It goes with Green issues, Gaia, wind chimes, crystals, Nature, sustainability, vegetarianism, and macrobiotic diets, and it goes against anything to do with reason, logic, planning, chemicals, genetics, science or materials.
Not so with the Holy Spirit. The Spirit is purposeful, thoughtful, concerned and a person. He is there to point people to Jesus. He stands alongside, encouraging, controling, thinking, planning, guarding and protecting. That 'other' spirituality is just about being controled by your emotions.
Monday, May 09, 2011
John 3:4
"How can a man be born when he is old?" Nicodemas asked. "Surely he cannot enter a second time into his mother's womb to be born!"
The supreme example of taking things too literally! This seems to have been a common failing with the Jews, yet Jesus was a a wonderful teacher in his use of metaphor and other figures of speech. Today many of our greatest scientists are of Jewish extraction. Is it a genetic thing, the ability to think logically in straight lines? Yet the Bible shows us that Jewish literature is filled with flights of fancy and invention. Perhaps it is just down to individuals, but Nicodemus is being obtuse here.
The supreme example of taking things too literally! This seems to have been a common failing with the Jews, yet Jesus was a a wonderful teacher in his use of metaphor and other figures of speech. Today many of our greatest scientists are of Jewish extraction. Is it a genetic thing, the ability to think logically in straight lines? Yet the Bible shows us that Jewish literature is filled with flights of fancy and invention. Perhaps it is just down to individuals, but Nicodemus is being obtuse here.
Sunday, May 08, 2011
John 3:3
In reply Jesus declared, "I tell you the truth, no-one can see the kingdom of God unless he is born again
Being born again has become a cliche, but it is still true. The rebirth is not physical but spiritual and very specific - not spiritual in the sense of crystals and meditation. It involves starting over in a transformed way and it is not something you can do for yourself -as we shall see.
You can't give birth to yourself; you need to be delivered.
Being born again has become a cliche, but it is still true. The rebirth is not physical but spiritual and very specific - not spiritual in the sense of crystals and meditation. It involves starting over in a transformed way and it is not something you can do for yourself -as we shall see.
You can't give birth to yourself; you need to be delivered.
Richter's Syndrome: important new information
Richter's syndrome (RS) is the development of a diffuse large cell lymphoma from a background of conventional CLL. It has clearly been recognized that this can occur in two separate ways: either from the progression of the CLL clone to a different, more aggressive, histology or by the development of a clonally unrelated large cell lymphoma.
Much of the literature about Richter's syndrome is inadequate, relying on small or old series, often not confirmed histologically, so the paper in Blood of March 24th is welcome. This Italian study looks at a series of 86 patients.
Median time from the diagnosis of CLL to the diagnosis of RS was 3.7 years (range 0.2-6.7 years). 83/86 were evaluable for survival.The median survival time was 19 months. The follow up was 57 months during which 62.6% had died. Only 40 of the cases of RS were CD5 positive (48.2%); 92.7% displayed a non-germinal center type cell of origin and EBV infection was demonstrated in only 5.9%. The IGHV genes were unmutated in 64.7% and stereotyped VH CDR3 occurred in 36.4%
47.1% carried disruption of TP53 by either deletion or mutation or both. c-MYC abnormalities were present in 26.3%, but BCL2 and BCL6 translocations did not occur. In 50% of cases the c-MYC abnormality was paired with a TP53 abnormality.
Disruption of TP53 was a major prognostic factor. Median survival for those with a disruption was 9.4 months versus 47.1 months for those without a problem at TP53. By univariate analysis other factors associated with poor survival were age over 60, Performance score of >1, tumor size >5cm, platelet count <100, LDH >1.5 x upper limit of normal. Associated with good survival were achievement of CR after remission induction therapy and allogeneic transplant after remission.
By multivariate analysis TP53 disruption was an independent predictor of poor survival along with failure of achievement of CR after remission induction therapy and poor performance score. Use of these three factors stratifies patients into risk groups. Patients with poor performance status had a median survival of 7.8 months. Patients with good performance status but harboring TP53 disruption or not achieving a CR had a median survival of 24.6 months. Patients with none of the adverse risk factors had a 5-year survival of 70%.
It was not possible to determine the clonal relationship between the CLL and RS in 23 cases because paired material was not available, but in the remainder there was a clonal relationship in 79.3% of cases. Those that were clonally unrelated had significantly less TP53 disruption (3 of 13 compared with 30 of 50) and had a lower prevalence of stereotyped VH CDR3. Clonally unrelated cases had a longer median survival (62.5 months) compared to clonally related cases (14.2 months).
I think this is an extremely important paper because we are at a loss as where to go with RS. Generally, patients are treated on clinical suspicion of RS without histological proof and without molecular dissection of the tumor, usually with CHOP-R. What this paper tells us is that while resembling diffuse large B-cell lymphoma (DLBCL), RS is mostly very different. Approximately 4 in 5 cases derive from the CLL clone and in these cases particularly the pattern is quite distinct. DLBCL carries mutated IGHV genes and is usually positive for BCL2 and BCL6. RS carries unmutated IGHV genes in 60% of cases and is negative for BCL2 and BCL6. RS tends to be like refractory CLL in having disruption of TP53 and is therefore unlikely to respond to conventional drugs.
The RS cases that are unrelated to the CLL presumabl occur because of the genetic damage inflicted on normal tissue by the cytotoxic drugs and the release of T-cell suppression caused by drugs like fludarabine. Thankfully, CHOP-R is a good choice in this context, but it just isn't going to work in TP53 disrupted cases.
How then should we proceed? It seems to me that there should be a high index of suspicion. The old literature suggested that the incidence of RS in CLL was 3.5%, but with the advent of more aggressive therapy it might be as high as 10% in multiply treated patients. It is important to treat early when performance status is still good and the tumor small. It is also important to get histological proof so the physician knows what he is dealing with. One thing that should be avoided is blind treatment with CHOP-R, which in many cases will be futile and only serve to impair performance status of the patient.
Which drugs are useful in TP53 resistant cases of intermediate grade lymphoma? Only one that we are sure of, high dose steroids. Other drugs like Revlimid, Campath and flavapiridol have no track record in DLBCL. Perhaps the Btk or PI3Kdelta inhibitors might have a place?
Much of the literature about Richter's syndrome is inadequate, relying on small or old series, often not confirmed histologically, so the paper in Blood of March 24th is welcome. This Italian study looks at a series of 86 patients.
Median time from the diagnosis of CLL to the diagnosis of RS was 3.7 years (range 0.2-6.7 years). 83/86 were evaluable for survival.The median survival time was 19 months. The follow up was 57 months during which 62.6% had died. Only 40 of the cases of RS were CD5 positive (48.2%); 92.7% displayed a non-germinal center type cell of origin and EBV infection was demonstrated in only 5.9%. The IGHV genes were unmutated in 64.7% and stereotyped VH CDR3 occurred in 36.4%
47.1% carried disruption of TP53 by either deletion or mutation or both. c-MYC abnormalities were present in 26.3%, but BCL2 and BCL6 translocations did not occur. In 50% of cases the c-MYC abnormality was paired with a TP53 abnormality.
Disruption of TP53 was a major prognostic factor. Median survival for those with a disruption was 9.4 months versus 47.1 months for those without a problem at TP53. By univariate analysis other factors associated with poor survival were age over 60, Performance score of >1, tumor size >5cm, platelet count <100, LDH >1.5 x upper limit of normal. Associated with good survival were achievement of CR after remission induction therapy and allogeneic transplant after remission.
By multivariate analysis TP53 disruption was an independent predictor of poor survival along with failure of achievement of CR after remission induction therapy and poor performance score. Use of these three factors stratifies patients into risk groups. Patients with poor performance status had a median survival of 7.8 months. Patients with good performance status but harboring TP53 disruption or not achieving a CR had a median survival of 24.6 months. Patients with none of the adverse risk factors had a 5-year survival of 70%.
It was not possible to determine the clonal relationship between the CLL and RS in 23 cases because paired material was not available, but in the remainder there was a clonal relationship in 79.3% of cases. Those that were clonally unrelated had significantly less TP53 disruption (3 of 13 compared with 30 of 50) and had a lower prevalence of stereotyped VH CDR3. Clonally unrelated cases had a longer median survival (62.5 months) compared to clonally related cases (14.2 months).
