Have you ever heard of Martin Hurson? How about Raymond McCreesh? I must admit that these names meant nothing to me even though in 1981 I used to read the newspapers avidly. Of course, if you had said Bobby Sands, I would have known instantly what you were talking about; the hunger strike by the provisional IRA members in the Maze prison. I think it was about their wanting to be recognized as prisoners of war while the British government saw them as simply criminals.
Depending on how you viewed the Irish cause, you either saw them as martyrs or murderers. I don't want to debate the rights or wrongs of Ireland, but to consider how we ought to deal with hunger strikes. This has been prompted by an article in today's Lancet .
The article has been prompted by the current situation in Guantanamo, and of course, The Lancet, as a left-wing journal, wants to hold Obama to his promises to end torture in the USA. As the author says, hunger strikes are extremely difficult for prison officials and physicians to deal with, especially if they are done in groups, as they are in Guantánamo where about 30 prisoners are currently on hunger strike. Hunger strikers are not suicidal in that their goal is to change a policy or the conditions of their confinement, not to die. The primary issue the continuing hunger strikes at Guantanamo raise with the medical profession and human rights groups is the use of military physicians to break the hunger striker's will by force-feeding in eight-point restraint chairs.
Apparently army doctors have been taking part in the forced feeding of inmates against the rules and regulations of the World Medical Association.
A hunger strike is a non-violent protest that aims to provoke feelings of guilt in others in order to change a policy. It has a long history, particularly in India and Ireland. In both countries those who felt that they had been swindled would camp on the perpetrators doorstep and starve themselves.
In modern days the most prominent instance was by the suffragettes on both Britain and America. Marion Dunlop was the first in 1909. Because the authorities did not want her to become a martyr, she was released. Other suffragettes were subjected to force-feeding, which the suffragettes categorized as a form of torture. Several of them died as a result of force-feeding. In 1913 the Prisoner's Temporary Discharge of Ill Health Act changed policy. Hunger strikers were tolerated but when they became sick the prisoners were released, only to be rearrested to finish their sentences when they had recovered.
In the end what won women the vote was their willingness to act as substitute men in factories and farms during the Great War.
Irish republicans first used the hunger strike as a weapon in 1917. It was countered by the British with force-feeding, which culminated in 1917 in the death of Thomas Ashe in Mountjoy Prison. In October 1920, the Lord Mayor of Cork, Terence MacSwiney, died on hunger strike in Brixton prison. Three other IRA men, Joe Murphy, Conor McElvaney and Michael Fitzgerald, also died on hunger strike in this protest. John and Peter Crowley, Thomas Donovan, Michael Burke, Michael O'Reilly, Christopher Upton, John Power, Joseph Kenny and Seán Hennessy at the prison of Cork had their hunger strike called off by the Sinn Fein leadership after the deaths of MacSwiney, Murphy and Fitzgerald. Some of the strikers had fasted for 94 days – such a long period makes it likely that they were surreptitiously taking food.
Although there was a natural sympathy for the underdog, there was little agreement with some of the views of the Sinn Fein leadership. They defended anti-semitic rioters in Limerick, denounced socialists and pacifists as conscious tools of the British Empire, and successively praised Tsarist Russia and Wilhelm II as morally superior to Great Britain.
Eventually, there was an agreement between Britain and Ireland which established the Irish Free State, though it was impossible to incorporate the Protestant North within the Catholic South without a blood bath.
Oppression of Catholics in the North by the Protestant government reignited the troubles in Ireland in the 1960s. Again, the hunger strike was used as a weapon. Bobby Sands was the first of ten Irish republican paramilitary prisoners to die during the hunger strike in 1981. There was support for the hunger strikers from Irish republicans and the broader nationalist community on both sides of the Irish border. After the deaths of the men and severe public disorder, the British government granted partial concessions to the prisoners, and the strike was called off. The hunger strikes gave a huge propaganda boost to a severely demoralized Provisional IRA. Bobby Sands, who was elected to the UK Parliament is still remembered but few but ardent republicans remember the names of the others. In the end, the IRA agreed a deal with the British. It was a deal that they could have had at almost any time during the troubles. It was brokered by John Major and Tony Blair. It is probable that the hunger strikes prolonged the conflict rather than shortened it. The IRA was always going to be defeated militarily and Londoners, who had survived the Blitz, were not going to be cowed by the Irish bombers. The real enemy of the IRA was the Protestant North which would never come to an agreement with the IRA while the South was in their view, priest-ridden.
British animal-rights activist Barry Horne died on November 5, 2001 after a series of four hunger strikes, the longest of which lasted 68 days leaving him partially blind and with kidney damage. Almost nobody sympathized with his views. Sine the same group resorted to kidnapping the dead body of a farmer’s mother, who would sympathize with them.
On the 15th of August 1987 at the Nallur Murugan Temple Thileepan began his fast. His main objective was to bring awareness and action to a list of public demands made by himself and the Tamil Tigers. The Tamils live mainly in the north of Sri Lanka and are Hindus and probably of Indian origin, whereas the majority of Sinhalese are Buddhist. Although several groups requested him to stop the fast, Thileepan died on the 26th of September 1987. There was widespread grief in Tamil areas. Thousands of people from the North and East flooded Jaffna in northern Sri Lanka as news of his death spread. His death created an anti-Indian mood in Jaffna, which had been pro-India till then.
From the above, it can be seen that hunger strikes are a double edged weapon. If the authorities call the bluff of the striker then he or she dies. The authorities are caught is a vice; let the striker die and they are accused of callousness, force feed him and they are accused of torture. If the striker dies then it does not guarantee martyrdom; if the cause is unpopular then the public are likely to cry, “Good riddance.” No-one would weep if the Yorkshire Ripper or the Southam pedophile starved themselves to death.
The inmates of Guantánamo are the basis of the current Lancet article. In 2006 the New York Times reported that hunger strikers in Guantánamo were being strapped into restraining chairs for hours a day for force-feeding. The number of strikers peaked at 131 around the fourth anniversary of 9/11. There was concern over the international impact if a striker were to die. Prisoners’ lawyers called the methods brutal and inhumane, and said other coercive methods were used, such as being placed in cold air-conditioned isolation cells. The assistant secretary of defense for health affairs said it was a moral question: allow suicide, or take steps to preserve life.
Article 6 of the 1975 World Medical Association Tokyo Declaration states that doctors can undertake force-feeding under certain very restricted rules and only where a second, independent physician is consulted and agrees that the prisoner is not rational. "Where a prisoner refuses nourishment and is considered by the physician as capable of forming an unimpaired and rational judgment concerning the consequences of such a voluntary refusal of nourishment, he or she shall not be fed artificially. The decision as to the capacity of the prisoner to form such a judgment should be confirmed by at least one other independent physician. The consequences of the refusal of nourishment shall be explained by the physician to the prisoner."
The World Medical Association recently revised and updated its Declaration of Malta on Hunger Strikers. Among many changes, it unambiguously states that force feeding is a form of inhuman and degrading treatment in its Article 21. The American Medical Association is a member of the World Medical Association, but the AMA's members are not bound by the WMA's decisions, and neither organization has formal legal powers.
The British government under Maggie Thatcher took the decision not to force-feed the Irish terrorists, a decision that was probably correct. Probably the Americans should do the same. It comes hard for a physician to stand by and watch a person commit suicide, but medicine can only be offered with consent.
Friday, November 20, 2009
Thursday, November 19, 2009
A Maradonna Moment
We used to have a saying when I was young to the effect that cheats never prosper. An incident occurred in last night's soccer match between France and Ireland which questions that premise. A goal by Ireland had cancelled out one by France in the first leg and the match was heading towards a penalty shoot-out. Then late into overtime, France scored the winning goal. It was scored by William Gallas, but he received the ball from Thierry Henry who illegally handled it before hooking it back across the goalmouth to be headed in. The goal should have been disallowed and Henry might well have been dismissed the field of play. After the match Henry admitted the offence but claimed that it was the referee's responsibility to spot it. Indeed, had he drawn the referee's attention to the handball, he would have been denigrated by his own team and the French supporters.
However, that is what an honest man would have done. It is hardly honest to protest about fouls committed by the other side and then turn a blind eye to one's own misdemeanors. Honesty is really tested when you suffer for it.
Sports fans the world over turned on the football star, who enjoys a global profile partly thanks to an advertising campaign by Gillette, the shaving brand, that placed him in the very top tier alongside Tiger Woods, the golfer and first $1 billion athlete, and Roger Federer, the man who has won more grand slam tournaments than any other tennis player. The sponsors expect to inflict no punishment on him; they say that he can't be blamed for the referee's mistake.
Diego Maradonna committed a similar piece of dishonesty in 1986 at the World Cup finals. Maradonna was at time thought of as the finest footballer of his generation. After that match, his reputation sank. He became a cocaine addict; he became obese; and he went on the manage the worst Argentina team for half a century. He was recently banned from anything to do with football after an outburst of bad language against the press. I guess he couldn't live with himself after cheating like that. Thierry Henry had better beware.
However, that is what an honest man would have done. It is hardly honest to protest about fouls committed by the other side and then turn a blind eye to one's own misdemeanors. Honesty is really tested when you suffer for it.
Sports fans the world over turned on the football star, who enjoys a global profile partly thanks to an advertising campaign by Gillette, the shaving brand, that placed him in the very top tier alongside Tiger Woods, the golfer and first $1 billion athlete, and Roger Federer, the man who has won more grand slam tournaments than any other tennis player. The sponsors expect to inflict no punishment on him; they say that he can't be blamed for the referee's mistake.
Diego Maradonna committed a similar piece of dishonesty in 1986 at the World Cup finals. Maradonna was at time thought of as the finest footballer of his generation. After that match, his reputation sank. He became a cocaine addict; he became obese; and he went on the manage the worst Argentina team for half a century. He was recently banned from anything to do with football after an outburst of bad language against the press. I guess he couldn't live with himself after cheating like that. Thierry Henry had better beware.
Progress at NIH
A stem cell allograft is the only way of curing CLL, but how does it work? It seems that there is immune response from the grafted immune system against the leukemia. Now a paper in this week's Blood suggests how this might work. Hitherto, it has been thought that post-transplant immunity against the leukemia was mediated by T cells, but Baskar and colleagues have asked whether it might be mediated by antibody.
They have looked at stored serial blood samples from two patients who remain in molecular remission respectively 6 and 7 years after their transplant. They have looked by flow cytometry to see whether any of the sera from these samples reacted with CLL cells. This is technically difficult because CLL cells already have immunoglobulin on their surface and they have a receptor that binds to immunoglobulin surrounding them in fluid, so both of these have first to be blocked. Nevertheless both cases had detectable anti-CLL cells antibody in their blood, one peaking at 6 months post-transplant and one peaking at 6 months and the other at 10 months post-transplant. Interestingly these coincided with the disappearance of minimal residual disease in each patient.
The next thing was to find the B cells circulating at the time that were circulating at the time that were responsible for the production of these antibodies. To do this a phage library was constructed. This is a complicated procedure in which the total RNA was extracted from the cryopreserved B cells and the RNA coding for the immunoglobulin fragment containing the antibody activity (known as Fab) was amplified by PCR using appropriate primers. This process also inserts appropriate RNA into bacteriophages (a bacteriophage is a virus that infects a bacterium). E.coli bacteria were then infected by the phage (this process makes the Fab stick out from the surface of the e.coli. This can be used to select those bacteriophage that have a code for an anti-CLL cell Fab. The selection process was dominated by one antibody that in all its manifestations could be predicted to react with the same antigen, which was present on nearly all CLL cells and more weakly on normal B cells, but not on other B-cell tumors or tumor cell lines.
The significance of this study is that it may identify an antigen on CLL cells which is extremely susceptible to killing by antibody, so that a new monoclonal that eliminates CLL cells completely may be produced, or if the antigen is fully identified, other small molecules might be derived that kill CLL cells. This paper also provides a method that could be applied to other leukemias that can be cured by stem cell transplantation.
They have looked at stored serial blood samples from two patients who remain in molecular remission respectively 6 and 7 years after their transplant. They have looked by flow cytometry to see whether any of the sera from these samples reacted with CLL cells. This is technically difficult because CLL cells already have immunoglobulin on their surface and they have a receptor that binds to immunoglobulin surrounding them in fluid, so both of these have first to be blocked. Nevertheless both cases had detectable anti-CLL cells antibody in their blood, one peaking at 6 months post-transplant and one peaking at 6 months and the other at 10 months post-transplant. Interestingly these coincided with the disappearance of minimal residual disease in each patient.
The next thing was to find the B cells circulating at the time that were circulating at the time that were responsible for the production of these antibodies. To do this a phage library was constructed. This is a complicated procedure in which the total RNA was extracted from the cryopreserved B cells and the RNA coding for the immunoglobulin fragment containing the antibody activity (known as Fab) was amplified by PCR using appropriate primers. This process also inserts appropriate RNA into bacteriophages (a bacteriophage is a virus that infects a bacterium). E.coli bacteria were then infected by the phage (this process makes the Fab stick out from the surface of the e.coli. This can be used to select those bacteriophage that have a code for an anti-CLL cell Fab. The selection process was dominated by one antibody that in all its manifestations could be predicted to react with the same antigen, which was present on nearly all CLL cells and more weakly on normal B cells, but not on other B-cell tumors or tumor cell lines.
The significance of this study is that it may identify an antigen on CLL cells which is extremely susceptible to killing by antibody, so that a new monoclonal that eliminates CLL cells completely may be produced, or if the antigen is fully identified, other small molecules might be derived that kill CLL cells. This paper also provides a method that could be applied to other leukemias that can be cured by stem cell transplantation.
Wednesday, November 18, 2009
Sydney Opera House
Over the past few weeks I have been reading The Saga if the Sydney Opera House by Peter Murray. The building is one of the modern wonders of the world and one of the few located in the Southern Hemisphere. It has been recognized as a World Heritage Site and is an icon of Australia.
It was designed by the Danish architect, Jorn (that ‘o’ should have a diagonal line through it) Utzon. He was very good at winning architectural competitions but few of his designs ever got built. His design won the competition in 1957.
The remit was to build a large 3000 seater concert hall come opera house with a second smaller hall to seat 1200 for theater productions. It would be rude to say that Utzon’s design was a back of a fag packet affair (fag being a British word for cigarette without the American connotation), but the design was another of those that wins competitions but doesn’t get built. Indeed in 1957 it was doubtful that it could be. The task of building it was given to another Dane, Ove Arup and Partners, consulting engineers.
The book details the difficulties there were in translating, what was obviously a beautiful design into a real three dimensional building that functioned as it should.
Although praised as a masterpiece, the Sydney Opera House has been criticized. Many people say that the acoustics are poor and that the theater doesn't have enough performance or backstage space. Yet the architectural community has been extremely supportive of Utzon and extremely critical of the Australian governmental machine and the Australian press. Most prominent articles on the Internet are supportive too.
Peter Murray is less so. He points out that the Opera House took 14 years to build and cost 14 times the original estimate. Utzon was impossible to work with and seemed astonished that he should get paid according to work done, rather than simply reimbursed what it cost to keep his Sydney office running, even when most of them were working on other projects like the Zurich concert hall. Arups, whose design solutions for the shells had made use of computer design (and remember what computers were like in the 1960s) were his constant supporters, but he even managed to fall out with them and in 1966 he resigned from the project with only the base and the shells completed. His designs for the interior were in his head with virtually nothing on paper. For the first two stages of the project he had relied on Arups to provide working drawings to build from; now he had fallen out with the engineers he had no-one capable of doing it. There were no drawings for the interior when he eventually resigned.
His resignation was really a sort of negotiating position, but David Hughes the minister responsible had had enough of Utzon. For months he had been out of contact, holidaying inn Hawaii and his offices in Sydney didn’t even have a telephone. Hughes called his bluff and assembled a committee to take his place. There were four main criticisms of Utzon: he insisted on the wrong organizational approach; he ignored questions of time; he ignored questions of cost; and he was not a practical man.
Although Utzon may have been a talented artist, he seemed to have no conception of the difficulties that sub-contractors would have in building his designs. His knowledge of acoustics was minimal and he had no idea how large an area was needed to sit in comfortably at a concert. There was no way that his large hall could accommodate both symphony concerts and opera. Eventually opera was moved to the smaller hall, but even so Sydney still has acoustic problems, especially for those 579 in the large hall who sit behind the orchestra. The total seating in the large hall was for 2679 – more than 300 short of the 3000 asked for, though they did have sufficient leg room.