I think this is an extremely important paper because we are at a loss as where to go with RS. Generally, patients are treated on clinical suspicion of RS without histological proof and without molecular dissection of the tumor, usually with CHOP-R. What this paper tells us is that while resembling diffuse large B-cell lymphoma (DLBCL), RS is mostly very different. Approximately 4 in 5 cases derive from the CLL clone and in these cases particularly the pattern is quite distinct. DLBCL carries mutated IGHV genes and is usually positive for BCL2 and BCL6. RS carries unmutated IGHV genes in 60% of cases and is negative for BCL2 and BCL6. RS tends to be like refractory CLL in having disruption of TP53 and is therefore unlikely to respond to conventional drugs.
The RS cases that are unrelated to the CLL presumabl occur because of the genetic damage inflicted on normal tissue by the cytotoxic drugs and the release of T-cell suppression caused by drugs like fludarabine. Thankfully, CHOP-R is a good choice in this context, but it just isn't going to work in TP53 disrupted cases.
How then should we proceed? It seems to me that there should be a high index of suspicion. The old literature suggested that the incidence of RS in CLL was 3.5%, but with the advent of more aggressive therapy it might be as high as 10% in multiply treated patients. It is important to treat early when performance status is still good and the tumor small. It is also important to get histological proof so the physician knows what he is dealing with. One thing that should be avoided is blind treatment with CHOP-R, which in many cases will be futile and only serve to impair performance status of the patient.
Which drugs are useful in TP53 resistant cases of intermediate grade lymphoma? Only one that we are sure of, high dose steroids. Other drugs like Revlimid, Campath and flavapiridol have no track record in DLBCL. Perhaps the Btk or PI3Kdelta inhibitors might have a place?
Saturday, May 07, 2011
Can we pick the MBLs that won't progress?
Does everybody with a monoclonal B cell lymphocytosis or stage 0 CLL need to be followed up? CLL has got commoner over the years because we have got cleverer at diagnosing it. It is now clear that 3.5% of the population over 40 has a population of CLL-like cells in their blood. Does it matter?
It must be clear that since the incidence of CLL is only about 4 per 100,000, that it does not matter a jot for most people. There are a lot of people out there being worried unnecessary. To allay these fears a new condition, monoclonal B cell lymphocytosis, has been invented and it is separated from stage 0 CLL by counting the B-cells in the blood. There must be 5000 per cubic millimeter for it to be CLL. But this is an arbitrary figure and to give it some evidence base there have been two studies. One from the Mayo Clinic suggested that a more appropriate figure might be 11,000 per cu mm and now a new study from Italy has been published in Haematologica.
They looked at 1158 patients with newly diagnosed Binet stage A CLL.The levels of 11,500 for absolute lymphocyte count and 10,000 for B cell count were the best discriminators between those who would never require treatment and those who would. Those with a B cell count of less than 10,000 would progress at a rate of 2.3% per year to eventually requiring treatment, while those with more than 10,000 would progress at a rate of 5.2% per year.
I am not sure that this is much help since it appears from their graph that even after 20 years 78% of those with a B cell count of <10,000 will never be treated and even at greater than 11,000 50% will remain untreated at 20 years.
The recommendation still means that everybody with a lymphocytosis should have flow cytometry in order to count the B cells.
I know that in the UK it is common practice for mild lymphocytoses to be ignored as having no clinical significance, but I wonder whether there is a more certain way of looking at this, perhaps using CD38.
It must be clear that since the incidence of CLL is only about 4 per 100,000, that it does not matter a jot for most people. There are a lot of people out there being worried unnecessary. To allay these fears a new condition, monoclonal B cell lymphocytosis, has been invented and it is separated from stage 0 CLL by counting the B-cells in the blood. There must be 5000 per cubic millimeter for it to be CLL. But this is an arbitrary figure and to give it some evidence base there have been two studies. One from the Mayo Clinic suggested that a more appropriate figure might be 11,000 per cu mm and now a new study from Italy has been published in Haematologica.
They looked at 1158 patients with newly diagnosed Binet stage A CLL.The levels of 11,500 for absolute lymphocyte count and 10,000 for B cell count were the best discriminators between those who would never require treatment and those who would. Those with a B cell count of less than 10,000 would progress at a rate of 2.3% per year to eventually requiring treatment, while those with more than 10,000 would progress at a rate of 5.2% per year.
I am not sure that this is much help since it appears from their graph that even after 20 years 78% of those with a B cell count of <10,000 will never be treated and even at greater than 11,000 50% will remain untreated at 20 years.
The recommendation still means that everybody with a lymphocytosis should have flow cytometry in order to count the B cells.
I know that in the UK it is common practice for mild lymphocytoses to be ignored as having no clinical significance, but I wonder whether there is a more certain way of looking at this, perhaps using CD38.
FCR as salvage therapy
What is the best treatment for relapsed CLL? The MDACC group makes a plea that it is still FCR. In the Blood of 17th March a final report of the large phase II study of FCR in relapsed CLL is made. The overall response rate was 74% and the CR rate 30%. The median overall survival was 47 months and progression-free survival 21 months.
They proposed a hierarchical model of the likelihood of a good response. Patients who were previously exposed to antibody therapy or purine analogues but not to alkylating agents had the highest response rates and survival. Patients who had previous exposure to purine analogues and alkylating agents had a perfectly acceptable respons unless they were refractory to fludarabine. Patients refractory to fludarabine or those who had received more than three previous types of treatment should not be offered FCR.
Drawing from the REACH trial, FCR still seems to have an advantage in patients with del 11q, but obviously not with patients with del 17p.
There were too few data on patients with other modern prognostic markers to draw any conclusions about them.
There are risks with older patients especially in patients who have received prior FCR. Prolonged cytopenias may be more of a risk than from other problems, but from these data it it seems that younger patients who had experienced a remission of at least 3 years are candidates for retreatment with FCR.
They proposed a hierarchical model of the likelihood of a good response. Patients who were previously exposed to antibody therapy or purine analogues but not to alkylating agents had the highest response rates and survival. Patients who had previous exposure to purine analogues and alkylating agents had a perfectly acceptable respons unless they were refractory to fludarabine. Patients refractory to fludarabine or those who had received more than three previous types of treatment should not be offered FCR.
Drawing from the REACH trial, FCR still seems to have an advantage in patients with del 11q, but obviously not with patients with del 17p.
There were too few data on patients with other modern prognostic markers to draw any conclusions about them.
There are risks with older patients especially in patients who have received prior FCR. Prolonged cytopenias may be more of a risk than from other problems, but from these data it it seems that younger patients who had experienced a remission of at least 3 years are candidates for retreatment with FCR.
The SEER-Medicare data on CLL
One of the problems about clinical trials is that they seldom address the disease where it is at. Most patients with CLL are over 70 and have co-morbidities. Such patients are seldom entered into clinical trials. Ideally we should be doing trials in this group of patients, but it ain't gonna happen.
In the Blood of March 31 an article by Danese et al tried to help with this problem. With his co-workers he examined the SEER-Medicare database for how patients with CLL were treated. Although I have waxed lyrical about the German CLL8 trial, it has to be admitted that the median age of entry to this trial was 61 and most patients were of high performance status. Although generally CLL8 demonstrated the benefit to adding rituximab to FC, for patients who were older than 70 years, the numbers were too small to show any benefit. It was also not possible to show benefit for patients with stage C disease.
The SEER-Medicare study were able to look at a large group of CLL patients from defined areas and characterize their initial use of infused therapy (chemotherapy and rituximab) and to evaluate the outcomes in patients using different types of infused therapy. One of the drawbacks of the study is that it is unable to make any comment about the use of oral therapy like chlorambucil so that those apparently receiving rituximab alone might have been receiving chlorambucil plus rituximab or even oral fludarabine and rituximab.
Patients registered between January 1999 and December 2005 were studied. 6433 patients were identified with an average of 40 months follow-up. The median age at diagnosis was 77 years and 1675 were of advanced stage (had anemia or thrombocytopenia. No allowance was made for immune or other types of cytopenia though 3.8% were known to have hemolytic anemia). The SEER population differs slightly from the overall population of the USA in being more urban with more ethnic minorities.
2040 patients received infusional therapy, 1429 receiving chemotherapy alone and 319 rituximab alone. 292 received both, of whom 95 received flufarabine and most of the rest cyclophosphamide. Only 53 patients were identified as receiving FC plus or minus rituximab. Lower rates of infusional therapy was seen in patients older than 80 years, those with more co-morbidities, women, racial ethnic minorities and those residing in poor neighborhoods. Median survival was 52 months for those receiving rituximab with chemotherapy compared with 34 months for those receiving chemotherapy alone. Those receiving rituximab alone had a median survival of 53 months.
There are all sorts of ways of interpreting these figures. We have no data on prognostic factors and no way of matching those having chemotherapy alone and chemotherapy plus immunotherapy patients. We might reasonably expect that those who got rituximab alone were not such severe cases but we do not know. One explanation might be that adding rituximab does indeed enhance survival just as CLL8 says it does and this translates into the ordinary rather than trials population. In this study the advantage continued for the elderly but was not present for those with significant cytopenias. It was greatest when compared with those who had fludarabine rather than other types of chemotherapy.