The opera house was opened on October 20th 1973 by the Queen of Australia. The organ, the largest pipe organ in the world, was not completed until 1979. The final cost was 102 million Australian dollars against an original estimate of 7 million.
In 1976 Dame Edna Everage attempted to enter the Royal enclosure at Royal Acsot wearing this hat.
Ofatumumab at ASH
Those expecting a load of new information on Ofatumumab (O) from ASH are likely to be disappointed. Only three papers have been accepted and only one of these is clinically relevant.
A multi centre trial looked at two doses of O (500mg and 1000mg) used in combination with FC in previously untreated patients with CLL. Only 61 patients were involved, so nothing much can be made of the study statistically. The overall response rate was 70% and 73% respectively, but there were more CRs with the higher dose (50% v 32%) but the difference was not statistically significant. The overall response rates were less than historical controls with FCR, but the make up of cases could account for that. For example 20% of those receiving the higher dose had del 17p. I think all that can be said of this study is that O can be given safely with FC and that responses are in the same ball-park as with FCR. There were no unexpected toxicities.
The other two studies were more technical. One looked at the pharmacokinetics (PK) of O. It demonstrated that baseline factors reflecting disease burden significantly influenced ofatumumab PK. Additionally, higher serum concentrations of ofatumumab at Doses 8 and 12 were associated with positive clinical outcomes in univariate analyses. In other words the more disease there is to soak up the antibody, the lower the serum concentration and the higher the serum concentration, the better the response. Not exactly counter-intuitive, is it.
It is known for NHL (but not for CLL) that a polymorphism on the FC receptor affects response to rituximab. The third paper assessed FcgRIIIa affinity and potency to induce ADCC by purified NK cells for ofatumumab and rituximab in a blinded study. Expected differences in affinity for the 158V and 158F allotypes of FcgRIIIa were observed for both ofatumumab and rituximab. These differences correlated with a stronger ADCC by FcgRIIIa 158V/V compared to 158F/F expressing NK cells. Significantly, ofatumumab was able to induce ADCC more potently than rituximab for both Fc receptor allotypes. Ofatumumab binds CD20 stably and at a distinct membrane-proximal epitope compared to rituximab. Our data suggest that these binding characteristics may positively impact ofatumumab’s ability to direct killing of tumor cells via ADCC. Most of this information was already available from experiments in our lab by Martin Glennie.
A multi centre trial looked at two doses of O (500mg and 1000mg) used in combination with FC in previously untreated patients with CLL. Only 61 patients were involved, so nothing much can be made of the study statistically. The overall response rate was 70% and 73% respectively, but there were more CRs with the higher dose (50% v 32%) but the difference was not statistically significant. The overall response rates were less than historical controls with FCR, but the make up of cases could account for that. For example 20% of those receiving the higher dose had del 17p. I think all that can be said of this study is that O can be given safely with FC and that responses are in the same ball-park as with FCR. There were no unexpected toxicities.
The other two studies were more technical. One looked at the pharmacokinetics (PK) of O. It demonstrated that baseline factors reflecting disease burden significantly influenced ofatumumab PK. Additionally, higher serum concentrations of ofatumumab at Doses 8 and 12 were associated with positive clinical outcomes in univariate analyses. In other words the more disease there is to soak up the antibody, the lower the serum concentration and the higher the serum concentration, the better the response. Not exactly counter-intuitive, is it.
It is known for NHL (but not for CLL) that a polymorphism on the FC receptor affects response to rituximab. The third paper assessed FcgRIIIa affinity and potency to induce ADCC by purified NK cells for ofatumumab and rituximab in a blinded study. Expected differences in affinity for the 158V and 158F allotypes of FcgRIIIa were observed for both ofatumumab and rituximab. These differences correlated with a stronger ADCC by FcgRIIIa 158V/V compared to 158F/F expressing NK cells. Significantly, ofatumumab was able to induce ADCC more potently than rituximab for both Fc receptor allotypes. Ofatumumab binds CD20 stably and at a distinct membrane-proximal epitope compared to rituximab. Our data suggest that these binding characteristics may positively impact ofatumumab’s ability to direct killing of tumor cells via ADCC. Most of this information was already available from experiments in our lab by Martin Glennie.
Tuesday, November 17, 2009
Alemtuzumab at ASH
Alemtuzumab is thought to be a superior monoclonal to rituximab for the treatment of CLL. The question ought then to be asked as to whether FCA would be superior to FCR. In fact the ASH abstracts report just such a trial from France and Belgium.
178 previously untreated patients under the age of 65 who did not have del 17p, were randomized between standard FCR and FCA, with the alemtuzumab being given sc in a dose of 30mg for 3 days every 28 days. Although the overall response rate and CR rate were not statistically different, they were both greater for the FCR arm (96% v 85% and 78% v 58%). The trial is too immature to calculate PFS or OS. The trial was terminated because of excess toxicity in the FCA arm. Febrile neutropenia was twice as common in the FCA arm and there were 7 deaths with FCA and none with FCR.
The German CLL2 trial looked at the safety profile of FCA in 61 patients aged 36-78, some of whom had been previously treated. Twelve out of 56 patients died within 6 months of completing treatment of which 5 were treatment-related. The fact that 7 died of CLL or concomitant disease suggests that this was a particularly sick group of patients. Serious adverse events included CMV-reactivation (5 patients), herpes-zoster-reactivation (1 patient), pneumonia (5 patients, 2 of which had Aspergillosis-pneumonias), AIHA (1 patient) and fever of unknown origin (12 patients). It was felt that there was more toxicity with this regimen than for FA, which had been tested previously.
If it is not to be used as a substitute for rituximab, how then might it best be used? The CALG conducted a trial of alemtuzumab as consolidation treatment after FR induction. The results were hardly promising. Patients who had stable disease or responsive disease 4 months after the last dose of fludarabine were treated with SC alemtuzumab 3 mg on day 1, 10 mg on day 3, and 30 mg on day 5, and then thrice weekly thereafter for 6 weeks (18 total doses). Fifty-eight pts out of the original 102 received alemtuzumab, and 42 (72%) completed the planned 6 weeks of therapy. OR, CR, and PR rates after alemtuzumab were 91%, 66% and 26%, and 50% were MRD negative. Twenty-eight of 45 pts (62%) in PR after FR who received alemtuzumab attained CR. Of 11 pts in CR after FR who received alemtuzumab, 5 were MRD negative prior to consolidation and 3 of the other 6 converted to MRD negative afterwards. Two-year PFS (76% vs 70%, p=0.54) and OS (84% vs 88%, p=0.89) were similar for pts who did and did not receive alemtuzumab. There were no differences in PFS or OS among the 30 pts in CR after FR whether or not they received alemtuzumab, although the numbers were small.
Grade 3-4 neutropenia and thrombocytopenia were observed in 43% and 19% of pts during alemtuzumab therapy. Grade 3-4 non-hematologic toxicity was observed in 41% of pts, including 19% infections and 19% febrile neutropenia, during alemtuzumab therapy. Five pts in CR after FR who received alemtuzumab died from infections (viral meningitis, Listeria meningitis, Legionella pneumonia, CMV and PCP pneumonia), and one pt in PR after FR who received alemtuzumab died of Epstein-Barr (EBV) viremia without evidence of EBV lymphoma. These deaths occurred both during and for up to 7 months after alemtuzumab therapy. Patients had received standard Pneumocystis (PCP) and Varicella zoster virus prophylaxis and were monitored weekly by PCR for Cytomegalovirus (CMV) viremia.
The MDS Anderson has added alemtuzumab to FCR as CFAR; it is given as -30mg iv on days 1, 3 and 5 of each course. Eighty patients with previously treated CLL received CFAR for an intended total of 6 courses. There were 21 CR (27%), 3 NPR (4%) and 29 PR (37%) for an ORR 67%. Median OS and time to treatment failure (TTF) were 16.6 and 10.6 months respectively for all pts. For pts achieving CR, median OS (50+ months) and TTF (28+ months) have not been reached. Grade 3/4 infectious complications included pneumonia (n=7) or sepsis (n=3). Other infections included minor infections (n=32), CMV reactivation (n=13), and other herpes virus infections (n=5). CFAR is an effective therapy in this group of heavily treated pts with CLL. They demonstrated favorable responses in patients younger than 70 years with F-sensitive disease who had 5 or fewer prior therapies. They concluded that CFAR is a good salvage regimen for patients who have received prior FC based regimen.
CFAR has also been used as first line treatment in patients with high risk disease, defined as those with a beta-2-microglobulin greater than 4. Sixty patients under the age of 70 were enrolled. Thirty-five patients couldn't complete the intended 6 courses. The reasons included delayed recovery of counts (18), infection (8), AIHA (4), treatment failure (3) and patient choice (2). The overall response rate was 92% with CRs in 70%, but the median time to progression was only 38 months. Patients with 17p deletion, 11q deletion and unmutated IgVH had significantly shorter times to progression (18 months, 27 months and 33 months respectively.
Eleven (19%) patients have died: 4 with disease progression after achieving CR; 2 who did not respond; 2 with Richter's transformation; 1 who developed AML; 1 due to metastatic lung cancer; and 1 due to severe pneumonia 8 months after achieving CR. Grade 3/4 neutropenia and thrombocytopenia occurred in 31% and 13% courses respectively. Major infections, including pneumonia and sepsis, were reported for 10(17%) pts. Minor infectious such as bronchitis, urinary tract infections and herpes zoster were reported for 15(25%) pts. These figures are similar to figures obtained for FCR at MDACC. CMV reactivation occurred in 7 (12%) patients, but many of the patients who were spared this were on valgancyclovir prophylaxis. There was one death due to CMV pneumonia. CFAR does not seem to be much of an improvement over FCR.
Alemtuzumab is licensed for first line use in CLL. The ASH papers do not support the idea that it should be used in this way whether as FCA or CFAR. FCR remains the best first line treatment. The use of alemtuzumab as consolidation treatment can be seen to be hazardous on the basis of the CALGB trial and indeed on the basis of an earlier German trial. Early evidence from a British trial not reported at ASH, suggests that these hazards can be overcome. The place of alemtuzumab in fludarabine refractory disease awaits determination. It may also have a place in stem cell transplantation, but I will report on this on another day.
178 previously untreated patients under the age of 65 who did not have del 17p, were randomized between standard FCR and FCA, with the alemtuzumab being given sc in a dose of 30mg for 3 days every 28 days. Although the overall response rate and CR rate were not statistically different, they were both greater for the FCR arm (96% v 85% and 78% v 58%). The trial is too immature to calculate PFS or OS. The trial was terminated because of excess toxicity in the FCA arm. Febrile neutropenia was twice as common in the FCA arm and there were 7 deaths with FCA and none with FCR.
The German CLL2 trial looked at the safety profile of FCA in 61 patients aged 36-78, some of whom had been previously treated. Twelve out of 56 patients died within 6 months of completing treatment of which 5 were treatment-related. The fact that 7 died of CLL or concomitant disease suggests that this was a particularly sick group of patients. Serious adverse events included CMV-reactivation (5 patients), herpes-zoster-reactivation (1 patient), pneumonia (5 patients, 2 of which had Aspergillosis-pneumonias), AIHA (1 patient) and fever of unknown origin (12 patients). It was felt that there was more toxicity with this regimen than for FA, which had been tested previously.
If it is not to be used as a substitute for rituximab, how then might it best be used? The CALG conducted a trial of alemtuzumab as consolidation treatment after FR induction. The results were hardly promising. Patients who had stable disease or responsive disease 4 months after the last dose of fludarabine were treated with SC alemtuzumab 3 mg on day 1, 10 mg on day 3, and 30 mg on day 5, and then thrice weekly thereafter for 6 weeks (18 total doses). Fifty-eight pts out of the original 102 received alemtuzumab, and 42 (72%) completed the planned 6 weeks of therapy. OR, CR, and PR rates after alemtuzumab were 91%, 66% and 26%, and 50% were MRD negative. Twenty-eight of 45 pts (62%) in PR after FR who received alemtuzumab attained CR. Of 11 pts in CR after FR who received alemtuzumab, 5 were MRD negative prior to consolidation and 3 of the other 6 converted to MRD negative afterwards. Two-year PFS (76% vs 70%, p=0.54) and OS (84% vs 88%, p=0.89) were similar for pts who did and did not receive alemtuzumab. There were no differences in PFS or OS among the 30 pts in CR after FR whether or not they received alemtuzumab, although the numbers were small.
Grade 3-4 neutropenia and thrombocytopenia were observed in 43% and 19% of pts during alemtuzumab therapy. Grade 3-4 non-hematologic toxicity was observed in 41% of pts, including 19% infections and 19% febrile neutropenia, during alemtuzumab therapy. Five pts in CR after FR who received alemtuzumab died from infections (viral meningitis, Listeria meningitis, Legionella pneumonia, CMV and PCP pneumonia), and one pt in PR after FR who received alemtuzumab died of Epstein-Barr (EBV) viremia without evidence of EBV lymphoma. These deaths occurred both during and for up to 7 months after alemtuzumab therapy. Patients had received standard Pneumocystis (PCP) and Varicella zoster virus prophylaxis and were monitored weekly by PCR for Cytomegalovirus (CMV) viremia.
The MDS Anderson has added alemtuzumab to FCR as CFAR; it is given as -30mg iv on days 1, 3 and 5 of each course. Eighty patients with previously treated CLL received CFAR for an intended total of 6 courses. There were 21 CR (27%), 3 NPR (4%) and 29 PR (37%) for an ORR 67%. Median OS and time to treatment failure (TTF) were 16.6 and 10.6 months respectively for all pts. For pts achieving CR, median OS (50+ months) and TTF (28+ months) have not been reached. Grade 3/4 infectious complications included pneumonia (n=7) or sepsis (n=3). Other infections included minor infections (n=32), CMV reactivation (n=13), and other herpes virus infections (n=5). CFAR is an effective therapy in this group of heavily treated pts with CLL. They demonstrated favorable responses in patients younger than 70 years with F-sensitive disease who had 5 or fewer prior therapies. They concluded that CFAR is a good salvage regimen for patients who have received prior FC based regimen.
CFAR has also been used as first line treatment in patients with high risk disease, defined as those with a beta-2-microglobulin greater than 4. Sixty patients under the age of 70 were enrolled. Thirty-five patients couldn't complete the intended 6 courses. The reasons included delayed recovery of counts (18), infection (8), AIHA (4), treatment failure (3) and patient choice (2). The overall response rate was 92% with CRs in 70%, but the median time to progression was only 38 months. Patients with 17p deletion, 11q deletion and unmutated IgVH had significantly shorter times to progression (18 months, 27 months and 33 months respectively.
Eleven (19%) patients have died: 4 with disease progression after achieving CR; 2 who did not respond; 2 with Richter's transformation; 1 who developed AML; 1 due to metastatic lung cancer; and 1 due to severe pneumonia 8 months after achieving CR. Grade 3/4 neutropenia and thrombocytopenia occurred in 31% and 13% courses respectively. Major infections, including pneumonia and sepsis, were reported for 10(17%) pts. Minor infectious such as bronchitis, urinary tract infections and herpes zoster were reported for 15(25%) pts. These figures are similar to figures obtained for FCR at MDACC. CMV reactivation occurred in 7 (12%) patients, but many of the patients who were spared this were on valgancyclovir prophylaxis. There was one death due to CMV pneumonia. CFAR does not seem to be much of an improvement over FCR.
Alemtuzumab is licensed for first line use in CLL. The ASH papers do not support the idea that it should be used in this way whether as FCA or CFAR. FCR remains the best first line treatment. The use of alemtuzumab as consolidation treatment can be seen to be hazardous on the basis of the CALGB trial and indeed on the basis of an earlier German trial. Early evidence from a British trial not reported at ASH, suggests that these hazards can be overcome. The place of alemtuzumab in fludarabine refractory disease awaits determination. It may also have a place in stem cell transplantation, but I will report on this on another day.
Monday, November 16, 2009
Is free speech an absolute right?
Is free speech an absolute freedom that should not be countermanded? The recent appearance of the leader of the British National Party on the flagship public debate program on the BBC was defended on the grounds of free speech. Today on BBC radio there was a campaign to stop cyber bullying. Cyber bullying is the use of social networking sites like Facebook to write cruel and unpleasant things about an individual. Recently, a young woman killed herself after being the victim of cyber bullying.
Political correctness has been developed in order to limit the offence cause to others by the way that we speak. It is a lost cause. Whatever you say, someone is bound to be offended. Some local authorities have stopped saying Merry Christmas for fear of offending non-Christians. In doing so they have offended Christians. Attempts at limiting offence to Muslims have offended homosexuals. Attempts at limiting offence to homosexuals have offended Muslims. Some politically correct language has offended pedants like me who want to preserve the English language in all its glory.