One other thing of note was that the use of rituximab increased over this period despite the fact that at no time was it licensed for use in CLL. remember these patients were all Medicare patients.
In the Blood of March 31 an article by Danese et al tried to help with this problem. With his co-workers he examined the SEER-Medicare database for how patients with CLL were treated. Although I have waxed lyrical about the German CLL8 trial, it has to be admitted that the median age of entry to this trial was 61 and most patients were of high performance status. Although generally CLL8 demonstrated the benefit to adding rituximab to FC, for patients who were older than 70 years, the numbers were too small to show any benefit. It was also not possible to show benefit for patients with stage C disease.
The SEER-Medicare study were able to look at a large group of CLL patients from defined areas and characterize their initial use of infused therapy (chemotherapy and rituximab) and to evaluate the outcomes in patients using different types of infused therapy. One of the drawbacks of the study is that it is unable to make any comment about the use of oral therapy like chlorambucil so that those apparently receiving rituximab alone might have been receiving chlorambucil plus rituximab or even oral fludarabine and rituximab.
Patients registered between January 1999 and December 2005 were studied. 6433 patients were identified with an average of 40 months follow-up. The median age at diagnosis was 77 years and 1675 were of advanced stage (had anemia or thrombocytopenia. No allowance was made for immune or other types of cytopenia though 3.8% were known to have hemolytic anemia). The SEER population differs slightly from the overall population of the USA in being more urban with more ethnic minorities.
2040 patients received infusional therapy, 1429 receiving chemotherapy alone and 319 rituximab alone. 292 received both, of whom 95 received flufarabine and most of the rest cyclophosphamide. Only 53 patients were identified as receiving FC plus or minus rituximab. Lower rates of infusional therapy was seen in patients older than 80 years, those with more co-morbidities, women, racial ethnic minorities and those residing in poor neighborhoods. Median survival was 52 months for those receiving rituximab with chemotherapy compared with 34 months for those receiving chemotherapy alone. Those receiving rituximab alone had a median survival of 53 months.
There are all sorts of ways of interpreting these figures. We have no data on prognostic factors and no way of matching those having chemotherapy alone and chemotherapy plus immunotherapy patients. We might reasonably expect that those who got rituximab alone were not such severe cases but we do not know. One explanation might be that adding rituximab does indeed enhance survival just as CLL8 says it does and this translates into the ordinary rather than trials population. In this study the advantage continued for the elderly but was not present for those with significant cytopenias. It was greatest when compared with those who had fludarabine rather than other types of chemotherapy.
One other thing of note was that the use of rituximab increased over this period despite the fact that at no time was it licensed for use in CLL. remember these patients were all Medicare patients.
Shingles again
There still seems to be a lot of confusion about shingles and it seems a good time to write about it again.
Shingles and chicken pox are caused by the same virus known as varicella/zoster. Normally, children catch the virus at a young age and develop chicken pox, which can vary from an itchy spotty disease to an asymptomatic attack. In the immunodeficient it can cause a severe and often fatal viral pneumonia. Most people rapidly recover from chicken pox, but the virus remains in the body hidden in one or more nerve cells in the spine.
In the elderly and especially in the immune deficient the virus can be reactivated and migrate down a peripheral nerve to cause a painful blistering rash over the skin where the nerve supplies sensation. This is called shingles. Very occasionally in the immunodeficient there are recurrent attacks, not necessarily in the same nerve, and even more occasionally in the very immunodeficient the virus can disseminate causing chicken pox which may be fatal.
A little while ago a vaccine made from attenuated live virus was developed and used to prevent chicken pox in children in some countries (though not in the UK). This same vaccine is offered to older people to prevent shingles. CLL experts have determined that as it is a live vaccine it should not be given to CLL patients, although small numbers have had it safely.
It needs to be stated clearly that normal people do not catch shingles from people with chicken pox, although children can catch chicken pox from adults with shingles.
There is an unanswered question. Do patients with CLL have enough anti-zoster immunity to withstand a fresh attack of the virus, either from someone with chicken pox or zoster who is excreting the virus, or from someone who has been vaccinated and is excreting the attenuated virus? The answer to that question is that we don't know. Clearly some do have enough immunity, even though they may have no zoster antibodies. I would suspect that CLL patients are more at risk from the virus living inside them than from a virus that someone else is shedding which may never gain entry to their bodies.
What advice can we give? Obviously the safest advice is to quarantine yourself from anyone who may be shedding virus, this means until the blisters have healed up. Unfortunately, this is not always practical. If it is not, then the next best advice is to take prophylactic aciclovir or equivalent. The good news is that almost all cases of varicella/zoster infection respond to these drugs.
Shingles and chicken pox are caused by the same virus known as varicella/zoster. Normally, children catch the virus at a young age and develop chicken pox, which can vary from an itchy spotty disease to an asymptomatic attack. In the immunodeficient it can cause a severe and often fatal viral pneumonia. Most people rapidly recover from chicken pox, but the virus remains in the body hidden in one or more nerve cells in the spine.
In the elderly and especially in the immune deficient the virus can be reactivated and migrate down a peripheral nerve to cause a painful blistering rash over the skin where the nerve supplies sensation. This is called shingles. Very occasionally in the immunodeficient there are recurrent attacks, not necessarily in the same nerve, and even more occasionally in the very immunodeficient the virus can disseminate causing chicken pox which may be fatal.
A little while ago a vaccine made from attenuated live virus was developed and used to prevent chicken pox in children in some countries (though not in the UK). This same vaccine is offered to older people to prevent shingles. CLL experts have determined that as it is a live vaccine it should not be given to CLL patients, although small numbers have had it safely.
It needs to be stated clearly that normal people do not catch shingles from people with chicken pox, although children can catch chicken pox from adults with shingles.
There is an unanswered question. Do patients with CLL have enough anti-zoster immunity to withstand a fresh attack of the virus, either from someone with chicken pox or zoster who is excreting the virus, or from someone who has been vaccinated and is excreting the attenuated virus? The answer to that question is that we don't know. Clearly some do have enough immunity, even though they may have no zoster antibodies. I would suspect that CLL patients are more at risk from the virus living inside them than from a virus that someone else is shedding which may never gain entry to their bodies.
What advice can we give? Obviously the safest advice is to quarantine yourself from anyone who may be shedding virus, this means until the blisters have healed up. Unfortunately, this is not always practical. If it is not, then the next best advice is to take prophylactic aciclovir or equivalent. The good news is that almost all cases of varicella/zoster infection respond to these drugs.
Dasatanib in CLL
A paper in the BJHaem looks at the possibility of using Dasatinib in CLL. As well as antagonising bcr/abl signaling, Dasatanib inhibits Syk phosphorylation with downstream affects on calcium flux, PI3K and MAPkinase activation and the the Mcl-1 inhibition of apoptosis. However, CLL cells can be rescued from these effects by stromal cell contact of by stimulation with CD154L and IL-4. Our old friend 17-DMAG the HSP90 inhibitor restores the effect of Dasatanib. The combination might have promise.
Social Housing
Over the past few days I have watched a couple of BBC documentaries on Council Houses. At the end of the Victorian era the housing stock in London and some of the other larger cities of the UK was terrible. The poor lived in overcrowded and unhygienic condition, renting rooms of multiple occupancy from private landlords, that were damp, cold and poorly ventilated. It was nothing for three of four families to live in a single room, their quarters separated by a sheet hanging over a line strung across the room. Washing and toilet facilities were outside and shared. Usually there was no heating and little employment.
Of course, the working classes were better catered for in service of the large country mansions, but that was strict servitude. Some philanthropists such as Cadbury, Rowntree and Fry and established garden cities around their factories for their workers and there were many tied cottages for railway workers, miners and agricultural workers.
A Royal Commission concluded that Local Authorities might be permitted to take the lead in providing social housing and first London County Council and then Liverpool and other large cities began to build tenements, houses, apartments, and garden cities to house the working classes.
These were an immediate success and proved a Godsend to the 'deserving' poor. There were always working people who sought to better themselves by the virtue of hard work and by and large it was these who took up the challenge of moving into carefully designed properties. The difference between these 'Council Houses' and their previously rented accommodation was immense. Indoor sanitation was universal. Fitted kitchens, pantries to store food, no more cooking over an open fire, gas lamps and then electricity, good ventilation, gardens, space; all were provided. Even better than the local flats were the garden cities just outside the London green belt; towns like Stevenage. Here ever man had his vegetable patch.
By the 1960s having overcome the challenges of two world wars and homes for returning heroes, the councils began to cater for consumerism, with more electric plugs for the kitchen, space for washing machines and fridges and garages and parking spaces.
The councils were surprisingly paternalistic, laying down how many times the house had to be cleaned, the windows washed, the inside decorated and the hedges clipped, but the occupants took no offence, such was the improvement of their living standard.
The earliest residence that I remember was a basement flat with one bedroom a kitchen and a living room. I lived there until I was 5 with my parents and younger sister. My first cot was a drawer of a chest of drawers, pulled out and padded with blankets. My sister and I had the bedroom and my parents slept in the living room on a bed-settee covered with 'leatherette' with a cigarette hole in it.
I think my father would have been called one of the deserving poor. His mother was a single mum by the time I knew her. She lived in one of the worst slums in Worcester, two up and two down, with no water, gas, electricity or inside sanitation. A pump at the end of the road was the source of water and there was an outside lavatory for every three houses in the street. Cooking was over a coal fire. She died at the age of 48.
My father served a 7-year apprenticeship as a tailor's cutter and found work as a tailor during the war (he was unable to serve in the forces because of past TB) following the troops making and repairing uniforms for Bernard Weatherall, the tailor (His son went on to be Speaker of the House of Commons). He and my mother lived in rented rooms and on one occasion in a Gypsy caravan parked in a field. While we were in the basement flat my mother fell pregnant again and my father, who was now employed as a bar steward in the officer's mess for the Royal Army Medical Corps in Aldershot, found extra work, moonlighting doing alterations for a local tailor. This kind man bought us a house to rent for our larger family and my father was able to take on extra moonlighting for the big multiple tailors like Burtons and Hepworths.
Our new house, that we moved into in 1948 had an outside toilet, no bathroom, three bedrooms, two reception rooms and a kitchen with a stone sink and cold running water. There was a small garden where we grew vegetables and kept chickens. We lived there for 8 years and when my youngest brother was born we bought our first house in 1956. This had a bathroom and a back boiler so we had hot running water for the first time. The galley kitchen was small but the kitchen sink was porcelain rather than stone, with two taps. We built a conservatory onto it in 1959 and extended into the roof for an extra bedroom that clearly did not meet building regulations. It had no window and I slept up there on an old camp bed.
After I went to University my parents bought a new house which my mother still lives in in her 92nd year. He background was just as poor as my father's. She was the daughter of the oldest daughter of a well-to-do builder. Despite the wealth in the family, she got nothing; all the money went to the boys. At the age of 12 my mother went into service with her grandmother, performing menial household tasks. My grandmother was married off to a builder's labourer and set up in a two-up and two down house owned by her parents. I remember it well as I used to holiday there as a child. It had no bathroom and an outside lavatory, a stone flagged kitchen that contained a solid fuel boiler and a mangle. People washed in the kitchen. It did have gas and electricity but no electric points. My grandmother brought up eight children in this little house and was there until she died.
My point in telling you this is that my mother's sister got a council house in Worcester. It was huge with a bathroom and a fitted kitchen. It had a large garden which backed on to open farmland. It was a far higher quality than most privately rented accommodation available then.
However by the 1970s policy had changed. You no longer earned points to raise yourself on the council house waiting list. Priority was given instead for the indigenous poor; the unemployed, the destitute, the drug addicts, the unmarried mothers. Council estates became tips. Rubbish, like old bikes, sofas and old TVs were dumped in front gardens and never cleared away. Drug pushing and casual crime abounded. Whole streets of fat, ugly, illiterate and lazy people proliferated. The neighborhood went down hill. The 'deserving' poor were offered the chance to buy their council houses at a discount in the 1980s and this did something to improve the estates, but others, especially the high-rise estates built in the 1960s and 1970s rapidly decayed. Nobody wanted to live in them. They had been cheaply constructed and had become slums worse that those they had replaced in less than 20 years.
Today there are people on Council House waiting lists that will never be rehoused. A large degree of criminality has entered into the situation. In London over 50,000 council houses are being sublet at a profit. Some council tenants have become millionaires from the largess of the local council. One man shown on one documentary owns several properties including a chateau in France. The housing problem has been exacerbated by huge amount of immigration that has taken place in the past 10 years.
In the 1960s the UK was building over 300,000 new homes every year. Today, only a fraction of that number are being constructed. We have a real problem awaiting us. There are many derelict houses in the north waiting to be reclaimed, but there are no jobs to sustain them. In London quite ordinary apartments regularly sell for over a million pounds. With interest rates so low, rents have become very high to get a return on investment. I fear for our young people. Many live at home with parents in overcrowded conditions until their late thirties.
The governments responses - council tenancies have to be reapplied for every two years, council houses being seen as stop-gaps rather than permanent solutions, a limit on housing bnefit, may make cosmetic changes, but they don't seem to be a solution.
Of course, the working classes were better catered for in service of the large country mansions, but that was strict servitude. Some philanthropists such as Cadbury, Rowntree and Fry and established garden cities around their factories for their workers and there were many tied cottages for railway workers, miners and agricultural workers.
A Royal Commission concluded that Local Authorities might be permitted to take the lead in providing social housing and first London County Council and then Liverpool and other large cities began to build tenements, houses, apartments, and garden cities to house the working classes.
These were an immediate success and proved a Godsend to the 'deserving' poor. There were always working people who sought to better themselves by the virtue of hard work and by and large it was these who took up the challenge of moving into carefully designed properties. The difference between these 'Council Houses' and their previously rented accommodation was immense. Indoor sanitation was universal. Fitted kitchens, pantries to store food, no more cooking over an open fire, gas lamps and then electricity, good ventilation, gardens, space; all were provided. Even better than the local flats were the garden cities just outside the London green belt; towns like Stevenage. Here ever man had his vegetable patch.
By the 1960s having overcome the challenges of two world wars and homes for returning heroes, the councils began to cater for consumerism, with more electric plugs for the kitchen, space for washing machines and fridges and garages and parking spaces.
The councils were surprisingly paternalistic, laying down how many times the house had to be cleaned, the windows washed, the inside decorated and the hedges clipped, but the occupants took no offence, such was the improvement of their living standard.
The earliest residence that I remember was a basement flat with one bedroom a kitchen and a living room. I lived there until I was 5 with my parents and younger sister. My first cot was a drawer of a chest of drawers, pulled out and padded with blankets. My sister and I had the bedroom and my parents slept in the living room on a bed-settee covered with 'leatherette' with a cigarette hole in it.
I think my father would have been called one of the deserving poor. His mother was a single mum by the time I knew her. She lived in one of the worst slums in Worcester, two up and two down, with no water, gas, electricity or inside sanitation. A pump at the end of the road was the source of water and there was an outside lavatory for every three houses in the street. Cooking was over a coal fire. She died at the age of 48.
My father served a 7-year apprenticeship as a tailor's cutter and found work as a tailor during the war (he was unable to serve in the forces because of past TB) following the troops making and repairing uniforms for Bernard Weatherall, the tailor (His son went on to be Speaker of the House of Commons). He and my mother lived in rented rooms and on one occasion in a Gypsy caravan parked in a field. While we were in the basement flat my mother fell pregnant again and my father, who was now employed as a bar steward in the officer's mess for the Royal Army Medical Corps in Aldershot, found extra work, moonlighting doing alterations for a local tailor. This kind man bought us a house to rent for our larger family and my father was able to take on extra moonlighting for the big multiple tailors like Burtons and Hepworths.
Our new house, that we moved into in 1948 had an outside toilet, no bathroom, three bedrooms, two reception rooms and a kitchen with a stone sink and cold running water. There was a small garden where we grew vegetables and kept chickens. We lived there for 8 years and when my youngest brother was born we bought our first house in 1956. This had a bathroom and a back boiler so we had hot running water for the first time. The galley kitchen was small but the kitchen sink was porcelain rather than stone, with two taps. We built a conservatory onto it in 1959 and extended into the roof for an extra bedroom that clearly did not meet building regulations. It had no window and I slept up there on an old camp bed.
After I went to University my parents bought a new house which my mother still lives in in her 92nd year. He background was just as poor as my father's. She was the daughter of the oldest daughter of a well-to-do builder. Despite the wealth in the family, she got nothing; all the money went to the boys. At the age of 12 my mother went into service with her grandmother, performing menial household tasks. My grandmother was married off to a builder's labourer and set up in a two-up and two down house owned by her parents. I remember it well as I used to holiday there as a child. It had no bathroom and an outside lavatory, a stone flagged kitchen that contained a solid fuel boiler and a mangle. People washed in the kitchen. It did have gas and electricity but no electric points. My grandmother brought up eight children in this little house and was there until she died.