I do not think free speech is an absolute. Whether you have free speech depends on the context. If you live on a mountain in Montana you can just about say what you want, principally because nobody likely to be offended is going to hear you. As with so many things, context is vital. You do not have freedom to yell, "Fire!" in a crowded concert hall.
There is no law that prevents you from saying something offensive, just the convention of good manners. As I have said before, a secular book I read on the great virtues puts politeness at the head of the list since, since society is impossible without it.
The Wire was reckoned to be the best TV program to come out of America in years. However, the dialogue was replete with offensive words. One sequence showing two detectives tracing the path of a bullet was free of dialogue apart from the dozens of 'F**ks' uttered. African Americans generally referred to each other as 'N*gg*r', but, of course, no 'Honky' would be allowed to do so. Oh! Am I allowed to use that word? When the program was broadcast in the UK, the BBC gave clear warnings of what some viewers would find offensive. There is such a thing as an 'off' switch.
We have a grading system for movies and videos. We have parental PINS to prevent our children getting access to some Internet sites. When my wife was a librarian some books were kept 'under the counter' because they were thought unsuitable for minors. In some newsagents the 'Girlie' magazines are kept on the top shelf, out of the way of the prying eyes of young children. Over the years there has been a liberalising approach to anything concerned with sex. We find it hard to believe that our forebears put skirts on table legs. Some years ago an editor was sent to prison for publishing a blasphemous libel; a homoerotic poem about Jesus. It is very unlikely that the same thing would happen now.
Yet Britain is the libel capital of the world; the offended sue here to get bigger payouts. We limit free speech by law if it seeks to defame with an untruth. The question that concerns libertarians is whether the state wishes to extend the powers it has to censor what people say. Minority groups are worried that legislation that, no doubt, with good intent wants to enshrine good manners in law, might restrict legitimate comment. The trouble with free speech legislation is that it goes too far. Homosexuals want to be protected from bullying and free to express their sexuality in public in the same way that heterosexuals do. But if it is granted to homosexuals under the heading of free speech, what is to stop pedophiles or those who like sex with animals claiming the same? I am not equating all these practices, but there is no disguising the fact that homosexuality disgusts a sizable section of the population. There are not enough prisons to punish Disgusted of Tunbridge Wells.
The liberalising tendency is winning at the moment, but it will not always be so. A backlash is developing against unfettered immigration. In 1979 the unrestrained power of the Unions left the dead unburied and rats running loose in the streets as garbage went uncollected. As a result, Mrs Thatcher's government cut off the Unions at the knees. Privatisation sapped the power of organized labor. Restrictive legislation (unrepealed by Tony Blair) enfeebled the strike threat. Right wing governments have not gone for ever.
What is the Christian perspective on free speech? It centers mainly on the freedom to preach the gospel. In many countries this is restricted, but not yet in the UK. Christians generally prefer to live in an ordered society and not to question the right of the government to govern; render unto Caesar... even if he is a tyrant. However, rendering unto God comes first and if there is a conflict they are willing to suffer the punishment the state decrees. Not that this means that they will not campaign against perceived wrongs. Men like Wilberforce campaigned against the slave trade when most of society thought slavery in Jamaica preferable to wage-slavery in Lancashire. Is free speech something that they should campaign for? Remember what was said about those who lead children astray. Something about millstones and deep sea diving, as I recall. If children are to be protected there is already an exception. Freedom of expression is a lot more complicated and blanket laws are not helpful.
Should Christians be offended? I think we have a responsibility not to seek out offence. I would never go to a Gay-Pride parade. I would not watch late-night TV programs meant to titillate. I would not buy Girlie magazines. But I might protest if I thought that bad language was commonplace in all television programs, or same-sex-snogging became a part of children's TV. Everything must be seen in context. I believe there are absolutes when it comes to right and wrong. Not everything that is sinful is unlawful. Jesus's take on murder was having hateful thoughts about another person. How do you legislate for that. There are far more adulterers than homosexuals in our churches, and far more gossips than both. We should start putting our own house in order before we insist on reform in unbelievers. While sexual sins are important, they are not more important than the many other sins listed in Scripture - including gossip, neglect of parents and mean-spiritedness.
So, no I do not think free speech is an absolute. I do believe in politeness and in only giving offence when you may legitimately intend to.
Political correctness has been developed in order to limit the offence cause to others by the way that we speak. It is a lost cause. Whatever you say, someone is bound to be offended. Some local authorities have stopped saying Merry Christmas for fear of offending non-Christians. In doing so they have offended Christians. Attempts at limiting offence to Muslims have offended homosexuals. Attempts at limiting offence to homosexuals have offended Muslims. Some politically correct language has offended pedants like me who want to preserve the English language in all its glory.
I do not think free speech is an absolute. Whether you have free speech depends on the context. If you live on a mountain in Montana you can just about say what you want, principally because nobody likely to be offended is going to hear you. As with so many things, context is vital. You do not have freedom to yell, "Fire!" in a crowded concert hall.
There is no law that prevents you from saying something offensive, just the convention of good manners. As I have said before, a secular book I read on the great virtues puts politeness at the head of the list since, since society is impossible without it.
The Wire was reckoned to be the best TV program to come out of America in years. However, the dialogue was replete with offensive words. One sequence showing two detectives tracing the path of a bullet was free of dialogue apart from the dozens of 'F**ks' uttered. African Americans generally referred to each other as 'N*gg*r', but, of course, no 'Honky' would be allowed to do so. Oh! Am I allowed to use that word? When the program was broadcast in the UK, the BBC gave clear warnings of what some viewers would find offensive. There is such a thing as an 'off' switch.
We have a grading system for movies and videos. We have parental PINS to prevent our children getting access to some Internet sites. When my wife was a librarian some books were kept 'under the counter' because they were thought unsuitable for minors. In some newsagents the 'Girlie' magazines are kept on the top shelf, out of the way of the prying eyes of young children. Over the years there has been a liberalising approach to anything concerned with sex. We find it hard to believe that our forebears put skirts on table legs. Some years ago an editor was sent to prison for publishing a blasphemous libel; a homoerotic poem about Jesus. It is very unlikely that the same thing would happen now.
Yet Britain is the libel capital of the world; the offended sue here to get bigger payouts. We limit free speech by law if it seeks to defame with an untruth. The question that concerns libertarians is whether the state wishes to extend the powers it has to censor what people say. Minority groups are worried that legislation that, no doubt, with good intent wants to enshrine good manners in law, might restrict legitimate comment. The trouble with free speech legislation is that it goes too far. Homosexuals want to be protected from bullying and free to express their sexuality in public in the same way that heterosexuals do. But if it is granted to homosexuals under the heading of free speech, what is to stop pedophiles or those who like sex with animals claiming the same? I am not equating all these practices, but there is no disguising the fact that homosexuality disgusts a sizable section of the population. There are not enough prisons to punish Disgusted of Tunbridge Wells.
The liberalising tendency is winning at the moment, but it will not always be so. A backlash is developing against unfettered immigration. In 1979 the unrestrained power of the Unions left the dead unburied and rats running loose in the streets as garbage went uncollected. As a result, Mrs Thatcher's government cut off the Unions at the knees. Privatisation sapped the power of organized labor. Restrictive legislation (unrepealed by Tony Blair) enfeebled the strike threat. Right wing governments have not gone for ever.
What is the Christian perspective on free speech? It centers mainly on the freedom to preach the gospel. In many countries this is restricted, but not yet in the UK. Christians generally prefer to live in an ordered society and not to question the right of the government to govern; render unto Caesar... even if he is a tyrant. However, rendering unto God comes first and if there is a conflict they are willing to suffer the punishment the state decrees. Not that this means that they will not campaign against perceived wrongs. Men like Wilberforce campaigned against the slave trade when most of society thought slavery in Jamaica preferable to wage-slavery in Lancashire. Is free speech something that they should campaign for? Remember what was said about those who lead children astray. Something about millstones and deep sea diving, as I recall. If children are to be protected there is already an exception. Freedom of expression is a lot more complicated and blanket laws are not helpful.
Should Christians be offended? I think we have a responsibility not to seek out offence. I would never go to a Gay-Pride parade. I would not watch late-night TV programs meant to titillate. I would not buy Girlie magazines. But I might protest if I thought that bad language was commonplace in all television programs, or same-sex-snogging became a part of children's TV. Everything must be seen in context. I believe there are absolutes when it comes to right and wrong. Not everything that is sinful is unlawful. Jesus's take on murder was having hateful thoughts about another person. How do you legislate for that. There are far more adulterers than homosexuals in our churches, and far more gossips than both. We should start putting our own house in order before we insist on reform in unbelievers. While sexual sins are important, they are not more important than the many other sins listed in Scripture - including gossip, neglect of parents and mean-spiritedness.
So, no I do not think free speech is an absolute. I do believe in politeness and in only giving offence when you may legitimately intend to.
Saturday, November 14, 2009
Forgiveness
A couple of days ago a 16-year old was jailed for raping a five-year-old boy. The offence took place just days after he had been spared a custodial sentence for a previous attack. The young man, who is said to have Asperger's syndrome, abducted and repeatedly abused the child only eight days after being shown leniency for the rape of a seven-year-old boy. The first victim's family were committed Christians and the court had heard that they forgave him and called for a "corrective" rather than punitive sentence.
During this week I have been watching a TV mini-series called Collision. A multi-car pile-up was being investigated by a cop who had lost his own wife in a car crash the previous year. His daughter had been paralysed in the same crash and was now in a wheelchair. During the course of the program, the drunken driver responsible for his wife's death was released from prison. He sought out the cop and explained that during his time in prison he had become a Christian and now felt that he ought to go to the cop and beg for forgiveness. The cop beat him up. As the story proceeded, exploring the lives of those involved in the crash, it was clear that each of them had done something reprehensible. What was noticeable was how wives forgave errant husbands so as to keep their families together. The cop's crippled daughter even suggested that he forgive the drunken driver. She had, after all, forgiven her father for his affair with a policewoman. She emphasized that without forgiveness he would never be able to move on.
So the question is posed, "Should we forgive?" Even more pertinent, should Christians forgive.
I think there are several points to make. You cannot forgive on behalf of someone else. Even the parents of the abused child cannot forgive on his behalf. They were themselves offended by the abuser's act and they can forgive that, but not really the harm done to the child.
Forgiveness may well be undesired. When the Christian in the play asked forgiveness of the cop, the cop pushed him away. The Christian then said, "I forgive you for pushing me." This raised the level of anger in the cop so that he almost killed him. The cop didn't want forgiving.
Forgiveness does take away responsibility. God's forgiveness may save us from Hell, but it doesn't save us from prison. The judge shouldn't have spared the rapist from jail after the first offence. The thief on the cross was forgiven by Jesus, but he still had to complete his sentence - he had to die.
In a recent episode of House, a young doctor murdered an African tyrant under his care and got away with it. However, it weighed on his Catholic conscience and he went to confession. The priest, quite rightly, says, "You can't be absolved by saying a few Hail Marys; you must go to the police."
Finally, forgiveness is ineffectual without repentance. And repentance means more than saying you're sorry. It means a whole change around in your life.
But isn't God's forgiveness unconditional? Doesn't the Bible say, "While we were still sinners, Christ died for us."?
The offer of forgiveness is unconditional. God made the first move without asking us to do anything first. We are not offered forgiveness because we have made amends, done some community service, given to the poor or spent years as a missionary. God describes all such attempts at atonement as 'dirty rags'. Forgiveness is free; the price has already been paid.
However, we are given the free will to reject the offer. Just like the cop in the mini-series we can give the person doing the offering a punch on the nose. Forgiveness is not forced upon us. As the cop's daughter implied, forgiveness is a great healer. It can induce repentance, but without repentance it is ineffectual.
What difference did it make to the young rapist that he had been forgiven by his victim's parents? None at all. There was no repentance (perhaps because of the diagnosis attached to him he was unable to repent. Perhaps he was like the soldiers at the foot of the cross - they know not what they do.) Whatever the answer he had to be locked up. A beast in a zoo does not know what it is doing when it attacks the visitors; it still needs locking up.
If your brother/son/mother were blown up by a suicide bomber, you would have a hard time forgiving the perpetrator; perhaps in forgiving Islam and everyone associated with it. So would I. A Christian must learn to forgive. "Forgive us our sins as we forgive those who sin against us." That does not mean that the man who planned the atrocity and those who funded and facilitated it are free from blame. They broke the law and must face the punishment that the law decrees. We do not operate under Shariah law, where the payment of blood money can absolve the crime. Our law demands a penalty (in different places, imprisonment or execution). Our ability to forgive doesn't come into it and should not influence the judge when passing sentence.
But being able to forgive unburdens the victim.
During this week I have been watching a TV mini-series called Collision. A multi-car pile-up was being investigated by a cop who had lost his own wife in a car crash the previous year. His daughter had been paralysed in the same crash and was now in a wheelchair. During the course of the program, the drunken driver responsible for his wife's death was released from prison. He sought out the cop and explained that during his time in prison he had become a Christian and now felt that he ought to go to the cop and beg for forgiveness. The cop beat him up. As the story proceeded, exploring the lives of those involved in the crash, it was clear that each of them had done something reprehensible. What was noticeable was how wives forgave errant husbands so as to keep their families together. The cop's crippled daughter even suggested that he forgive the drunken driver. She had, after all, forgiven her father for his affair with a policewoman. She emphasized that without forgiveness he would never be able to move on.
So the question is posed, "Should we forgive?" Even more pertinent, should Christians forgive.
I think there are several points to make. You cannot forgive on behalf of someone else. Even the parents of the abused child cannot forgive on his behalf. They were themselves offended by the abuser's act and they can forgive that, but not really the harm done to the child.
Forgiveness may well be undesired. When the Christian in the play asked forgiveness of the cop, the cop pushed him away. The Christian then said, "I forgive you for pushing me." This raised the level of anger in the cop so that he almost killed him. The cop didn't want forgiving.
Forgiveness does take away responsibility. God's forgiveness may save us from Hell, but it doesn't save us from prison. The judge shouldn't have spared the rapist from jail after the first offence. The thief on the cross was forgiven by Jesus, but he still had to complete his sentence - he had to die.
In a recent episode of House, a young doctor murdered an African tyrant under his care and got away with it. However, it weighed on his Catholic conscience and he went to confession. The priest, quite rightly, says, "You can't be absolved by saying a few Hail Marys; you must go to the police."
Finally, forgiveness is ineffectual without repentance. And repentance means more than saying you're sorry. It means a whole change around in your life.
But isn't God's forgiveness unconditional? Doesn't the Bible say, "While we were still sinners, Christ died for us."?
The offer of forgiveness is unconditional. God made the first move without asking us to do anything first. We are not offered forgiveness because we have made amends, done some community service, given to the poor or spent years as a missionary. God describes all such attempts at atonement as 'dirty rags'. Forgiveness is free; the price has already been paid.
However, we are given the free will to reject the offer. Just like the cop in the mini-series we can give the person doing the offering a punch on the nose. Forgiveness is not forced upon us. As the cop's daughter implied, forgiveness is a great healer. It can induce repentance, but without repentance it is ineffectual.
What difference did it make to the young rapist that he had been forgiven by his victim's parents? None at all. There was no repentance (perhaps because of the diagnosis attached to him he was unable to repent. Perhaps he was like the soldiers at the foot of the cross - they know not what they do.) Whatever the answer he had to be locked up. A beast in a zoo does not know what it is doing when it attacks the visitors; it still needs locking up.
If your brother/son/mother were blown up by a suicide bomber, you would have a hard time forgiving the perpetrator; perhaps in forgiving Islam and everyone associated with it. So would I. A Christian must learn to forgive. "Forgive us our sins as we forgive those who sin against us." That does not mean that the man who planned the atrocity and those who funded and facilitated it are free from blame. They broke the law and must face the punishment that the law decrees. We do not operate under Shariah law, where the payment of blood money can absolve the crime. Our law demands a penalty (in different places, imprisonment or execution). Our ability to forgive doesn't come into it and should not influence the judge when passing sentence.
But being able to forgive unburdens the victim.
Friday, November 13, 2009
ASH 2009
It is now possible to view the ASH abstracts for 2009. Although I have already broken the news that for the first time a first line treatment has been shown to improve overall survival, we can now view the details here.
We owe a great deal to Michael Hallek and his team for doing this trial, and we ought to ought to complain to the drug company for not doing the trial at an earlier stage. Their perfidy has deprived many people of what is the best available treatment for CLL.