My point in telling you this is that my mother's sister got a council house in Worcester. It was huge with a bathroom and a fitted kitchen. It had a large garden which backed on to open farmland. It was a far higher quality than most privately rented accommodation available then.
However by the 1970s policy had changed. You no longer earned points to raise yourself on the council house waiting list. Priority was given instead for the indigenous poor; the unemployed, the destitute, the drug addicts, the unmarried mothers. Council estates became tips. Rubbish, like old bikes, sofas and old TVs were dumped in front gardens and never cleared away. Drug pushing and casual crime abounded. Whole streets of fat, ugly, illiterate and lazy people proliferated. The neighborhood went down hill. The 'deserving' poor were offered the chance to buy their council houses at a discount in the 1980s and this did something to improve the estates, but others, especially the high-rise estates built in the 1960s and 1970s rapidly decayed. Nobody wanted to live in them. They had been cheaply constructed and had become slums worse that those they had replaced in less than 20 years.
Today there are people on Council House waiting lists that will never be rehoused. A large degree of criminality has entered into the situation. In London over 50,000 council houses are being sublet at a profit. Some council tenants have become millionaires from the largess of the local council. One man shown on one documentary owns several properties including a chateau in France. The housing problem has been exacerbated by huge amount of immigration that has taken place in the past 10 years.
In the 1960s the UK was building over 300,000 new homes every year. Today, only a fraction of that number are being constructed. We have a real problem awaiting us. There are many derelict houses in the north waiting to be reclaimed, but there are no jobs to sustain them. In London quite ordinary apartments regularly sell for over a million pounds. With interest rates so low, rents have become very high to get a return on investment. I fear for our young people. Many live at home with parents in overcrowded conditions until their late thirties.
The governments responses - council tenancies have to be reapplied for every two years, council houses being seen as stop-gaps rather than permanent solutions, a limit on housing bnefit, may make cosmetic changes, but they don't seem to be a solution.
John 3:2
He came to Jesus at night and said, "Rabbi, we know you are a teacher who has come from God. For no-one could perform the miraculous signs you are doing if God were not with him."
The Pharisees have got a bad press. We see them as the arch villains in the Biblical story, yet among them were Nicodemus and St Paul. We must be careful not to judge a book by its cover. This is particularly true of members of political parties. There are many who are earnestly seeking yet have taken a wrong path and other who are apparently on the right path for all the wrong reasons.
My readers will know that I am right of center, yet some of the activities of my fellow right-wingers appall me, while I recognize that some left wingers say what they say out of compassion and self-sacrifice, they just seem to have chosen an impossible solution. Nicodemus was brought up short by the evidence of his own eyes. Perhaps he was beginning to see that the way to salvation was not by tithing mint and cumin.
The Pharisees have got a bad press. We see them as the arch villains in the Biblical story, yet among them were Nicodemus and St Paul. We must be careful not to judge a book by its cover. This is particularly true of members of political parties. There are many who are earnestly seeking yet have taken a wrong path and other who are apparently on the right path for all the wrong reasons.
My readers will know that I am right of center, yet some of the activities of my fellow right-wingers appall me, while I recognize that some left wingers say what they say out of compassion and self-sacrifice, they just seem to have chosen an impossible solution. Nicodemus was brought up short by the evidence of his own eyes. Perhaps he was beginning to see that the way to salvation was not by tithing mint and cumin.
Friday, May 06, 2011
Immunodeficiency of CLL explained
It may help to explain my post from yesterday if I put more in lay language. There seem to be two processes going on to account for the immunodeficiency that we see in indolent lymphomas. For all lymphomas, whether node based or not, there seems to be an underlying inflammatory phase (a good example would be the H.pylori infection behind gastric lymphoma). Helper T cells get attracted to the inflammatory reaction and activated to help in antibody production (Th2 cells). As a result there is a shortage of naive T helper cells to be directed to other tasks like responding to Hepatitis B vaccine. The second type of immunosuppression occurs where there are circulating tumor cells as in CLL. Here, cell to cell contact between CLL cells and T helper cells affects the T helper cell finction so that they are unable to make the normal T helper cytokines and start to die, so there is an absolute deficiency of T helper cells and therefore an inability to respond to vaccines.
People should now come up with ideas to remedy this.
People should now come up with ideas to remedy this.
Burn before watching
I watched the recent Coen Brothers film, Burn after Reading last night. I cannot recomend it. In fact I barely managed to last the distance. The language was foul and it was not funny. It had nothing important to say and a lot of fine actors were wasted.
John 3:1
Now there was a man of the Pharisees named Nicodemus, a member of the Jewish ruling council.
Leaders! Where would be without them? Our leaders have come in for a hammering in the past few days. Obama has still not managed to satisfy the 'birther zealots' and may have acted unlawfully in sanctioning the Osama 'hit'. The republicans have not exactly covered themselves with glory over the whole incident. Back home, Nick Clegg has taken a hammering in the elections, Cameron has only done alright, Milliband has been disappointing, especially in Scotland. The Israelis have suffered a setback as Hamas and Fatah seal a pact.
I have been reading about the First World War. 'Lions led by donkeys' they said. None of the leaders then could escape criticism. They say that all political careers end in failure and that is probably true. The Archbishop of Canterbury has come out with an equivocal statement about the bin Laden killing. Probably better to have said nothing like the Roman Catholic Church. Osama, himself, was a busted flush, holed up in a single room for five years, sidelined by his organization which was split, anyway.
The middle verse in the whole Bible is Psalm 118 v8: It is better to take refuge in the Lord than to trust in man.
Leaders! Where would be without them? Our leaders have come in for a hammering in the past few days. Obama has still not managed to satisfy the 'birther zealots' and may have acted unlawfully in sanctioning the Osama 'hit'. The republicans have not exactly covered themselves with glory over the whole incident. Back home, Nick Clegg has taken a hammering in the elections, Cameron has only done alright, Milliband has been disappointing, especially in Scotland. The Israelis have suffered a setback as Hamas and Fatah seal a pact.
I have been reading about the First World War. 'Lions led by donkeys' they said. None of the leaders then could escape criticism. They say that all political careers end in failure and that is probably true. The Archbishop of Canterbury has come out with an equivocal statement about the bin Laden killing. Probably better to have said nothing like the Roman Catholic Church. Osama, himself, was a busted flush, holed up in a single room for five years, sidelined by his organization which was split, anyway.
The middle verse in the whole Bible is Psalm 118 v8: It is better to take refuge in the Lord than to trust in man.
Thursday, May 05, 2011
Immunodeficiency in early CLL and other lymphomas
There is a mystery as to why indolent lymphomas become immunodeficient. Oh, I know about the low immunoglobulins, but it is apparent that not just CLL, but myeloma and other types of lymphoma all fail to respond well to immunization with vaccines. Response to vaccines is generally a T-cell responsibility, so what's gone wrong with the T cells?
A paper in this week's Blood addresses the problem. Reduced T cell counts are common in the untreated indolent lymphoid tumors and there is an almost universal pattern of unresponsiveness to vaccination against Hepatitis B. They identified two different patterns of dysregulation of the T-helper cell compartment.
Pattern 1: chronic immune activation with Th2 shift, in vitro hyperreactivity and T cell senescence with propensity to undergo apoptosis.
This exists in follicular lymphoma and extranodal marginal zone lymphomas. This is characterized by a marked reduction of naive T-helper cells and recent thymus emigrants. There is an activated T helper phenotype and a Th2 shift (a tendency to make IL-4 rather than IL-2). It seems that naive T cells are attracted to lymphoma sites and reprogrammed to make IL-4 by cytokines such as CCL17 and CCL22. Activated T cells (CD69+ of OX40+ T helper cells) are absent from the peripheral blood but abound at lymphoma sites. Some of these are aberrantly activated and return to the circulation where they are sensitive to activation via the TCR or CD28. These cells are prone to apoptosis. These processes act together to decrease the numbers of T helper cells available for immune reactions.
This pattern may be seen in late CLL but not in early CLL. It may also be seen in some inflammatory conditions such as SLE and rheumatoid arthritis and in some elderly persons.
The second pattern: down regulation of TCR signaling and cytokine secretion. This pattern is characterized by a reduced expression of multiple genes associated with co-stimulation of the TCR and CD28 resulting in a reduced secretion of cytokines. Among the genes under-expressed are those of the NFkappaB and PI3K pathways. A consequence of this type of T-cell dysfunction is severely impaired formation of the immunological synapse and as well as in early stage CLL it is seen in the leukemia phase of follicular lymphoma. It can be induced in normal T cells by contact with CLL cells.