The German CLL8 trial was a large one, involving 817 patients with CLL that needed treating. They were randomized to either FC or FCR in standard doses. The group receiving FCR had a higher response rate (95.1 vs 88.4%) and more complete remissions (44.1 vs 21.8%; p<0.001). and a longer progression-free survival 51.8 months v 32.8 months (p<0.001). We've seen this sort of result before, but do the patients live any longer? Note that the follow up is relatively short (median just over 3 years). The Overall Survival rate was 84.1% in the FCR arm versus 79.0 % in the FC arm (p=0.01).
They were able to do a multivariate analysis to look for what factors predict poorer survival. Several factors acted as independent prognostic factors for both progression-free survival and overall survival, including age, sex, FCR-treatment v FC treatment, receiving fewer or more than 3 cycles of treatment, response, 17p-deletion, serum levels of thymidine kinase and ß2-microglobulin and mutational status of the IGVH genes.
Adding rituximab seems to lead to more neutropenia, but this does not lead to more infections. I presume that the neutrophils are consumed by the CD20/anti-CD20 immune complexes. In fact there were more deaths in the FC arm (86/396, 21.7% versus 65/404, 16.1%). Most commonly death was cause by progressive disease (FC 48/86, FCR 33/65), but there were also more deaths from secondary malignancies in the FC arm (13/86 v 5/65). Of course in this age group there were also deaths from unrelated causes. Treatment related mortality was just 2.0% in each arm.
One strange finding was that the benefit of FCR did not reach statistical significance for stage C patients (Rai stages III and IV). Why this was so is not clear, but it might be due to the relative immaturity of the study or it may be that these patients, with a higher tumor load, need more intensive treatment. Since platelets falling to below 100 or HB falling below 10 are indication for treatment, perhaps a higher threshold for starting treatment should be adopted.
However in another study from the German group the better efficacy of the FCR regimen in terms of response rates and progression-free survival does not yet result in an improved quality of life.
We owe a great deal to Michael Hallek and his team for doing this trial, and we ought to ought to complain to the drug company for not doing the trial at an earlier stage. Their perfidy has deprived many people of what is the best available treatment for CLL.
The German CLL8 trial was a large one, involving 817 patients with CLL that needed treating. They were randomized to either FC or FCR in standard doses. The group receiving FCR had a higher response rate (95.1 vs 88.4%) and more complete remissions (44.1 vs 21.8%; p<0.001). and a longer progression-free survival 51.8 months v 32.8 months (p<0.001). We've seen this sort of result before, but do the patients live any longer? Note that the follow up is relatively short (median just over 3 years). The Overall Survival rate was 84.1% in the FCR arm versus 79.0 % in the FC arm (p=0.01).
They were able to do a multivariate analysis to look for what factors predict poorer survival. Several factors acted as independent prognostic factors for both progression-free survival and overall survival, including age, sex, FCR-treatment v FC treatment, receiving fewer or more than 3 cycles of treatment, response, 17p-deletion, serum levels of thymidine kinase and ß2-microglobulin and mutational status of the IGVH genes.
Adding rituximab seems to lead to more neutropenia, but this does not lead to more infections. I presume that the neutrophils are consumed by the CD20/anti-CD20 immune complexes. In fact there were more deaths in the FC arm (86/396, 21.7% versus 65/404, 16.1%). Most commonly death was cause by progressive disease (FC 48/86, FCR 33/65), but there were also more deaths from secondary malignancies in the FC arm (13/86 v 5/65). Of course in this age group there were also deaths from unrelated causes. Treatment related mortality was just 2.0% in each arm.
One strange finding was that the benefit of FCR did not reach statistical significance for stage C patients (Rai stages III and IV). Why this was so is not clear, but it might be due to the relative immaturity of the study or it may be that these patients, with a higher tumor load, need more intensive treatment. Since platelets falling to below 100 or HB falling below 10 are indication for treatment, perhaps a higher threshold for starting treatment should be adopted.
However in another study from the German group the better efficacy of the FCR regimen in terms of response rates and progression-free survival does not yet result in an improved quality of life.
Thursday, November 12, 2009
Scientists rule. OK?
Would you trust a scientist? Quite apart from whether he is honest or not; is his opinion worth anything? I suppose, in this day and age when actors, pop-singers and sports stars are supposed to have the last word on everything, you might think that a scientist is a bit of an improvement.
The correct answer is, "If he knows what he's talking about." And for the purpose of this article so I don't have to keep writing his/her, let's assume that the male embraces the female.
I have always prided myself on reading widely and picking up scraps of information from many different places. However, if you got me on astrophysics then my opinion would be worth no more than that of Tiger Woods. On CLL though, I could wipe the floor with Stephen Hawking.
Even on CLL it is possible to disagree. Michael Keating and I, though agreeing on many things, had a fierce debate on one aspect of CLL on which we disagreed.
The best committee that I ever sat on was chaired by a non-specialist who had no detailed knowledge of the subject under consideration. He allowed debate to flow.
Scientists as a group dig very deep and narrow holes. They often know an awful lot about very little. Politicians, on the other hand, skim the surface from a large area. They can't be expected to know a subject deeply, but, if they are honest, they will look at a topic fairly and seek expert help over detail.
To go back to the topic of drugs. A complete libertarian would say that if someone wants to take a drug that harms his own body the let him; it is his, and only his, responsibility. On the other hand, if he has the same health insurance as I do, why should my premiums go up just because he indulges himself?
However, many drugs cause harm to the community. Alcoholics, apart from raising my insurance premium, beat their wives, cause motor car accidents, vomit in the streets, desert their children, reduce their families to penury and can't work properly. So what? Banning alcohol does not work; we saw how much harm it did during Prohibition. It just leads to an increase in criminal behavior. Look at it another way; legalizing it hasn't worked either. We still have wife-beatings, car accidents and poverty.
Scientists may tell us that cannabis is less harmful than tobacco and alcohol. How do they know? At first glance cigarette smoking seemed an attractive proposition. Actors, singers and sports stars endorsed the product. Even doctors agreed. Given, it did make your clothes stink, but it helped your cough, didn't it? Then in 1951, Richard Doll demonstrated that smoking caused lung cancer. The evidence was convincing enough to make him stop smoking. Nevertheless, it took many years before anybody believed him and many more before everybody believed him. Such convincing evidence is hard to obtain. There are no such studies for cannabis or ecstasy. People lie - either because of guilt of bravado - about their drug taking. How would you isolate the effect of one drug compared to another?
Cannabis apparently induces a degree of intoxication. How long after smoking a joint is it safe to drive? If you were stopped, what test would the policeman use to determine whether you were safe to drive? Supposing you had popped an 'E' and later on smoked some pot. Are you safe to fly your aeroplane tomorrow? A scientist who has opinion on such a thing had better couch it in conditional clauses if he doesn't want to be sued.
If the question is a simpler one such as, "Do cannabis users develop schizophrenia more commonly than non-users?" then the answer is yes, but asked how commonly, a wise scientist will demur. Remember the guy who won the Nobel Prize for inventing the transistor? This was a proper Nobel Prize; not like the Mickey Mouse ones they gave to Gore and Obama. Well, he turned out to espouse the discredited science of Eugenics, and even started a sperm bank for geniuses. Do you want to be ruled by scientists? I don't. There is a quote from the New Testament where Festus, the Roman governor says to the Apostle Paul, "Your great learning is driving you insane!" We would be insane to be ruled by scientists.
The correct answer is, "If he knows what he's talking about." And for the purpose of this article so I don't have to keep writing his/her, let's assume that the male embraces the female.
I have always prided myself on reading widely and picking up scraps of information from many different places. However, if you got me on astrophysics then my opinion would be worth no more than that of Tiger Woods. On CLL though, I could wipe the floor with Stephen Hawking.
Even on CLL it is possible to disagree. Michael Keating and I, though agreeing on many things, had a fierce debate on one aspect of CLL on which we disagreed.
The best committee that I ever sat on was chaired by a non-specialist who had no detailed knowledge of the subject under consideration. He allowed debate to flow.
Scientists as a group dig very deep and narrow holes. They often know an awful lot about very little. Politicians, on the other hand, skim the surface from a large area. They can't be expected to know a subject deeply, but, if they are honest, they will look at a topic fairly and seek expert help over detail.
To go back to the topic of drugs. A complete libertarian would say that if someone wants to take a drug that harms his own body the let him; it is his, and only his, responsibility. On the other hand, if he has the same health insurance as I do, why should my premiums go up just because he indulges himself?
However, many drugs cause harm to the community. Alcoholics, apart from raising my insurance premium, beat their wives, cause motor car accidents, vomit in the streets, desert their children, reduce their families to penury and can't work properly. So what? Banning alcohol does not work; we saw how much harm it did during Prohibition. It just leads to an increase in criminal behavior. Look at it another way; legalizing it hasn't worked either. We still have wife-beatings, car accidents and poverty.
Scientists may tell us that cannabis is less harmful than tobacco and alcohol. How do they know? At first glance cigarette smoking seemed an attractive proposition. Actors, singers and sports stars endorsed the product. Even doctors agreed. Given, it did make your clothes stink, but it helped your cough, didn't it? Then in 1951, Richard Doll demonstrated that smoking caused lung cancer. The evidence was convincing enough to make him stop smoking. Nevertheless, it took many years before anybody believed him and many more before everybody believed him. Such convincing evidence is hard to obtain. There are no such studies for cannabis or ecstasy. People lie - either because of guilt of bravado - about their drug taking. How would you isolate the effect of one drug compared to another?
Cannabis apparently induces a degree of intoxication. How long after smoking a joint is it safe to drive? If you were stopped, what test would the policeman use to determine whether you were safe to drive? Supposing you had popped an 'E' and later on smoked some pot. Are you safe to fly your aeroplane tomorrow? A scientist who has opinion on such a thing had better couch it in conditional clauses if he doesn't want to be sued.
If the question is a simpler one such as, "Do cannabis users develop schizophrenia more commonly than non-users?" then the answer is yes, but asked how commonly, a wise scientist will demur. Remember the guy who won the Nobel Prize for inventing the transistor? This was a proper Nobel Prize; not like the Mickey Mouse ones they gave to Gore and Obama. Well, he turned out to espouse the discredited science of Eugenics, and even started a sperm bank for geniuses. Do you want to be ruled by scientists? I don't. There is a quote from the New Testament where Festus, the Roman governor says to the Apostle Paul, "Your great learning is driving you insane!" We would be insane to be ruled by scientists.
Wednesday, November 11, 2009
How long to train a surgeon?
Concern has been raised about the training of doctors. Gretchen Purcell Jackson and John L Tapley, pediatric surgeons from Nashville, have just published an article in the BMJ which suggests that our surgeons are in danger of being seriously undertrained. Typically, a surgical training takes 5 years to obtain the necessary skills to be come a general surgeon with extra years for research and subspecialty training. Educational psychologists have shown that acquiring an elite level of expertise or performance requires 10 years of intense involvement and 10,000 hours of practice. This would be true for musicians, chess players or Olympic divers. The authors suggest that surgery, which requires both manual dexterity and cognitive understanding, needs twice that amount of training.
In the States surgeons are rejecting the idea that an 80 hour working week is sufficient to train a surgeon while in Europe the working-time directive is insisting on a 48 hour week. Sleep researchers have demonstrated that heavy night call, defined as every fourth or fifth night, compromises attention and vigilance as much as alcohol intoxication. One institution that introduced the 80 hour week found it produced happier trainees with a better quality of life but it also may well have compromised the surgeons' educational experience.
5 years at 80 hours a week does give the necessary 20,000 hours, but only if no more than 2 weeks holiday is taken. How can Denmark train its surgeons with a 37 hour week?
Although, the prime purpose in reducing surgeons' hours has been to enhance patient safety, it seems to have had the opposite effect where it has been tried. at one center preventable and non-preventable complication rates increased significantly after the introduction of an 80 hour week. In New York, where Teaching Hospitals adopted the 80-hour week but non-teaching hospitals did not, there were increases in unintentional punctures and thromboembolic events in those with the hours restrictions. The extra duties have to be done by someone - the answer is often moonlighting or else lying about hours.
When I think back to my own training, in the early days I worked alternate nights and then on a 1 in 4 rota. Hematologists in the UK have to obtain both the MRCP like internal medicine specialists and then the MRCPath like pathologists. They are also expected to publish. I completed my training 6 years after qualifying, but I did take work home. It may well be that surgeons need a longer period of training because of the 'piano practice' required. Musicians don't expect their instruments to start hemorrhaging uncontrollably.
When I was younger there were trainee surgeons in their early forties. Such were the rewards in private practice that they were prepared to put up with this extended training. Nowadays we see consultant surgeons appointed in their early thirties. They do far fewer operations than their forbears, both in range and number. I know one surgeon who never opens an abdomen, but is an expert in taking out lymph nodes and removes spleens through a laparoscope. Perhaps they are all a lot more talented than they used to be.
In the States surgeons are rejecting the idea that an 80 hour working week is sufficient to train a surgeon while in Europe the working-time directive is insisting on a 48 hour week. Sleep researchers have demonstrated that heavy night call, defined as every fourth or fifth night, compromises attention and vigilance as much as alcohol intoxication. One institution that introduced the 80 hour week found it produced happier trainees with a better quality of life but it also may well have compromised the surgeons' educational experience.
5 years at 80 hours a week does give the necessary 20,000 hours, but only if no more than 2 weeks holiday is taken. How can Denmark train its surgeons with a 37 hour week?
Although, the prime purpose in reducing surgeons' hours has been to enhance patient safety, it seems to have had the opposite effect where it has been tried. at one center preventable and non-preventable complication rates increased significantly after the introduction of an 80 hour week. In New York, where Teaching Hospitals adopted the 80-hour week but non-teaching hospitals did not, there were increases in unintentional punctures and thromboembolic events in those with the hours restrictions. The extra duties have to be done by someone - the answer is often moonlighting or else lying about hours.
When I think back to my own training, in the early days I worked alternate nights and then on a 1 in 4 rota. Hematologists in the UK have to obtain both the MRCP like internal medicine specialists and then the MRCPath like pathologists. They are also expected to publish. I completed my training 6 years after qualifying, but I did take work home. It may well be that surgeons need a longer period of training because of the 'piano practice' required. Musicians don't expect their instruments to start hemorrhaging uncontrollably.
When I was younger there were trainee surgeons in their early forties. Such were the rewards in private practice that they were prepared to put up with this extended training. Nowadays we see consultant surgeons appointed in their early thirties. They do far fewer operations than their forbears, both in range and number. I know one surgeon who never opens an abdomen, but is an expert in taking out lymph nodes and removes spleens through a laparoscope. Perhaps they are all a lot more talented than they used to be.
Tuesday, November 10, 2009
Apologies
Never complain; never explain; never apologize. The words are variously attributed to Neville Chamberlain, John Wayne and Benjamin Disraeli. But someone who should perhaps have taken them to heart is our esteemed Prime Minister, Gordon Brown.
We have learnt that Gordon Brown takes it on himself to hand-write a personal letter to the relatives bereaved by a soldier's death in Afghanistan. One mother, who has lost her son, complained loudly (to a tabloid newspaper) that the letter sent by GB was illegible, and spelt both her and her son's name wrong. Mrs Janes was addressed as Mrs James and her son, Jamie, as James, though GB did score through the terminal 'es' and replace it with 'ie'. Later Brown telephoned to apologize, blaming it on his bad writing (it is very bad and he writes in a thick black felt-tip). There are some spelling errors that can be put down to his bad writing - he tends to omit the letter 'e' near the ends of words as they finish in a terminal squiggle, but the excuse seems lame since he called the family 'James' when announcing the death of the son at Prime Minister's Questions in the Commons, and he clearly realized that 'James' should be 'Jamie', but rather than trying to correct it, he should have wasted that piece of paper and started again. It does give the impression that this was a hurried scribble.
Now, he did not need to write a personal letter and no doubt he was in a hurry. A prime minister's job is a hard one and he can't behave like Campbell Bannerman did in 1906 and take a nap in the afternoon. But apologize? PG Wodehouse once wrote, "It is a good rule in life never to apologize. The right sort of people does not want apologies, and the wrong sort of people takes a mean advantage of them.”
This is certainly what happened to GB. The mother, no doubt at the behest of the tabloid newspaper, taped the phone call. She did not accept the apology and easily pointed out the inherent lie in his excuse. She further turned the complaint into what was probably bugging her in the first place. Her son didn't need to die. Had a helicopter been available he might have been evacuated in time, but there weren't enough helicopters.