There does not seem to be a role for Tregs in either pattern. Previous reports of relative increases of Tregs in indolent lymphoma, early CLL and MGUS appear to be due to an absolute reduction in naive T helper cells.
A paper in this week's Blood addresses the problem. Reduced T cell counts are common in the untreated indolent lymphoid tumors and there is an almost universal pattern of unresponsiveness to vaccination against Hepatitis B. They identified two different patterns of dysregulation of the T-helper cell compartment.
Pattern 1: chronic immune activation with Th2 shift, in vitro hyperreactivity and T cell senescence with propensity to undergo apoptosis.
This exists in follicular lymphoma and extranodal marginal zone lymphomas. This is characterized by a marked reduction of naive T-helper cells and recent thymus emigrants. There is an activated T helper phenotype and a Th2 shift (a tendency to make IL-4 rather than IL-2). It seems that naive T cells are attracted to lymphoma sites and reprogrammed to make IL-4 by cytokines such as CCL17 and CCL22. Activated T cells (CD69+ of OX40+ T helper cells) are absent from the peripheral blood but abound at lymphoma sites. Some of these are aberrantly activated and return to the circulation where they are sensitive to activation via the TCR or CD28. These cells are prone to apoptosis. These processes act together to decrease the numbers of T helper cells available for immune reactions.
This pattern may be seen in late CLL but not in early CLL. It may also be seen in some inflammatory conditions such as SLE and rheumatoid arthritis and in some elderly persons.
The second pattern: down regulation of TCR signaling and cytokine secretion. This pattern is characterized by a reduced expression of multiple genes associated with co-stimulation of the TCR and CD28 resulting in a reduced secretion of cytokines. Among the genes under-expressed are those of the NFkappaB and PI3K pathways. A consequence of this type of T-cell dysfunction is severely impaired formation of the immunological synapse and as well as in early stage CLL it is seen in the leukemia phase of follicular lymphoma. It can be induced in normal T cells by contact with CLL cells.
There does not seem to be a role for Tregs in either pattern. Previous reports of relative increases of Tregs in indolent lymphoma, early CLL and MGUS appear to be due to an absolute reduction in naive T helper cells.
Osama bin Laden, Dead
How should we react to the slaying of Osama bin Laden by Navy SEALS? It is clear by now that the original story of how it was done was not exactly true. Would it have been preferable to just have arrested him? Even that might have been tested in court since the US did not have Pakistani authority for an incursion into their territory. A court might have declared the arrest invalid and ordered his release. Then there would have been all the arguments about the validity of the trial and the necessity of long, drawn out, litigation. I think it takes a decade or more to execute someone under US law.
However, I can think of no law by which the SEALS had the right to execute him in Pakistan.
I have been reading about the 1st World War, when tens of thousands were killed in a single day. The weapons used at the time were often of dubious legality for the rules of war. (The bombing of civilians from airships was definitely forbidden). We talk about the fog of war. The original reason for invading Afghanistan was to capture or kill bin Laden , who by his own admission was the instigator of 9/11 and in any case was already a wanted man for several heinous crimes committed by AK. But a decade has passed and the wounds have healed over a bit. This could hardly be called hot pursuit.
I am reminded of The Searchers and John Wayne's relentless pursuit of the brave who kidnapped Natalie Wood. Long after others had forgotten about the hurt, he pursued his revenge. Was this all about revenge?
What if it was? The USA can act pretty well as it likes in the world and no-one can hold it to account. It may not always be so. But it is a dangerous move for American citizens. If the American President can kill whom he likes without recourse to law, then who is safe?
I am sure many in America will today feel vindicated. The man was clearly a criminal and they will feel that justice has been done. No doubt we will hear a more complete story as the days pass, but one could wish that Osama had been found with an AK47 in his hand.
However, I can think of no law by which the SEALS had the right to execute him in Pakistan.
I have been reading about the 1st World War, when tens of thousands were killed in a single day. The weapons used at the time were often of dubious legality for the rules of war. (The bombing of civilians from airships was definitely forbidden). We talk about the fog of war. The original reason for invading Afghanistan was to capture or kill bin Laden , who by his own admission was the instigator of 9/11 and in any case was already a wanted man for several heinous crimes committed by AK. But a decade has passed and the wounds have healed over a bit. This could hardly be called hot pursuit.
I am reminded of The Searchers and John Wayne's relentless pursuit of the brave who kidnapped Natalie Wood. Long after others had forgotten about the hurt, he pursued his revenge. Was this all about revenge?
What if it was? The USA can act pretty well as it likes in the world and no-one can hold it to account. It may not always be so. But it is a dangerous move for American citizens. If the American President can kill whom he likes without recourse to law, then who is safe?
I am sure many in America will today feel vindicated. The man was clearly a criminal and they will feel that justice has been done. No doubt we will hear a more complete story as the days pass, but one could wish that Osama had been found with an AK47 in his hand.
Health update
It is now 5 weeks since the end of chemotherapy. I am making slow progress. I still have bloating after meals but my strength is improving. I have to be very careful about my bowels and am on a low residue diet. I am taking live yoghurt and small meals often. I am still taking steroids for edema around the anastomosis. My weight is steady and my appetite is good. My hair is growing back and I had to have it cut yesterday.
I reckon that there is a motility problem largely due to the altered anatomy and the autonomic neuropathy from the oxaloplatin, and I have to learn to cope with this. There seems to be no progressive obstruction which should mean that my condition will be stable for a while and I should be able to get back to a fairly normal life. I am taking simeticone to reduce the amount of wind that I have.
I am trying to get some exercise every day and hope to attend EHA next month, though I am having to give the MDS Workshop a miss in Edinburgh.
I reckon that there is a motility problem largely due to the altered anatomy and the autonomic neuropathy from the oxaloplatin, and I have to learn to cope with this. There seems to be no progressive obstruction which should mean that my condition will be stable for a while and I should be able to get back to a fairly normal life. I am taking simeticone to reduce the amount of wind that I have.
I am trying to get some exercise every day and hope to attend EHA next month, though I am having to give the MDS Workshop a miss in Edinburgh.
John 2:23-25
Now while he was in Jerusalem at the Passover Feast, many people saw the miraculous signs he was doing and believed in his name. But Jesus would not entrust himself to them, for he knew all men. He did not need man’s testimony about man, for he knew what was in a man.
These three verses could as easily be a preface to chapter 3 rather than a coda to chapter 2. The chapter breaks are, of course, arbitrary.
By the time of the attendance at the Passover feast, Jesus was regularly performing miracles, which naturally drew men to him, but Jesus was not taken in by easy applause. He knew what man is like. I can never understand it when people say that men are naturally good; quite the reverse, we are naturally evil. The older I get and the more honest I am with myself, I recognize my own evil heart and have no reason to think that other people are different.
These three verses could as easily be a preface to chapter 3 rather than a coda to chapter 2. The chapter breaks are, of course, arbitrary.
By the time of the attendance at the Passover feast, Jesus was regularly performing miracles, which naturally drew men to him, but Jesus was not taken in by easy applause. He knew what man is like. I can never understand it when people say that men are naturally good; quite the reverse, we are naturally evil. The older I get and the more honest I am with myself, I recognize my own evil heart and have no reason to think that other people are different.
Wednesday, May 04, 2011
Galatians 5:19-21. Bin Laden gone.
The acts of the flesh are obvious: sexual immorality, impurity and debauchery; idolatry and witchcraft; hatred, discord, jealousy, fits of rage, selfish ambition, dissensions, factions and envy; drunkenness, orgies, and the like. I warn you, as I did before, that those who live like this will not inherit the kingdom of God.
I'm not sure how many of these sins Osama bin Laden was guilty of; he was on his fifth wife and had countless children, despite being a teetotaller he had a healthy appetite for the caffeine of Coke and Pepsi, he was certainly guilty of hatred, discord, jealousy, fits of rage, selfish ambition, dissensions, factions and envy towards the United States. He was altogether a wicked man, though like Adolf Hitler, he was apparently kind to dumb animals. From reports he was devoted to an interpretation of Islam which sought to wage war on Western values and was equally ranged against other Islamic traditions. He inspired a generation of Islamist fascists who took part in mayhem and murder across the globe. He claimed to be the planner and inspiration of much of it.
Now he is gone. There will no doubt be conspiracy theories about his still surviving, but I have no truck with them. It would have been preferable, perhaps, if like Saddam Hussain he had been captured and brought to trial, but he was truly a participant in a war and has died the death of a common soldier. No-one should mourn his demise. No doubt we shall see retaliatory atrocities. We must weather them.
Be assured, "those who live like this will not inherit the kingdom of God." there will be no 72 virgins waiting for him.