The transcript of the telephone call was plastered over the tabloids this morning. Although the public reaction is slightly in Gordon Brown's favor, he would have been wise to have kept his head down. People understand that he went the extra mile in writing the letter, but he has appeared maladroit in the way he has handled himself, and who wants a clumsy Prime Minister.
So what are rules about apologizing?
First: don't apologize for something you are not responsible for. It has been unseemly and nauseating to see politicians apologizing for things that happened 200 years ago when standards were different. Even when standards are the same. Young Germans should not apologize for Hitler - he was Austrian anyway. What's done is done. Nothing will change the past. Get over it; that's the way things are. Anyone ever thought of criticizing the Italians because Nero burnt Christians to light his arenas?
Second: if you are responsible for something, apologize in person, face to face to the offended party; but don't make a public spectacle of it. Do it quickly. Don't have it dragged out of you.
Third: don't make excuses. If you are truly sorry it is because it is your fault - not the fault of the weather, your work being too onerous or some other fool putting you off.
Fourth: do better in future.
We have learnt that Gordon Brown takes it on himself to hand-write a personal letter to the relatives bereaved by a soldier's death in Afghanistan. One mother, who has lost her son, complained loudly (to a tabloid newspaper) that the letter sent by GB was illegible, and spelt both her and her son's name wrong. Mrs Janes was addressed as Mrs James and her son, Jamie, as James, though GB did score through the terminal 'es' and replace it with 'ie'. Later Brown telephoned to apologize, blaming it on his bad writing (it is very bad and he writes in a thick black felt-tip). There are some spelling errors that can be put down to his bad writing - he tends to omit the letter 'e' near the ends of words as they finish in a terminal squiggle, but the excuse seems lame since he called the family 'James' when announcing the death of the son at Prime Minister's Questions in the Commons, and he clearly realized that 'James' should be 'Jamie', but rather than trying to correct it, he should have wasted that piece of paper and started again. It does give the impression that this was a hurried scribble.
Now, he did not need to write a personal letter and no doubt he was in a hurry. A prime minister's job is a hard one and he can't behave like Campbell Bannerman did in 1906 and take a nap in the afternoon. But apologize? PG Wodehouse once wrote, "It is a good rule in life never to apologize. The right sort of people does not want apologies, and the wrong sort of people takes a mean advantage of them.”
This is certainly what happened to GB. The mother, no doubt at the behest of the tabloid newspaper, taped the phone call. She did not accept the apology and easily pointed out the inherent lie in his excuse. She further turned the complaint into what was probably bugging her in the first place. Her son didn't need to die. Had a helicopter been available he might have been evacuated in time, but there weren't enough helicopters.
The transcript of the telephone call was plastered over the tabloids this morning. Although the public reaction is slightly in Gordon Brown's favor, he would have been wise to have kept his head down. People understand that he went the extra mile in writing the letter, but he has appeared maladroit in the way he has handled himself, and who wants a clumsy Prime Minister.
So what are rules about apologizing?
First: don't apologize for something you are not responsible for. It has been unseemly and nauseating to see politicians apologizing for things that happened 200 years ago when standards were different. Even when standards are the same. Young Germans should not apologize for Hitler - he was Austrian anyway. What's done is done. Nothing will change the past. Get over it; that's the way things are. Anyone ever thought of criticizing the Italians because Nero burnt Christians to light his arenas?
Second: if you are responsible for something, apologize in person, face to face to the offended party; but don't make a public spectacle of it. Do it quickly. Don't have it dragged out of you.
Third: don't make excuses. If you are truly sorry it is because it is your fault - not the fault of the weather, your work being too onerous or some other fool putting you off.
Fourth: do better in future.
Monday, November 09, 2009
A woman without her man.
I have just finished reading "My Grammar and I (or should that be 'Me'?)" by Caroline Taggart and J.A.Wines. I have always liked grammar because it is full of little jokes.
Take the section on tautology, for example. What could be funnier than 'honest truth'? Dishonest truth? Similarly what nonsense are 'PIN number', 'HIV virus', 'new innovation', 'free gift', 'skin rash', 'unconfirmed rumor', '8 p.m. in the evening', 'climb up' and 'fall down'!
Indeed, the examples scattered through the pages make us want to laugh out loud.
The longest sentence in English literature is spoken by Molly Bloom in James Joyce's Ulysses. It contains 4,391 words, which makes it far too long to be quoted here, even if the subject matter were not a bit dodgy (but it is).
Note the use of the subjunctive!
As far as I am concerned, whom is a word invented to make everyone sound like a butler.
A college professor wrote on a blackboard: A woman without her man is nothing.
He then asked the class to punctuate it. All the men in the class wrote: A woman, without her man, is nothing. All the women wrote: A woman: without her, man is nothing.
A linguistics professor was lecturing to his English class.
"In English," he said, "a double negative forms a positive. In some languages, though, such as Russian, a double negative is still a negative. However, there is no language where a double positive can form a negative."
"Yeah, right," piped a voice from the back of the room.
But my main purpose of this article is a plea in favor of retaining the semi-colon, which is going out of fashion.
It is there to connect two or more independent clauses that don't quite justify being sentences in their own right. For example: 'I have tickets for the match. I bet it rains.' This is correct, but an immature, jerky style makes it unattractive. 'I have tickets for the match, but I bet it rains' is clumsy. Far better is, 'I have tickets for the match; I bet it rains.'
Semi-colons can also be used to break up items in a long and complicated list. An example from Charles Dickens's A Christmas Carol illustrates this.
'... there were bunches of grapes, made, in the shopkeeper's benevolence, to dangle from conspicuous hooks, that people's mouths might water gratis as they past; there were piles of filberts, mossy and brown, recalling, in their fragrance, ancient walks among the woods, and pleasant shufflings ankle deep through withered leaves; there were...'; I am sure you get the idea. It is especially useful when a list has too many commas for comfort.
The semi-colon is in danger of being usurped by the dash (an en-dash in British English and an em-dash in American English).
Finally, readers always like to catch out grammarians at their own game. I have found an error in this book. When talking about the apostrophe, they say that it's is only correct when it is short for it is. Not quite right. In the sentence clause 'it's been said' it's is short for it has.
Take the section on tautology, for example. What could be funnier than 'honest truth'? Dishonest truth? Similarly what nonsense are 'PIN number', 'HIV virus', 'new innovation', 'free gift', 'skin rash', 'unconfirmed rumor', '8 p.m. in the evening', 'climb up' and 'fall down'!
Indeed, the examples scattered through the pages make us want to laugh out loud.
The longest sentence in English literature is spoken by Molly Bloom in James Joyce's Ulysses. It contains 4,391 words, which makes it far too long to be quoted here, even if the subject matter were not a bit dodgy (but it is).
Note the use of the subjunctive!
As far as I am concerned, whom is a word invented to make everyone sound like a butler.
A college professor wrote on a blackboard: A woman without her man is nothing.
He then asked the class to punctuate it. All the men in the class wrote: A woman, without her man, is nothing. All the women wrote: A woman: without her, man is nothing.
A linguistics professor was lecturing to his English class.
"In English," he said, "a double negative forms a positive. In some languages, though, such as Russian, a double negative is still a negative. However, there is no language where a double positive can form a negative."
"Yeah, right," piped a voice from the back of the room.
But my main purpose of this article is a plea in favor of retaining the semi-colon, which is going out of fashion.
It is there to connect two or more independent clauses that don't quite justify being sentences in their own right. For example: 'I have tickets for the match. I bet it rains.' This is correct, but an immature, jerky style makes it unattractive. 'I have tickets for the match, but I bet it rains' is clumsy. Far better is, 'I have tickets for the match; I bet it rains.'
Semi-colons can also be used to break up items in a long and complicated list. An example from Charles Dickens's A Christmas Carol illustrates this.
'... there were bunches of grapes, made, in the shopkeeper's benevolence, to dangle from conspicuous hooks, that people's mouths might water gratis as they past; there were piles of filberts, mossy and brown, recalling, in their fragrance, ancient walks among the woods, and pleasant shufflings ankle deep through withered leaves; there were...'; I am sure you get the idea. It is especially useful when a list has too many commas for comfort.
The semi-colon is in danger of being usurped by the dash (an en-dash in British English and an em-dash in American English).
Finally, readers always like to catch out grammarians at their own game. I have found an error in this book. When talking about the apostrophe, they say that it's is only correct when it is short for it is. Not quite right. In the sentence clause 'it's been said' it's is short for it has.
Sunday, November 08, 2009
Respect authority; do good. 1 Peter 2:13-17
Is our society breaking down? I remember getting the cane at school. The headmaster had made a new rule which I and several of the boys thought unreasonable. We deliberately flouted it in front of the teachers to demonstrate that whatever they said about it we didn't agree. We were not sly or underhand about it, we were not deceitful; we did not lie about it. The consequence was that we were all caned to demonstrate that there was a certain hierarchy in the school and we had to submit to it.
On another occasion a boy in my class deliberately flouted a rule that said we couldn't buy ice creams from a van parked outside the school gates. He didn't even want an ice cream; he just wanted to demonstrate that he didn't think the rule was reasonable. He too got his comeuppance.
This was back in the 1950s when society was more ordered. Today we tolerate campaigners for the environment breaking into power stations and chaining themselves to railings with their posters and slogans. We acquiesce to demonstrators shouting abuse at the police. Recently, individuals who have attempted to stop queue-jumpers or litter louts have found themselves cautioned by the police. We are supposed to allow this sort of societal disorder.
When they made the film Titanic they showed the 1st Class passengers behaving like louts, elbowing others out of their way as they made for the lifeboats and having to be restrained by a crew member firing his revolver. In fact it never happened. The 'toffs' of Edwardian society behaved impeccably, holding back to ensure that women and children were saved. Rich men like Colonel John Jacob Astor IV and Benjamin Guggenheim stood aside. Guggenheim and his manservant helped women and children into lifeboats. When all the boats had gone they changed into their best clothes and prepared to "Die like gentlemen." Astor kissed his wife good-bye as she was put in the lifeboat. Astor said: 'I resign myself to my fate' and saluted in farewell." Of the 175 male first class passengers, only 57 survived whereas 140 of the 144 women and 5 of the 6 children lived. Such acts of heroism and self sacrifice were omitted from the movie because they did not fit the spirit of the age, where only the steerage class could be heroes. A contemporary witness wrote, "A third-class passenger who tried to climb in the boats was shot and killed by a steward. This was the only shooting on board I know of." Another said, "The behavior of the men was magnificent. They stood back without murmuring and urged the women and children into the lifeboats. A few cowards tried to scramble into the boats, but they were quickly thrown back by the others. Let me say now that the only men who were saved were those who sneaked into the lifeboats or were picked up after the Titanic sank."
This sort of historical forgetfulness is an indication of how society has changed and it is with this in mind that I hesitate to open up the next passage in 1 Peter chapter 2.
Submit yourselves for the Lord's sake to every authority instituted among men: whether to the king, as the supreme authority, or to governors, who are sent by him to punish those who do wrong and to commend those who do right. For it is God's will that by doing good you should silence the ignorant talk of foolish men. Live as free men, but do not use your freedom as a cover-up for evil; live as servants of God. Show proper respect to everyone: Love the brotherhood of believers, fear God, honor the king.
Submission is not something we take easily to. In a rather strange passage in Matthew 17 (24-26) Jesus argues that sons of the king are exempt from tax. Some have argued that the sons of the King of Kings should not be under the authority of earthly kings. But Jesus has them pay the Temple tax so as not to give offence, and here Peter exhorts us to submit to earthly rulers. The authorities in Peter's day would have been Nero and Claudius - hardly benevolent dictators. In fact they were two of the most arbitrary and cruel kings that have ever lived. Yet Peter tells us to submit. We are free of earthly ties, yet for the Lord's sake we should submit. AS we proceed we will see how it is in the Lord's interest that his servants should submit.
The NIV translation here is a paraphrase. Literally, we are to submit to every 'human creation'. But the word 'creation' has within it the implication of a formed building, something constructed according to rules and physical law. Not a tumbledown shack made of grass and bamboo, but a brick built construction with foundations and perpendicular walls. Thus, the KJV has every human ordinance, the RSV and ASV and NEB 'institution' and the NIV and Good News Bible have 'authorities'. The emphasis is on an ordered society.
As members of a society, we must obey its laws. If women go to Saudi Arabia they should cover their head, not because covering the head is honoring to God, but because it is the local law and to flout authority is to dishonor God. Incidentally, we should expect Muslims coming to Europe or the US to obey our laws. There are indeed somethings in which we must choose to obey God rather than men, but we must recognise that if we do so and fall foul of what we see a an unjust law, we must accept the consequences. While we may detest abortion and we may protest against it inasmuch as the law allows, we should not break the law in our protests. By all means lobby Congress or Parliament. March or wave a placard, but don't shoot abortionists or blow up clinics.
In Ephesians 5:21 Paul writes "Submit to one another out of reverence for Christ." It is this basic politeness that is crucial to an ordered society. I once read a book about the cardinal virtues, written by an atheist. He proposed that the first basic virtue was politeness, because without it no society could exist. How can you hold a conversation unless you allow the other fellow to speak?
A child in arms who grabs candy at the supermarket checkout must submit to his mother; she must not submit to him. The meter maid who hands you a ticket when you park illegally must be submitted to. She doesn't have to submit to you. The soccer player must submit to the referee. It is positively evil when players crowd round him in an attempt to force him to change his mind. It is not that the child is worth less to God than his mother, or the motorist than Rita, or the footballer than the referee. There is a hierarchy of authority not of value. The footballer may be paid millions of dollars every year, far more than the referee, but on the pitch the player must submit to the authority of the ref.
The other night was Guy Fawkes night when we celebrate the uncovering of the Gunpowder Plot of 1605, when Catholic revolutionaries attempted to blow up parliament. With the recent scandals concerning MPs expenses where they have used taxpayers money to have their moats dredged or to build duck islands on their lakes, some have wished that Guy Fawkes had succeeded. But Parliament legitimately has authority over us. That doesn't make them better than us or of more value to God, but we have to submit to them. A famous blogger has called himself Guido Fawkes after the revolutionary bomber, but he restricts himself to lampooning the government - a legitimate tactic. We will have the opportunity to vote this government out if we disapprove of it, but blowing them up is not honoring to God. Even petty bureaucrats are part of the governing machine. Their pettifogging restrictions have to be submitted to. Protest and point out their deficiencies all you like, but in the end you must submit.
But it is more than submitting. Verse 15 tells us that it is also God's will that we do good. Why? To silence foolish men.
Have you read recently how commentators equate evangelical Christians with fundamentalist Muslims? They would not have done so in the nineteenth century, when the evangelical Christian William Wilberforce was battling to abolish the slave trade and the evangelical Lord Shaftesbury (incidentally a local family) reformed society with the Ten Hour Bill; the 1842 Mines Act; reform of the lunacy laws; abolition of child chimney-sweeping; improvements in public health and slum housing; institution of ragged schools; improvements in the the plight of agricultural labourers; and training for destitute children, when the evangelical William Booth rescued people from alcoholism and prostitution and Dr Barnardo established orphanages. Foolish men who equate suicide bombers with works of charity, selflessness and goodwill are foolish indeed.
Do we keep up the good work? Modern evangelicals sometimes criticise good works as 'the social gospel', which they despise. We do not criticise liberal Christians for their opposition to cruel regimes, for fighting hunger, disease, oppression and slavery, for their zeal in rescuing women from servitude to their husbands, children from sexual abuse, people from poverty and prisoners from torture. We approve and join them as co-belligerents against evil. No, we criticise their neglect of the gospel and their subjugation of men's souls to their bodies. It is not a question of either preach the gospel or do good works. We should do good works because of the gospel.
We are free men, but we must never abuse that freedom. We are free to do good, not to do evil. We are free from the subjection of men, but we are slaves of God. The Roman soldier had the authority to compel any citizen to carry his load for a mile, but after a mile he had no right to compel that individual further. A christian, according to Jesus, should offer to go an extra mile, not because he is a slave of the Roman soldier, but because he is a slave of Christ.
We should show respect to everyone. A story is told of a missionary waiting in his house while murdering rebels outside went through the town killing civilians for the fun of it. When the dread knock at the door came he invited them in for a meal. Because he showed them respect they left his home intact. A soft answer turns away wrath. You must have found it so. Bullies complain "He never showed me no respect!" as they shoot an adversary. Show proper respect for everyone.
But love the brethren, and fear God. Because you fear God, you will honor the king.
On another occasion a boy in my class deliberately flouted a rule that said we couldn't buy ice creams from a van parked outside the school gates. He didn't even want an ice cream; he just wanted to demonstrate that he didn't think the rule was reasonable. He too got his comeuppance.
This was back in the 1950s when society was more ordered. Today we tolerate campaigners for the environment breaking into power stations and chaining themselves to railings with their posters and slogans. We acquiesce to demonstrators shouting abuse at the police. Recently, individuals who have attempted to stop queue-jumpers or litter louts have found themselves cautioned by the police. We are supposed to allow this sort of societal disorder.
When they made the film Titanic they showed the 1st Class passengers behaving like louts, elbowing others out of their way as they made for the lifeboats and having to be restrained by a crew member firing his revolver. In fact it never happened. The 'toffs' of Edwardian society behaved impeccably, holding back to ensure that women and children were saved. Rich men like Colonel John Jacob Astor IV and Benjamin Guggenheim stood aside. Guggenheim and his manservant helped women and children into lifeboats. When all the boats had gone they changed into their best clothes and prepared to "Die like gentlemen." Astor kissed his wife good-bye as she was put in the lifeboat. Astor said: 'I resign myself to my fate' and saluted in farewell." Of the 175 male first class passengers, only 57 survived whereas 140 of the 144 women and 5 of the 6 children lived. Such acts of heroism and self sacrifice were omitted from the movie because they did not fit the spirit of the age, where only the steerage class could be heroes. A contemporary witness wrote, "A third-class passenger who tried to climb in the boats was shot and killed by a steward. This was the only shooting on board I know of." Another said, "The behavior of the men was magnificent. They stood back without murmuring and urged the women and children into the lifeboats. A few cowards tried to scramble into the boats, but they were quickly thrown back by the others. Let me say now that the only men who were saved were those who sneaked into the lifeboats or were picked up after the Titanic sank."
This sort of historical forgetfulness is an indication of how society has changed and it is with this in mind that I hesitate to open up the next passage in 1 Peter chapter 2.
Submit yourselves for the Lord's sake to every authority instituted among men: whether to the king, as the supreme authority, or to governors, who are sent by him to punish those who do wrong and to commend those who do right. For it is God's will that by doing good you should silence the ignorant talk of foolish men. Live as free men, but do not use your freedom as a cover-up for evil; live as servants of God. Show proper respect to everyone: Love the brotherhood of believers, fear God, honor the king.
Submission is not something we take easily to. In a rather strange passage in Matthew 17 (24-26) Jesus argues that sons of the king are exempt from tax. Some have argued that the sons of the King of Kings should not be under the authority of earthly kings. But Jesus has them pay the Temple tax so as not to give offence, and here Peter exhorts us to submit to earthly rulers. The authorities in Peter's day would have been Nero and Claudius - hardly benevolent dictators. In fact they were two of the most arbitrary and cruel kings that have ever lived. Yet Peter tells us to submit. We are free of earthly ties, yet for the Lord's sake we should submit. AS we proceed we will see how it is in the Lord's interest that his servants should submit.
The NIV translation here is a paraphrase. Literally, we are to submit to every 'human creation'. But the word 'creation' has within it the implication of a formed building, something constructed according to rules and physical law. Not a tumbledown shack made of grass and bamboo, but a brick built construction with foundations and perpendicular walls. Thus, the KJV has every human ordinance, the RSV and ASV and NEB 'institution' and the NIV and Good News Bible have 'authorities'. The emphasis is on an ordered society.
As members of a society, we must obey its laws. If women go to Saudi Arabia they should cover their head, not because covering the head is honoring to God, but because it is the local law and to flout authority is to dishonor God. Incidentally, we should expect Muslims coming to Europe or the US to obey our laws. There are indeed somethings in which we must choose to obey God rather than men, but we must recognise that if we do so and fall foul of what we see a an unjust law, we must accept the consequences. While we may detest abortion and we may protest against it inasmuch as the law allows, we should not break the law in our protests. By all means lobby Congress or Parliament. March or wave a placard, but don't shoot abortionists or blow up clinics.
In Ephesians 5:21 Paul writes "Submit to one another out of reverence for Christ." It is this basic politeness that is crucial to an ordered society. I once read a book about the cardinal virtues, written by an atheist. He proposed that the first basic virtue was politeness, because without it no society could exist. How can you hold a conversation unless you allow the other fellow to speak?
A child in arms who grabs candy at the supermarket checkout must submit to his mother; she must not submit to him. The meter maid who hands you a ticket when you park illegally must be submitted to. She doesn't have to submit to you. The soccer player must submit to the referee. It is positively evil when players crowd round him in an attempt to force him to change his mind. It is not that the child is worth less to God than his mother, or the motorist than Rita, or the footballer than the referee. There is a hierarchy of authority not of value. The footballer may be paid millions of dollars every year, far more than the referee, but on the pitch the player must submit to the authority of the ref.
The other night was Guy Fawkes night when we celebrate the uncovering of the Gunpowder Plot of 1605, when Catholic revolutionaries attempted to blow up parliament. With the recent scandals concerning MPs expenses where they have used taxpayers money to have their moats dredged or to build duck islands on their lakes, some have wished that Guy Fawkes had succeeded. But Parliament legitimately has authority over us. That doesn't make them better than us or of more value to God, but we have to submit to them. A famous blogger has called himself Guido Fawkes after the revolutionary bomber, but he restricts himself to lampooning the government - a legitimate tactic. We will have the opportunity to vote this government out if we disapprove of it, but blowing them up is not honoring to God. Even petty bureaucrats are part of the governing machine. Their pettifogging restrictions have to be submitted to. Protest and point out their deficiencies all you like, but in the end you must submit.
But it is more than submitting. Verse 15 tells us that it is also God's will that we do good. Why? To silence foolish men.
Have you read recently how commentators equate evangelical Christians with fundamentalist Muslims? They would not have done so in the nineteenth century, when the evangelical Christian William Wilberforce was battling to abolish the slave trade and the evangelical Lord Shaftesbury (incidentally a local family) reformed society with the Ten Hour Bill; the 1842 Mines Act; reform of the lunacy laws; abolition of child chimney-sweeping; improvements in public health and slum housing; institution of ragged schools; improvements in the the plight of agricultural labourers; and training for destitute children, when the evangelical William Booth rescued people from alcoholism and prostitution and Dr Barnardo established orphanages. Foolish men who equate suicide bombers with works of charity, selflessness and goodwill are foolish indeed.
Do we keep up the good work? Modern evangelicals sometimes criticise good works as 'the social gospel', which they despise. We do not criticise liberal Christians for their opposition to cruel regimes, for fighting hunger, disease, oppression and slavery, for their zeal in rescuing women from servitude to their husbands, children from sexual abuse, people from poverty and prisoners from torture. We approve and join them as co-belligerents against evil. No, we criticise their neglect of the gospel and their subjugation of men's souls to their bodies. It is not a question of either preach the gospel or do good works. We should do good works because of the gospel.
We are free men, but we must never abuse that freedom. We are free to do good, not to do evil. We are free from the subjection of men, but we are slaves of God. The Roman soldier had the authority to compel any citizen to carry his load for a mile, but after a mile he had no right to compel that individual further. A christian, according to Jesus, should offer to go an extra mile, not because he is a slave of the Roman soldier, but because he is a slave of Christ.
We should show respect to everyone. A story is told of a missionary waiting in his house while murdering rebels outside went through the town killing civilians for the fun of it. When the dread knock at the door came he invited them in for a meal. Because he showed them respect they left his home intact. A soft answer turns away wrath. You must have found it so. Bullies complain "He never showed me no respect!" as they shoot an adversary. Show proper respect for everyone.
But love the brethren, and fear God. Because you fear God, you will honor the king.
Saturday, November 07, 2009
Other trials in CLL
I managed to attend my first Committee meeting yesterday. I went to London to meet with other CLL experts to discuss the forthcoming British CLL trials.
If anti-CD20 antibodies add so much to CHOP, CVP and now FC, does it work for other forms of chemotherapy and for other anti-CD20 antibodies? There are several trials taking place in various countries to answer these questions. One such is the use of FC plus or minus Ofatumumab. This is having some difficulty getting off the ground. It intends to recruit 352 patients from 67 centers in 15 different countries. So far it has only recruited 30 patients. In the UK this will be an unpopular trial because the F and C have to be given intravenously whereas we give both orally. Oral fludarabine has been approved for use in the USA by the FDA. Of course the oncologist is paid less for giving out tablets than for giving an infusion, so we wait to see if it will prosper.
But another reason for its unpopularity may be the phase II study organized by Genmab. Patients in this open label study were randomized into two treatment groups. Each patient was to receive one infusion of 300 mg of ofatumumab in combination with FC followed by 5 monthly infusions of either 500 or 1000 mg of ofatumumab in combination with FC. Disease status was measured every 4 weeks until week 24 and every 3 months thereafter until disease progression or 24 months. Treatment response was assessed according to the 1996 National Cancer Institute Working Group guidelines by an Independent endpoints Review Committee. Patients not having
progressed on their disease at 24 months will be followed for disease progression at 6 month intervals until 60 months.
A total of 61 patients were treated in the study. The complete remission rate was 32% in patients who received 500 mg of ofatumumab (n=31) and 50% in patients who received 1000 mg of ofatumumab (n=30). The overall response rate was 77% in the 500 mg treatment group and 73% in the 1000 mg treatment group. Although these figures age good, they are not as good as have been achieved with FCR. Now this is not a head-to-head comparison with FCR and we know that it is dangerous to compare one phase 2 trial with another, but it does look likely that FCO will not be superior to FCR, so unless it has other advantages it doesn't look to be replacing rituximab any time soon. Of course when the trials mature it may turn out to have other advantages. The problem at the moment is that FCR is going to be a hard act to beat. This is one reason for going for MRD negativity as an end-point, as this is one area where FCR might be beaten.
Yet another reason for its unpopularity is that the comparison arm, FC, is no longer standard of care. The only possible trial is FCO versus FCR which no-one is going to fund.
Two current trials in the UK which might add something are ADMIRE and ARCTIC. ADMIRE stands for ADdition of Mitoxantrone to Improve REsponse. This is a randomized phase 2 study the main aim of which is to see whether adding mitoxantrone to FCR gives a deeper response - does it produce more MRD negativity? If it does it will be exopanded into a phase 3 trial with progression-free survival as primary end-point. (Just to remind readers about trials: phase 1 determines the dose of a drug it is safe to give, phase 2 determines whether it has an effect and phase 3 determines whether it improves survival compared to standard treatment.) 218 patients recruited over 18 months are needed for the phase 2 but more will be needed if it is expanded into a phase 3.
ARCTIC stands for Attenuated dose Rituximab with ChemoTherapy In CLL. This is the trial that tests out the 'shaving' hypothesis. Is it true that most of the rituximab that we give is ineffective because the first 100mg removes the CD20 from the surface of the cells? The comparison is between FCR and FCM-miniR. The endpoints are the same as for ADMIRE and 206 patients will be recruited in 18 months. Again it will be expanded into a phase 3 trial if the response rates are equivalent to FCR. The advantage of this regimen are completely a matter of cost. It is being funded not by Big Pharma, but by the NHS to see whether there are cheaper ways of doing the same thing.
A Phase 2 study of chlorambucil plus rituximab has been completed and an interim analysis of the first 50 patients will be presented at ASH. It shows an overall response rate of 84%. Although the CLL4 trial treated rather younger patients, it had a chlorambucil only arm and the response rate for these was 66.7%. So the the next move will be a phase 3 trial looking at the effect of adding rituximab in patients treated with chlorambucil. 100 patients have been recruited in total.
A randomized phase 3 trial comparing chlorambucil with chlorambucil plus ofatumumab is recruiting well with 114 / 444 patients already recruited. A quarter of these will be from the UK.
A further chlorambucil plus antibody phase 3 study with 800 patients is about to start. It will have 800 patients and compare chlorambucil alone with the addition of rituximab or the new Roche antibody GA-101.
It looks like GA-101 and ofatumumab will be competing for the same market.
For patients who fail to achieve MRD negativity, a consolidation stage of treatment is necessary. This is best done with alemtuzumab. A Phase 2 trial is attempting to recruit 54 patients. So far 44 have been recruited and there are another 14 patients registered. The trial closes in March 2010. This is a preliminary study to determine whether using alemtuzumab in this way is safe and efficacious. Analysis of the first 24 patients showed that 18 became MRD negative. Remember a similar CALGB trial showed 5 deaths from infection with this strategy and a German trial had to be stopped because of pancytopenia. It is clear that this sort of approach is littered with danger. So far there have been two deaths in patients who didn't live long enough to get the treatment. There have been 19 serious adverse events in this trial which include a number of viral infections and reactivations. I think there was a single death from parainfluenza - always a hazard with immunodeficient patients. This trial will proceed to a randomized phase 3 comparison between no further treatment and alemtuzumab consolidation if the safety profile is satisfactory.
For the treatment of high risk disease we are looking at the possibility of alemtuzumab, dexamethasone and Revlimid. We have switched from high dose methylprednisolone to dexamethasone partly because it is oral but mainly because of glucocorticoid effects like muscle wasting and hypertension which are less with dexamethasone. The HDMP + Campath trial was presented at EHA in the summer and will be published shortly.
Another approach to high risk disease will be the combination of Revlimid and Dexamethasone without Alemtuzumab.
For patients with stage A disease we are dividing them into those with two or more adverse markers, who will be started immediately on Revlimid, even though they do not meet the criteria for treatment. For those without high risk markers they will be given two weeks of broad spectrum antibiotics against the possibility that like marginal zone lymphoma, CLL is initiated by bacterial infection.
All patients in all trials will have their cells banked and categorized according to prognostic markers. Untreated patients will be followed in the pan-European data-collection study.
Finally, for Richter's syndrome, a trial of CHOP plus ofatumumab with antibody maintenance is to be started shortly.
If anti-CD20 antibodies add so much to CHOP, CVP and now FC, does it work for other forms of chemotherapy and for other anti-CD20 antibodies? There are several trials taking place in various countries to answer these questions. One such is the use of FC plus or minus Ofatumumab. This is having some difficulty getting off the ground. It intends to recruit 352 patients from 67 centers in 15 different countries. So far it has only recruited 30 patients. In the UK this will be an unpopular trial because the F and C have to be given intravenously whereas we give both orally. Oral fludarabine has been approved for use in the USA by the FDA. Of course the oncologist is paid less for giving out tablets than for giving an infusion, so we wait to see if it will prosper.
But another reason for its unpopularity may be the phase II study organized by Genmab. Patients in this open label study were randomized into two treatment groups. Each patient was to receive one infusion of 300 mg of ofatumumab in combination with FC followed by 5 monthly infusions of either 500 or 1000 mg of ofatumumab in combination with FC. Disease status was measured every 4 weeks until week 24 and every 3 months thereafter until disease progression or 24 months. Treatment response was assessed according to the 1996 National Cancer Institute Working Group guidelines by an Independent endpoints Review Committee. Patients not having
progressed on their disease at 24 months will be followed for disease progression at 6 month intervals until 60 months.
A total of 61 patients were treated in the study. The complete remission rate was 32% in patients who received 500 mg of ofatumumab (n=31) and 50% in patients who received 1000 mg of ofatumumab (n=30). The overall response rate was 77% in the 500 mg treatment group and 73% in the 1000 mg treatment group. Although these figures age good, they are not as good as have been achieved with FCR. Now this is not a head-to-head comparison with FCR and we know that it is dangerous to compare one phase 2 trial with another, but it does look likely that FCO will not be superior to FCR, so unless it has other advantages it doesn't look to be replacing rituximab any time soon. Of course when the trials mature it may turn out to have other advantages. The problem at the moment is that FCR is going to be a hard act to beat. This is one reason for going for MRD negativity as an end-point, as this is one area where FCR might be beaten.
Yet another reason for its unpopularity is that the comparison arm, FC, is no longer standard of care. The only possible trial is FCO versus FCR which no-one is going to fund.
Two current trials in the UK which might add something are ADMIRE and ARCTIC. ADMIRE stands for ADdition of Mitoxantrone to Improve REsponse. This is a randomized phase 2 study the main aim of which is to see whether adding mitoxantrone to FCR gives a deeper response - does it produce more MRD negativity? If it does it will be exopanded into a phase 3 trial with progression-free survival as primary end-point. (Just to remind readers about trials: phase 1 determines the dose of a drug it is safe to give, phase 2 determines whether it has an effect and phase 3 determines whether it improves survival compared to standard treatment.) 218 patients recruited over 18 months are needed for the phase 2 but more will be needed if it is expanded into a phase 3.