I'm not sure how many of these sins Osama bin Laden was guilty of; he was on his fifth wife and had countless children, despite being a teetotaller he had a healthy appetite for the caffeine of Coke and Pepsi, he was certainly guilty of hatred, discord, jealousy, fits of rage, selfish ambition, dissensions, factions and envy towards the United States. He was altogether a wicked man, though like Adolf Hitler, he was apparently kind to dumb animals. From reports he was devoted to an interpretation of Islam which sought to wage war on Western values and was equally ranged against other Islamic traditions. He inspired a generation of Islamist fascists who took part in mayhem and murder across the globe. He claimed to be the planner and inspiration of much of it.
Now he is gone. There will no doubt be conspiracy theories about his still surviving, but I have no truck with them. It would have been preferable, perhaps, if like Saddam Hussain he had been captured and brought to trial, but he was truly a participant in a war and has died the death of a common soldier. No-one should mourn his demise. No doubt we shall see retaliatory atrocities. We must weather them.
Be assured, "those who live like this will not inherit the kingdom of God." there will be no 72 virgins waiting for him.
John 2:18-22
The Jews then responded to him, “What sign can you show us to prove your authority to do all this?” Jesus answered them, “Destroy this temple, and I will raise it again in three days.” They replied, “It has taken forty-six years to build this temple, and you are going to raise it in three days?” But the temple he had spoken of was his body. After he was raised from the dead, his disciples recalled what he had said. Then they believed the scripture and the words that Jesus had spoken.
Here is another reminder that this gospel is thematically rather than chronologically arranged. This was a charge brought against Jesus at his trial. It would not have been sensible to bring a charge about something he had said three years ago; they would have gone for a current statement made only a few days ago.
The Jews were notorious for taking things literally and not seeing the spiritual content of the statement as John explains. He was not talking about the literal Temple but about the Temple of the Holy Spirit, his body.
Here again we have the same theme: the old has gone; the new has come. Temple worship with its animal sacrifice was to end; the new covenant would be based on the sacrificial death of Jesus Christ.
Here is another reminder that this gospel is thematically rather than chronologically arranged. This was a charge brought against Jesus at his trial. It would not have been sensible to bring a charge about something he had said three years ago; they would have gone for a current statement made only a few days ago.
The Jews were notorious for taking things literally and not seeing the spiritual content of the statement as John explains. He was not talking about the literal Temple but about the Temple of the Holy Spirit, his body.
Here again we have the same theme: the old has gone; the new has come. Temple worship with its animal sacrifice was to end; the new covenant would be based on the sacrificial death of Jesus Christ.
Tuesday, May 03, 2011
Btk inhibitors
We really have some excellent drugs for killing the circulating cells in CLL. Even chlorambucil is good at lowering the white count and fludarabine is excellent at it. I have seen FCR restore a white count to normal after a single course. The problem with CLL is that the peripheral blood is not where the action is. Although CLL cells are long lived and only die slowly, the real problem is that they are inexorably proliferating. This proliferation takes place in proliferation centers in the lymph nodes, spleen and bone marrow. Proliferation occurs because signals to proliferate are sent through messenger pathways from surface stimulation. In CLL the main signals come through the B-cell receptor (BCR). In unmutated CLL the BCR signaling works much better than in mutated CLL, which is why the former has a worse prognosis.
When the BCR is stimulated signaling through syk stimulates a host of other pathways that activate transcription factors in the nucleus. Chief among these pathways are the ERK, PI3K, and the NFkappaB pathways. It would be possible to develop drugs to inhibit these pathways, of course, but since they are used by every cell in the body, the effect would be a sort of universal toxicity as all cell types would be affected. Luckily, nature points the way.
Immunodeficiency diseases are great disasters for the patient. You probably have heard of the boys in the bubbles; young boys who have to live in plastic tents with sterile air pumped in, because they are susceptible to every germ. The only remedies for such diseases are a bone marrow transplant or else gene therapy. But there is a type of immunodeficiency that is easier to treat. Congenital hypogammaglobulinemia can be treated by regular infusions of gamma globulin. The type that occurs in young boys is called Bruton’s X-linked hypogammaglobulemia and is cause by a mutation in the gene for Bruton’s tyrosine kinase (Btk). Although this gene is expressed in many hematopoietic cells, when the gene is knocked out in mice it seems to be only effectively used by B cells; it doesn’t affect other cells in the blood and the only deficiency is in the immunoglobulins.
Since Gleevec, everybody is into tyrosine kinase inhibitors. Ideally they should be highly selective, only inhibiting specific tyrosine kinases, and that tyrosine kinase should have a narrow applicability. The orally available inhibitor PCI-32765 has been shown to be very useful at inhibiting the type of large diffuse B-cell lymphomas that are driven by BCR signaling. When used in dogs with aggressive B-cell lymphomas it produced remarkable clinical effects. Fairly specific kinase inhibitors have already been used in CLL with good effect; the syk inhibitor, fostamatinib, and the PI3K-delta specific inhibitor CAL-101. An article has been pre-published in Blood on the pre-clinical effects of PCI-32765.
They first showed that although BTK protein is variably expressed in CLL it does not correlate with prognostic markers. However, BTK mRNA was only modestly variable though significantly higher than that found in normal B cells.. They then showed that PCI-32765 induces cytotoxicity in CLL cells irrespective of IGVH mutations and FISH. However, the cytotoxicity is dependent on the Caspase pathway. In other words it is caused by apoptosis. PCI-32765 does not kill T cells but it alters their production of cytokines, inhibiting the production of IL-6.IL-10 and TNF-alfa after CD3 ligation. This suggests that PCI-32765 can inhibit other tyrosine kinases than Btk.
The authors also showed that in some CLL patients there is constitutive phosphorylation of of Btk independent of src activation. PCI-32765 inhibits both constitutive and activation induced phosphorylation of Btk as well as downstream activation of the PI3K, MAPK and NFkappaB pathways.
PCI-32765 also inhibits proliferation of CLL cells when stimulated by CpG oligonucleotides, (as a representative of Toll-like receptor signaling), and by CD40L and BAFF signaling, TNF-alfa, IL-6 and IL-4 signaling and by fibronectin signaling. The effect of PCI-32765 in squashing proliferation was not inhibited by co-incubation with Hs5 stromal cells. The overall effect of these experiments is to demonstrate that PCI-32765 has an inhibitory effect on proliferation centers in the tissues.
The effect of an early trial of PCI-32765 was reported at ASH last year (Abstract 57). 30 CLL/SLL patients were entered into the study. 84% of participants were man with a mean age of 68 (44-82).. The median number of prior therapies was 3 (1-4). Treatment was well tolerated; most of the 10 grade 3 side effects were thought to be unrelated to treatment. There was one case of grade 3 viral adenitis and one case of grade 2 viral infection related to the study medication. Btk inhibition was demonstrated. Of 14 patients available for evaluation of response, there was one CR, 8PRs, 4 SDs and one PD.
A second Btk inhibitor has been described. Avila Therapeutics presented a summary of the results of the first-in-human study AVL-292-001, at the Keystone Symposium on molecular and cell biology: evolving approaches for early-stage drug discovery. The study of AVL-292-001 was a double-blind, placebo-controlled, single ascending dose trial in healthy volunteers, in this study favourable safety, tolerability and pharmacokinetics were shown. About 50 healthy voluntary took in two studies, and based on these early and encouraging results, Avila are actively moving forward the clinical development of AVL-292 for treatment of B cell tumors, expecting to initiate a phase 1B study in CLL in mid-2011.
When the BCR is stimulated signaling through syk stimulates a host of other pathways that activate transcription factors in the nucleus. Chief among these pathways are the ERK, PI3K, and the NFkappaB pathways. It would be possible to develop drugs to inhibit these pathways, of course, but since they are used by every cell in the body, the effect would be a sort of universal toxicity as all cell types would be affected. Luckily, nature points the way.
Immunodeficiency diseases are great disasters for the patient. You probably have heard of the boys in the bubbles; young boys who have to live in plastic tents with sterile air pumped in, because they are susceptible to every germ. The only remedies for such diseases are a bone marrow transplant or else gene therapy. But there is a type of immunodeficiency that is easier to treat. Congenital hypogammaglobulinemia can be treated by regular infusions of gamma globulin. The type that occurs in young boys is called Bruton’s X-linked hypogammaglobulemia and is cause by a mutation in the gene for Bruton’s tyrosine kinase (Btk). Although this gene is expressed in many hematopoietic cells, when the gene is knocked out in mice it seems to be only effectively used by B cells; it doesn’t affect other cells in the blood and the only deficiency is in the immunoglobulins.