ARCTIC stands for Attenuated dose Rituximab with ChemoTherapy In CLL. This is the trial that tests out the 'shaving' hypothesis. Is it true that most of the rituximab that we give is ineffective because the first 100mg removes the CD20 from the surface of the cells? The comparison is between FCR and FCM-miniR. The endpoints are the same as for ADMIRE and 206 patients will be recruited in 18 months. Again it will be expanded into a phase 3 trial if the response rates are equivalent to FCR. The advantage of this regimen are completely a matter of cost. It is being funded not by Big Pharma, but by the NHS to see whether there are cheaper ways of doing the same thing.
A Phase 2 study of chlorambucil plus rituximab has been completed and an interim analysis of the first 50 patients will be presented at ASH. It shows an overall response rate of 84%. Although the CLL4 trial treated rather younger patients, it had a chlorambucil only arm and the response rate for these was 66.7%. So the the next move will be a phase 3 trial looking at the effect of adding rituximab in patients treated with chlorambucil. 100 patients have been recruited in total.
A randomized phase 3 trial comparing chlorambucil with chlorambucil plus ofatumumab is recruiting well with 114 / 444 patients already recruited. A quarter of these will be from the UK.
A further chlorambucil plus antibody phase 3 study with 800 patients is about to start. It will have 800 patients and compare chlorambucil alone with the addition of rituximab or the new Roche antibody GA-101.
It looks like GA-101 and ofatumumab will be competing for the same market.
For patients who fail to achieve MRD negativity, a consolidation stage of treatment is necessary. This is best done with alemtuzumab. A Phase 2 trial is attempting to recruit 54 patients. So far 44 have been recruited and there are another 14 patients registered. The trial closes in March 2010. This is a preliminary study to determine whether using alemtuzumab in this way is safe and efficacious. Analysis of the first 24 patients showed that 18 became MRD negative. Remember a similar CALGB trial showed 5 deaths from infection with this strategy and a German trial had to be stopped because of pancytopenia. It is clear that this sort of approach is littered with danger. So far there have been two deaths in patients who didn't live long enough to get the treatment. There have been 19 serious adverse events in this trial which include a number of viral infections and reactivations. I think there was a single death from parainfluenza - always a hazard with immunodeficient patients. This trial will proceed to a randomized phase 3 comparison between no further treatment and alemtuzumab consolidation if the safety profile is satisfactory.
For the treatment of high risk disease we are looking at the possibility of alemtuzumab, dexamethasone and Revlimid. We have switched from high dose methylprednisolone to dexamethasone partly because it is oral but mainly because of glucocorticoid effects like muscle wasting and hypertension which are less with dexamethasone. The HDMP + Campath trial was presented at EHA in the summer and will be published shortly.
Another approach to high risk disease will be the combination of Revlimid and Dexamethasone without Alemtuzumab.
For patients with stage A disease we are dividing them into those with two or more adverse markers, who will be started immediately on Revlimid, even though they do not meet the criteria for treatment. For those without high risk markers they will be given two weeks of broad spectrum antibiotics against the possibility that like marginal zone lymphoma, CLL is initiated by bacterial infection.
All patients in all trials will have their cells banked and categorized according to prognostic markers. Untreated patients will be followed in the pan-European data-collection study.
Finally, for Richter's syndrome, a trial of CHOP plus ofatumumab with antibody maintenance is to be started shortly.
MRD now
In the previous article I mentioned the value of becoming MRD negative. I should stress that the method used to determine MRD negativity is crucial. Not all PCR methods or 4 color flow cytometry methods are reliable. Most people use this method . which is straightforward and reliable, having been tested in many laboratories. Please beware of tests for MRD developed locally in individual labs that have not been subjected to this many-lab scrutiny.
Yesterday, at the UK CLL Forum Clinical Trials Group we took an important step in deciding to design trials around an end-point of achieving minimal residual disease negativity. One of the real problems we have with CLL trials is that they take so long. There are currently about 1000 CLL trials going on on the world and John Byrd recently identified 107 new drugs at various stages of testing. We have already accepted progression-free survival as a surrogate for overall survival in trials, but even this means that a clinical trial takes several years to complete. Now with the German CLL8 trial demonstrating that MRD negativity is a surrogate for overall survival for both FC and FCR, we are able to shorten the time it takes to reject a new drug or drug combination very considerably. With FCR we are talking about 48% of those tested achieving marrow MRD negativity with FCR. Of course, not everybody was tested so we need the greater detail of a peer-reviewed published report rather than the answer to a question at a meeting, but the German CLL8 trial will produce a standard to be bettered by other combinations.
The other combinations might include adding mitoxantrone, substituting Ofatumumab for rituximab or indeed the new fully glycosolated antibody, GA-101. There are quite a few other agents currently being considered.
The advantages of considering MRD negativity as an end-point include the fact that it can be assessed at 3 months after (starting - sorry this is an error) completing treatment and this can be used at interim assessments which will lead to abandonment of ineffective treatment at an early stage; trial results will be reportable within 12 months of completing recruitment rather than after several years; we will be able to answer induction and consolidation questions in the same trial; and trials may well be smaller and therefore less expensive.
Potential disadvantages include failure of a clear bone marrow to reflect the presence of disease elsewhere in the body. This is certainly true in follicular lymphoma, where it is possible to have residual disease in lymph nodes and elsewhere despite having a clear marrow. This is not true for CLL, even when treatment is with Campath which is notoriously unable to clear large lymph nodes despite having spectacular success in the marrow. As far as our experience allows us to say, if there is CLL in lymph nodes it will always be detectable in the peripheral blood by four-color flow.
It is also conceivable that an agent that is active against rapidly dividing cells would both lead to the rapid clearance of such cells but also rapid relapse after treatment is finished - just because the cells were rapidly dividing. At the same time slower growing cells might not be completely eliminated by such a drug yet because they are slowly growing, relapse might be delayed. The German trial suggests that this is not a problem as MRD negativity correlates with overall survival.
This is therefore an encouraging step. It looks as though we might have a chance of testing all the potential drugs an combinations for CLL.
Yesterday, at the UK CLL Forum Clinical Trials Group we took an important step in deciding to design trials around an end-point of achieving minimal residual disease negativity. One of the real problems we have with CLL trials is that they take so long. There are currently about 1000 CLL trials going on on the world and John Byrd recently identified 107 new drugs at various stages of testing. We have already accepted progression-free survival as a surrogate for overall survival in trials, but even this means that a clinical trial takes several years to complete. Now with the German CLL8 trial demonstrating that MRD negativity is a surrogate for overall survival for both FC and FCR, we are able to shorten the time it takes to reject a new drug or drug combination very considerably. With FCR we are talking about 48% of those tested achieving marrow MRD negativity with FCR. Of course, not everybody was tested so we need the greater detail of a peer-reviewed published report rather than the answer to a question at a meeting, but the German CLL8 trial will produce a standard to be bettered by other combinations.
The other combinations might include adding mitoxantrone, substituting Ofatumumab for rituximab or indeed the new fully glycosolated antibody, GA-101. There are quite a few other agents currently being considered.
The advantages of considering MRD negativity as an end-point include the fact that it can be assessed at 3 months after (starting - sorry this is an error) completing treatment and this can be used at interim assessments which will lead to abandonment of ineffective treatment at an early stage; trial results will be reportable within 12 months of completing recruitment rather than after several years; we will be able to answer induction and consolidation questions in the same trial; and trials may well be smaller and therefore less expensive.
Potential disadvantages include failure of a clear bone marrow to reflect the presence of disease elsewhere in the body. This is certainly true in follicular lymphoma, where it is possible to have residual disease in lymph nodes and elsewhere despite having a clear marrow. This is not true for CLL, even when treatment is with Campath which is notoriously unable to clear large lymph nodes despite having spectacular success in the marrow. As far as our experience allows us to say, if there is CLL in lymph nodes it will always be detectable in the peripheral blood by four-color flow.
It is also conceivable that an agent that is active against rapidly dividing cells would both lead to the rapid clearance of such cells but also rapid relapse after treatment is finished - just because the cells were rapidly dividing. At the same time slower growing cells might not be completely eliminated by such a drug yet because they are slowly growing, relapse might be delayed. The German trial suggests that this is not a problem as MRD negativity correlates with overall survival.
This is therefore an encouraging step. It looks as though we might have a chance of testing all the potential drugs an combinations for CLL.
Who now should get FCR?
The German CLL8 trial continues to give us useful information. For the first time one treatment arm has lead to an improvement in overall survival. Previously, in, for example, the British CLL4 trial, while one of the arms (FC) showed a higher response rate and longer progression-free survival, the overall survival for the different arms was exactly the same. However, in CLL8, FCR gives a statistically longer overall survival than FC. Another gem to come from the trial is the evidence that achieving minimal residual disease (MRD) negativity is associated with longer survival no matter how it is achieved. In other words, if you got MRD negativity from FC you did just as well as if you got it from FCR - it's just that you are more likely to get it from FCR.
The third gem is that while other trials have shown the deleterious effect of having del 11q23 or an ATM mutation, FCR abolishes the ill-effect and such patients have the same survival curve as those with trisomy 12 or no karyotypic abnormality.
What does all this mean for the CLL community? I think it is now clear that if you of an age where a 10 year survival is important to you then your best chance of getting one is to be treated with FCR - provided you are robust enough to withstand the side effects. Rather than decide who should get FCR we are now trying to decode who should not.
If you are aged over 70, then FCR may not to be the way to go. It is unlikely that you will be able to withstand the whole 6 courses that give the best effect and you are likely to have co-morbidities that will make FCR too toxic. The sort of co-morbidities that I am talking about would be a degree of impairment of kidney, heart or liver, any evidence of bone marrow failure, and a history of unusual infections, in particular fungal pneumonias.
Co-morbidity is not confined to the over-70s, but it is commoner at this age.
If you have FCR you should be aiming at MRD negativity. If you don't achieve it then you should think about further treatment - likely to be one of three drugs at present: high dose steroids, alemtuzumab or Revlimid. Ideally this should be in the context of a clinical trial, because their utility in this setting is still in doubt.
The group with del 17p13 or a p53 mutation, while only 5% of those needing treatment for the first time will almost certainly fail to respond to FCR and these should have a different approach.
For the very elderly, many find that a gentler approach gives a better quality of life. Remember, that not everybody who meets the IWCLL Guidelines indications for treatment will feel ill. A lowish platelet count, a biggish spleen, a fast lymphocyte doubling time, may all be without symptoms. Even a large lymph node may cause no problems other than the fact that you notice that it is there. If you are 82 years old and quite well, why would you need a treatment that certainly involves trips to hospital and will probably make you feel unwell? At that age your life probably won't be shortened by CLL, so what benefit will you get from the treatment?
The only cure of CLL is a bone marrow transplant, but most centers would be unwilling to enroll a patients for the program who has not had FCR - unless they had del 17p13.
You may see this as a change in attitude on my part. Well when the evidence changes, I change my mind. Don't you?
The third gem is that while other trials have shown the deleterious effect of having del 11q23 or an ATM mutation, FCR abolishes the ill-effect and such patients have the same survival curve as those with trisomy 12 or no karyotypic abnormality.
What does all this mean for the CLL community? I think it is now clear that if you of an age where a 10 year survival is important to you then your best chance of getting one is to be treated with FCR - provided you are robust enough to withstand the side effects. Rather than decide who should get FCR we are now trying to decode who should not.
If you are aged over 70, then FCR may not to be the way to go. It is unlikely that you will be able to withstand the whole 6 courses that give the best effect and you are likely to have co-morbidities that will make FCR too toxic. The sort of co-morbidities that I am talking about would be a degree of impairment of kidney, heart or liver, any evidence of bone marrow failure, and a history of unusual infections, in particular fungal pneumonias.
Co-morbidity is not confined to the over-70s, but it is commoner at this age.
If you have FCR you should be aiming at MRD negativity. If you don't achieve it then you should think about further treatment - likely to be one of three drugs at present: high dose steroids, alemtuzumab or Revlimid. Ideally this should be in the context of a clinical trial, because their utility in this setting is still in doubt.
The group with del 17p13 or a p53 mutation, while only 5% of those needing treatment for the first time will almost certainly fail to respond to FCR and these should have a different approach.
For the very elderly, many find that a gentler approach gives a better quality of life. Remember, that not everybody who meets the IWCLL Guidelines indications for treatment will feel ill. A lowish platelet count, a biggish spleen, a fast lymphocyte doubling time, may all be without symptoms. Even a large lymph node may cause no problems other than the fact that you notice that it is there. If you are 82 years old and quite well, why would you need a treatment that certainly involves trips to hospital and will probably make you feel unwell? At that age your life probably won't be shortened by CLL, so what benefit will you get from the treatment?
The only cure of CLL is a bone marrow transplant, but most centers would be unwilling to enroll a patients for the program who has not had FCR - unless they had del 17p13.
You may see this as a change in attitude on my part. Well when the evidence changes, I change my mind. Don't you?
Wednesday, November 04, 2009
Nostalgia
DO YOU REMEMBER WHEN . . . ?
All the girls had ugly gym uniforms instead of leotards?
When it took five minutes for the TV to warm up and the picture was black and white?
When nearly everyone's Mum was at home when the kids got home from school?
When all dogs were mongrels? When pocket money was a shilling (a quarter) and you'd reach into a muddy gutter for a penny?
When nylons came in two pieces and all your male teachers wore ties and your female teachers had their hair done every day and wore high heels?
When you got your windshield cleaned, oil checked, and gas pumped, without asking, all for free, every time?
And you didn't pay for air? And, you got Green Stamps to boot?
When laundry detergent had free glasses, dishes or towels hidden inside the box?
When they threatened to keep kids back a grade if they failed . . . and they meant it?
When boys and girls went steady?
When no one ever asked where the car keys were because they were always in the car, in the ignition, and the doors were never locked?
When you could lie on your back in the grass with your friends and say things like,” That cloud looks like a ..."
When you could play soccer with no adults to help kids with the rules of the game or to argue with the referee, because there was no referee?
When stuff from the store came without safety caps and hermetic seals because no one had yet tried to poison a perfect stranger?
When being sent to the headmaster’s office was nothing compared to the fate that awaited the student at home? Our parents and grandparents were a much bigger threat! But we survived because their love was greater than the threat.
When Saturday Morning Pictures showed Nancy Drew and the Hardy Boys, Laurel and Hardy, the Lone Ranger, Roy Rogers and Flash Gordon, and not extended commercials for toys?
And the long hot summers were filled with bike rides, pick-up games, Hula Hoops, swimming in the river, sucking sherbet through a liquorice straw, and sharing Tizer with your friends.
How many of these do you remember: sweet (or do you say candy) cigarettes, soda pop machines that dispensed glass bottles, coffee shops with tableside jukeboxes, penny chews, home milk delivery in glass bottles with cardboard stoppers and newsreels before the movie? How about telephone numbers with a word prefix (Mayfair 601), party lines, peashooters, home perms, 45 RPM records metal ice cubes trays with levers, carbon paper, roller-skate keys, cork pop guns, washtub wringers, reel-to-reel tape recorders, slide rules, Hornby wind-up train sets, Meccano, lead soldiers, cigarette cards, best friends, wooden dolls houses, catapults, Airfix kits and five-stones (or perhaps you called them dibs).
I remember saving a penny by walking one bus stop nearer to home and spending it on an apple. I remember when a foot of snow was a dream come true. I remember when the fat kid was always the last to be picked. I remember fixing a card to the spokes of my bicycle to make it sound like a motor-bike. I remember when you’d see soldiers in the street in uniform. I remember sitting in a pub garden drinking Vimto with the mums who were drinking milk stout while the dads were inside drinking mild and bitter. I remember Dandelion and Burdock delivered by the Corona lorry. I remember the ice truck taking two foot cubes of ice to the ice cellar belonging to the big house on the corner. I remember chimneys catching fire. I remember giving up my seat on buses to ladies and being thanked by being told she would pray for me. I remember chimney sweeps with soot-black faces. I remember holding a newspaper up against the fire-grate to make it draw. I remember second-hand bikes and hand-me-down clothes. I remember bomb sites. I remember slums.
It was a different world then – as different as the worlds of Isaac Asimov, James Blish and Theodore Sturgeon.
All the girls had ugly gym uniforms instead of leotards?
When it took five minutes for the TV to warm up and the picture was black and white?
When nearly everyone's Mum was at home when the kids got home from school?
When all dogs were mongrels? When pocket money was a shilling (a quarter) and you'd reach into a muddy gutter for a penny?
When nylons came in two pieces and all your male teachers wore ties and your female teachers had their hair done every day and wore high heels?