Since Gleevec, everybody is into tyrosine kinase inhibitors. Ideally they should be highly selective, only inhibiting specific tyrosine kinases, and that tyrosine kinase should have a narrow applicability. The orally available inhibitor PCI-32765 has been shown to be very useful at inhibiting the type of large diffuse B-cell lymphomas that are driven by BCR signaling. When used in dogs with aggressive B-cell lymphomas it produced remarkable clinical effects. Fairly specific kinase inhibitors have already been used in CLL with good effect; the syk inhibitor, fostamatinib, and the PI3K-delta specific inhibitor CAL-101. An article has been pre-published in Blood on the pre-clinical effects of PCI-32765.
They first showed that although BTK protein is variably expressed in CLL it does not correlate with prognostic markers. However, BTK mRNA was only modestly variable though significantly higher than that found in normal B cells.. They then showed that PCI-32765 induces cytotoxicity in CLL cells irrespective of IGVH mutations and FISH. However, the cytotoxicity is dependent on the Caspase pathway. In other words it is caused by apoptosis. PCI-32765 does not kill T cells but it alters their production of cytokines, inhibiting the production of IL-6.IL-10 and TNF-alfa after CD3 ligation. This suggests that PCI-32765 can inhibit other tyrosine kinases than Btk.
The authors also showed that in some CLL patients there is constitutive phosphorylation of of Btk independent of src activation. PCI-32765 inhibits both constitutive and activation induced phosphorylation of Btk as well as downstream activation of the PI3K, MAPK and NFkappaB pathways.
PCI-32765 also inhibits proliferation of CLL cells when stimulated by CpG oligonucleotides, (as a representative of Toll-like receptor signaling), and by CD40L and BAFF signaling, TNF-alfa, IL-6 and IL-4 signaling and by fibronectin signaling. The effect of PCI-32765 in squashing proliferation was not inhibited by co-incubation with Hs5 stromal cells. The overall effect of these experiments is to demonstrate that PCI-32765 has an inhibitory effect on proliferation centers in the tissues.
The effect of an early trial of PCI-32765 was reported at ASH last year (Abstract 57). 30 CLL/SLL patients were entered into the study. 84% of participants were man with a mean age of 68 (44-82).. The median number of prior therapies was 3 (1-4). Treatment was well tolerated; most of the 10 grade 3 side effects were thought to be unrelated to treatment. There was one case of grade 3 viral adenitis and one case of grade 2 viral infection related to the study medication. Btk inhibition was demonstrated. Of 14 patients available for evaluation of response, there was one CR, 8PRs, 4 SDs and one PD.
A second Btk inhibitor has been described. Avila Therapeutics presented a summary of the results of the first-in-human study AVL-292-001, at the Keystone Symposium on molecular and cell biology: evolving approaches for early-stage drug discovery. The study of AVL-292-001 was a double-blind, placebo-controlled, single ascending dose trial in healthy volunteers, in this study favourable safety, tolerability and pharmacokinetics were shown. About 50 healthy voluntary took in two studies, and based on these early and encouraging results, Avila are actively moving forward the clinical development of AVL-292 for treatment of B cell tumors, expecting to initiate a phase 1B study in CLL in mid-2011.
John 2:13-17
When it was almost time for the Jewish Passover, Jesus went up to Jerusalem. In the temple courts he found people selling cattle, sheep and doves, and others sitting at tables exchanging money. So he made a whip out of cords, and drove all from the temple courts, both sheep and cattle; he scattered the coins of the money changers and overturned their tables. To those who sold doves he said, “Get these out of here! Stop turning my Father’s house into a market!” His disciples remembered that it is written: “Zeal for your house will consume me.”
The cleansing of the Temple is an important episode for several reasons.
First, it demonstrates how corrupt mere ritual can become. No doubt under the High Priests commission, traders had entered the court of the Gentiles, which should have been for the evangelizing of the Gentiles, and instead had turned into a place of profiteering. Animals for sacrifice were available at the Mount of Olives, but they could be rejected by the Temple authorities and preference given for animals purchased in the Temple Courts. Moneychangers could engage in similar unscrupulous dealings, since they had the monopoly of Temple coinage.
Second, this is the only occasion when Jesus resorted to violence. We have a picture of Jesus as a simpering milksop dressed in a nightdress; but this is a false picture. One day he will be coming to judge and those who have not believed in him cannot expect to be treated kindly. The masculine gender of the word 'all' suggests that the whip was for people as well as for animals.
Third, there is the strong hint here that the whole process of animal sacrifice is coming to an end. If I am right in equating this episode with the one described in the Synoptics, then it is chronologically the last Passover before Jesus' appearance as the paschal lamb. The animals are driven away because Jesus replaces them.
The cleansing of the Temple is an important episode for several reasons.
First, it demonstrates how corrupt mere ritual can become. No doubt under the High Priests commission, traders had entered the court of the Gentiles, which should have been for the evangelizing of the Gentiles, and instead had turned into a place of profiteering. Animals for sacrifice were available at the Mount of Olives, but they could be rejected by the Temple authorities and preference given for animals purchased in the Temple Courts. Moneychangers could engage in similar unscrupulous dealings, since they had the monopoly of Temple coinage.
Second, this is the only occasion when Jesus resorted to violence. We have a picture of Jesus as a simpering milksop dressed in a nightdress; but this is a false picture. One day he will be coming to judge and those who have not believed in him cannot expect to be treated kindly. The masculine gender of the word 'all' suggests that the whip was for people as well as for animals.
Third, there is the strong hint here that the whole process of animal sacrifice is coming to an end. If I am right in equating this episode with the one described in the Synoptics, then it is chronologically the last Passover before Jesus' appearance as the paschal lamb. The animals are driven away because Jesus replaces them.
Monday, May 02, 2011
John 2:12
After this he went down to Capernaum with his mother and brothers and his disciples. There they stayed for a few days.
This linking verse is an important one. Does it complete the water into wine passage of does it introduce the cleansing of the Temple passage. If the latter then you have to postulate two Temple cleansings; one at the beginning of his ministry and one (as recounted in the Synoptics) at the end. If you take the former view then you must accept that John's gospel is not chronologically, but thematically organized.
I tend to take the former view. No gospel records two cleansings and there seems to be no difference in the message behind the two stories. So, as with the previous story, the theme is paramount; the message is the same: the old has gone; the new has come.
This linking verse is an important one. Does it complete the water into wine passage of does it introduce the cleansing of the Temple passage. If the latter then you have to postulate two Temple cleansings; one at the beginning of his ministry and one (as recounted in the Synoptics) at the end. If you take the former view then you must accept that John's gospel is not chronologically, but thematically organized.
I tend to take the former view. No gospel records two cleansings and there seems to be no difference in the message behind the two stories. So, as with the previous story, the theme is paramount; the message is the same: the old has gone; the new has come.
Sunday, May 01, 2011
John 2:7-11
Jesus said to the servants, “Fill the jars with water”; so they filled them to the brim. Then he told them, “Now draw some out and take it to the master of the banquet.” They did so, and the master of the banquet tasted the water that had been turned into wine. He did not realize where it had come from, though the servants who had drawn the water knew. Then he called the bridegroom aside and said, “Everyone brings out the choice wine first and then the cheaper wine after the guests have had too much to drink; but you have saved the best till now.” What Jesus did here in Cana of Galilee was the first of the signs through which he revealed his glory; and his disciples believed in him.
The story is familiar. What are we meant to get from it? We have drawn the inference that Jesus was not a killjoy or antisocial. We can see that although his public ministry is just beginning Jesus is still living with his family. We can see that although Mary did not recognize him for who he is, she still was aware of his authority and power. But this was the first of the 'sign' miracles. What did it signify?
We could say that it shows Jesus' power and authority; his creative ability, but remember that Elijah and Peter were also able to perform miracles as were the Pharaoh's magicians. Miracles don't make Jesus God. It think we must look at the detail. The vast water jars were there fore the Jewish ritual of purification. Jesus used them to provide new wine. I think the sign is that the old is gone; the new has come.
The story is familiar. What are we meant to get from it? We have drawn the inference that Jesus was not a killjoy or antisocial. We can see that although his public ministry is just beginning Jesus is still living with his family. We can see that although Mary did not recognize him for who he is, she still was aware of his authority and power. But this was the first of the 'sign' miracles. What did it signify?
We could say that it shows Jesus' power and authority; his creative ability, but remember that Elijah and Peter were also able to perform miracles as were the Pharaoh's magicians. Miracles don't make Jesus God. It think we must look at the detail. The vast water jars were there fore the Jewish ritual of purification. Jesus used them to provide new wine. I think the sign is that the old is gone; the new has come.
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