When you got your windshield cleaned, oil checked, and gas pumped, without asking, all for free, every time?
And you didn't pay for air? And, you got Green Stamps to boot?
When laundry detergent had free glasses, dishes or towels hidden inside the box?
When they threatened to keep kids back a grade if they failed . . . and they meant it?
When boys and girls went steady?
When no one ever asked where the car keys were because they were always in the car, in the ignition, and the doors were never locked?
When you could lie on your back in the grass with your friends and say things like,” That cloud looks like a ..."
When you could play soccer with no adults to help kids with the rules of the game or to argue with the referee, because there was no referee?
When stuff from the store came without safety caps and hermetic seals because no one had yet tried to poison a perfect stranger?
When being sent to the headmaster’s office was nothing compared to the fate that awaited the student at home? Our parents and grandparents were a much bigger threat! But we survived because their love was greater than the threat.
When Saturday Morning Pictures showed Nancy Drew and the Hardy Boys, Laurel and Hardy, the Lone Ranger, Roy Rogers and Flash Gordon, and not extended commercials for toys?
And the long hot summers were filled with bike rides, pick-up games, Hula Hoops, swimming in the river, sucking sherbet through a liquorice straw, and sharing Tizer with your friends.
How many of these do you remember: sweet (or do you say candy) cigarettes, soda pop machines that dispensed glass bottles, coffee shops with tableside jukeboxes, penny chews, home milk delivery in glass bottles with cardboard stoppers and newsreels before the movie? How about telephone numbers with a word prefix (Mayfair 601), party lines, peashooters, home perms, 45 RPM records metal ice cubes trays with levers, carbon paper, roller-skate keys, cork pop guns, washtub wringers, reel-to-reel tape recorders, slide rules, Hornby wind-up train sets, Meccano, lead soldiers, cigarette cards, best friends, wooden dolls houses, catapults, Airfix kits and five-stones (or perhaps you called them dibs).
I remember saving a penny by walking one bus stop nearer to home and spending it on an apple. I remember when a foot of snow was a dream come true. I remember when the fat kid was always the last to be picked. I remember fixing a card to the spokes of my bicycle to make it sound like a motor-bike. I remember when you’d see soldiers in the street in uniform. I remember sitting in a pub garden drinking Vimto with the mums who were drinking milk stout while the dads were inside drinking mild and bitter. I remember Dandelion and Burdock delivered by the Corona lorry. I remember the ice truck taking two foot cubes of ice to the ice cellar belonging to the big house on the corner. I remember chimneys catching fire. I remember giving up my seat on buses to ladies and being thanked by being told she would pray for me. I remember chimney sweeps with soot-black faces. I remember holding a newspaper up against the fire-grate to make it draw. I remember second-hand bikes and hand-me-down clothes. I remember bomb sites. I remember slums.
It was a different world then – as different as the worlds of Isaac Asimov, James Blish and Theodore Sturgeon.
Tuesday, November 03, 2009
Drugs and scientists
Drugs are in the headlines again. Professor David Nutt, Chairman of the body advising the government on the misuse of drugs has been fired for campaigning for the legalisation of certain drugs like Cannabis and Ecstasy. He had previously advised the government that Cannabis and Ecstasy were less dangerous than tobacco and alcohol; advice which the government rejected.
The issue is a complex one. If a government appoints you to an Advisory Council, have they bought your opinion? Clearly if you worked for Roche and you went around campaigning against the use of Roche drugs, they would be right to fire you, but the government only pays you for a day a month, surely your opinion is your own for the rest of the month. No. If your opinion is different from the government's and you voice it about, then they have every right not to employ you again. Let's be clear, scientists get a lot of kudos from chairing government committees. Sometimes they get a CBE or other award for doing so. If Professor Nutt says something, nobody listens, especially with a name like that, but if the Chairman of the Drugs Advisory Council says something the Government disapproves of then everybody listens.
But shouldn't an expert scientist's opinion be listened to? I have some sympathy with this point of view. After all, science is very hard. Students study the humanities rather than science in many cases because they can't do the Math. In the humanities, as the post modernists have told us, there is no correct answer, only opinions. You can't be post-modern about 2+2=4. The problem is that scientists are human too. Science varies. Mathmatics may be very pure, but in the applied sciences intellect is contaminated by emotion. It took many years to convince people that smoking causes lung cancer. Why? Because many people didn't want to believe; they liked their cigarettes. I have no idea whether Professor Nutt smokes pot at the weekend or whether he did at University, but if he did and he enjoyed it, his way of looking at the evidence might be a bit selective.
If a new law were to take pennies from your pocket, your view of it might not be objective. Who believes the evidence of the oil companies on global warming? Who believes Greenpeace on the virtues of vegetarianism? When we look at clinical trials, we know that some trial evidence is smothered at birth because it doesn't give the answer the pharmaceutical companies wanted. So who is doing the smothering here, Nutt or Brown?
An article in today's Times suggests that Nutt hasn't done the science correctly. The author, Robin Murray, is Professor of Psychiatric Research at the Institute of Psychiatry, King’s College London and a specialist in schizophrenia. He believes that Professor Nutt underestimates the risk of cannabis users developing schizophrenia. He states, "In his lecture last week Professor Nutt contrasted a 2.6-fold increase in the risk of psychosis from using cannabis with a twentyfold increase in the risk of lung cancer if one smokes cigarettes. Unfortunately he was not comparing like with like here. The twentyfold increased risk does not come just by being a smoker but by being a long-term heavy smoker. For cannabis, the risk of schizophrenia rises about sixfold if one is a long-term heavy user."
David Nutt is also a psychiatrist, in particular a neuropsychopharmacologist specialising in the research of drugs which affect the brain and conditions such as addiction, anxiety and sleep. He is a professor at the University of Bristol heading their Psychopharmacology Unit and also holds the Edmond J Safra chair in Neuropsychopharmacology at Imperial College, London. So we have two eminent psychiatrists falling out over the effect of drugs on the mind.
The point is that psychiatry is one of those half-sciences like economics. It is still permissable to have opinions about things.
Margaret Thatcher once said, "Advisors are there to advise; it's up to politicians to make decisions." The problem arises when politicians try to wriggle out of the decisions they have made.
On the substantive issue of whether illicit drugs should be legalized there are differing opinions. Prohibition of alcohol was tried in the USA for several years and is generally held to have been unsuccessful. Supply of alcohol became criminalized and many ordinary people broke the law with impunity. Lack of respect for the law may have been a long-lasting consequence. Many argue that the same situation exists today with drugs. Supply is by criminal gangs. Much police time is spent trying to enforce the law. Prisons are filled with drug addicts. Middle class people ignore the law with impunity.
Although banning alcohol didn't work, neither did unbanning it. More people die from alcohol-related diseases than ever before. The social consequences of alcohol abuse - wife-beating, poverty, child-neglect, public order offences, violence on the streets, football hooliganism, motor accidents, murder and mayhem - are there for all to see. Tobacco consumption is decreasing, but it has taken nearly 60 years since the first evidence linking smoking with lung cancer appeared. Price hikes, advertising bans and public education campaigns have still left is with one man in five smoking.
We do not have long term studies of people who take Ecstasy or Cannabis. Although legalising drugs might have some benefits - less spread of viruses, less contamination of the drugs that addicts take and even tax revenue for the government - we really can't begin to count the downsides.
The issue is a complex one. If a government appoints you to an Advisory Council, have they bought your opinion? Clearly if you worked for Roche and you went around campaigning against the use of Roche drugs, they would be right to fire you, but the government only pays you for a day a month, surely your opinion is your own for the rest of the month. No. If your opinion is different from the government's and you voice it about, then they have every right not to employ you again. Let's be clear, scientists get a lot of kudos from chairing government committees. Sometimes they get a CBE or other award for doing so. If Professor Nutt says something, nobody listens, especially with a name like that, but if the Chairman of the Drugs Advisory Council says something the Government disapproves of then everybody listens.
But shouldn't an expert scientist's opinion be listened to? I have some sympathy with this point of view. After all, science is very hard. Students study the humanities rather than science in many cases because they can't do the Math. In the humanities, as the post modernists have told us, there is no correct answer, only opinions. You can't be post-modern about 2+2=4. The problem is that scientists are human too. Science varies. Mathmatics may be very pure, but in the applied sciences intellect is contaminated by emotion. It took many years to convince people that smoking causes lung cancer. Why? Because many people didn't want to believe; they liked their cigarettes. I have no idea whether Professor Nutt smokes pot at the weekend or whether he did at University, but if he did and he enjoyed it, his way of looking at the evidence might be a bit selective.
If a new law were to take pennies from your pocket, your view of it might not be objective. Who believes the evidence of the oil companies on global warming? Who believes Greenpeace on the virtues of vegetarianism? When we look at clinical trials, we know that some trial evidence is smothered at birth because it doesn't give the answer the pharmaceutical companies wanted. So who is doing the smothering here, Nutt or Brown?
An article in today's Times suggests that Nutt hasn't done the science correctly. The author, Robin Murray, is Professor of Psychiatric Research at the Institute of Psychiatry, King’s College London and a specialist in schizophrenia. He believes that Professor Nutt underestimates the risk of cannabis users developing schizophrenia. He states, "In his lecture last week Professor Nutt contrasted a 2.6-fold increase in the risk of psychosis from using cannabis with a twentyfold increase in the risk of lung cancer if one smokes cigarettes. Unfortunately he was not comparing like with like here. The twentyfold increased risk does not come just by being a smoker but by being a long-term heavy smoker. For cannabis, the risk of schizophrenia rises about sixfold if one is a long-term heavy user."
David Nutt is also a psychiatrist, in particular a neuropsychopharmacologist specialising in the research of drugs which affect the brain and conditions such as addiction, anxiety and sleep. He is a professor at the University of Bristol heading their Psychopharmacology Unit and also holds the Edmond J Safra chair in Neuropsychopharmacology at Imperial College, London. So we have two eminent psychiatrists falling out over the effect of drugs on the mind.
The point is that psychiatry is one of those half-sciences like economics. It is still permissable to have opinions about things.
Margaret Thatcher once said, "Advisors are there to advise; it's up to politicians to make decisions." The problem arises when politicians try to wriggle out of the decisions they have made.
On the substantive issue of whether illicit drugs should be legalized there are differing opinions. Prohibition of alcohol was tried in the USA for several years and is generally held to have been unsuccessful. Supply of alcohol became criminalized and many ordinary people broke the law with impunity. Lack of respect for the law may have been a long-lasting consequence. Many argue that the same situation exists today with drugs. Supply is by criminal gangs. Much police time is spent trying to enforce the law. Prisons are filled with drug addicts. Middle class people ignore the law with impunity.
Although banning alcohol didn't work, neither did unbanning it. More people die from alcohol-related diseases than ever before. The social consequences of alcohol abuse - wife-beating, poverty, child-neglect, public order offences, violence on the streets, football hooliganism, motor accidents, murder and mayhem - are there for all to see. Tobacco consumption is decreasing, but it has taken nearly 60 years since the first evidence linking smoking with lung cancer appeared. Price hikes, advertising bans and public education campaigns have still left is with one man in five smoking.
We do not have long term studies of people who take Ecstasy or Cannabis. Although legalising drugs might have some benefits - less spread of viruses, less contamination of the drugs that addicts take and even tax revenue for the government - we really can't begin to count the downsides.
Monday, November 02, 2009
Offensive PC
A lot of comment about what gives offence recently. In general, it is good manners not to give offence unless you mean to and it is also good manners not to take offence unless a verbal slight was intended.
Recently, scriptwriters for the BBC are protesting that they are not allowed to use the phrase "Sweet Jesus" as an expletive in a sit-com. Of course, this phrase is offensive to Christians when used in this way and the BBC Trust is responding to complaints. Surely there are other phrases commonly used that do not give offence. Deliberate use of this phrase after notice has been given that it is offensive must mean that the writer intends to give offence.
I am offended my the PC use of 'partner' instead of 'wife'. I heard recently of a young widow whose husband was killed a few years ago in Iraq and had now remarried being asked at an antenatal clinic, "It is a long time since your last child; are you in a new relationship?" To her it placed her among a group of women who flitted from one man to another and she was offended by the implication.
Those anxious to be PC seem unaware of the offence they are giving. Christmas Greetings are now Seasonal Greetings or Happy Holidays! Muslims and Hindus were never offended by the Christmas holiday. They were happy to join in in many cases. I know some extreme puritans who insist that Christmas is just a Christianized pagan festival and will have nothing to do with it, but that's their choice. they certainly don't spoil it for everybody else. (At least not since Oliver Cromwell.)
So, lets have a backlash. When you spot a PC statement that offends you, don't be held back by good manners. Let them know how offensive it is. In a polite sort of way.
Recently, scriptwriters for the BBC are protesting that they are not allowed to use the phrase "Sweet Jesus" as an expletive in a sit-com. Of course, this phrase is offensive to Christians when used in this way and the BBC Trust is responding to complaints. Surely there are other phrases commonly used that do not give offence. Deliberate use of this phrase after notice has been given that it is offensive must mean that the writer intends to give offence.
I am offended my the PC use of 'partner' instead of 'wife'. I heard recently of a young widow whose husband was killed a few years ago in Iraq and had now remarried being asked at an antenatal clinic, "It is a long time since your last child; are you in a new relationship?" To her it placed her among a group of women who flitted from one man to another and she was offended by the implication.
Those anxious to be PC seem unaware of the offence they are giving. Christmas Greetings are now Seasonal Greetings or Happy Holidays! Muslims and Hindus were never offended by the Christmas holiday. They were happy to join in in many cases. I know some extreme puritans who insist that Christmas is just a Christianized pagan festival and will have nothing to do with it, but that's their choice. they certainly don't spoil it for everybody else. (At least not since Oliver Cromwell.)
So, lets have a backlash. When you spot a PC statement that offends you, don't be held back by good manners. Let them know how offensive it is. In a polite sort of way.
Sunday, November 01, 2009
The Good Life - 1 Peter 2:11-12.
There is a current controversy in Norfolk. Norfolk is a very rural county. Apart from in the county town of Norwich, most people seem to be engaged in agriculture and even the local football team is nicknamed "The Tractormen". It is one of those places about which townies make lewd jokes suggesting that there are a lot of brother-sister marriages. The implication is that people who live there are a few ants short of a picnic in their mental capacity. It is said that when a cerebrally challenged child is admitted to hospital, the doctors talk about it as NFN which stands for "normal for Norfolk". These slurs are, of course, completely untrue, but are typical of metropolitan prejudice.
The problem is that the local Conservatives have selected a parliamentary candidate with a reputation. In 2005 she was in the newspapers having conducted an extra-marital affair with a Tory MP. Following this exposure she returned to her husband while the MP divorced his wife and has since remarried. Now, she has since been selected as a parliamentary candidate, but her selection has now been challenged on the grounds that she never told the selection committee of her former indiscretion. Since this is the first thing that comes up when you Google her name, one might argue that the omission was that of the selection committee rather than hers, but the bigger question is should it count against her that she has been an adulteress?
On Jeremy Vine's Radio 2 program, a discussion took place on the merits of the case between Iain Dale, a well known blogger and Anne Atkins, a well known columnist. These two come from widely different backgrounds. Dale is gay, and his stand is libertarian, Atkins is the wife of a Church of England vicar and stresses 'family values'. Should a Christian protest at the morality of our elected representatives? The argument is that if you can't trust them to keep a solemn vow made before God at their marriage, how could you trust them with their electoral promises? The counter argument is, shouldn't a Christian be willing to forgive an adulteress, just as Jesus did in John chapter 8?
In 1 Peter 2 verse 11, the apostle begins to tell us how we should live in the world we are in. He writes to Christians, not to pagans. He tells us that we are aliens and strangers in the world. "Dear Friends" as the NIV translates it is too weak. "Dear loved ones" would be nearer. He is assigning us to the team made up of those for whom Christ has died. And though we are loved by Christ we are not playing at home; we are the away team. We are aliens and strangers in the world.
Go to any Premier division football match and you will understand what this means. Among a crowd of 50,000 you may be among 1000 cramped in the visitors' enclosure. Even the word 'enclosure' makes you sound like an animal in a zoo. You are certainly treated like one. The majority in the crowd sing their chants at you, mocking you and making you feel small. They are trying to intimidate you. But minority that you are, you are still part of a team. You sing back, determined not to be silenced. Imagine yourself to be the one Spurs supporter sitting among the Arsenal fans. You would certainly keep quiet. When they sang "You're not singing any more!" it would be true for you. But here in the visitor's enclosure you are among friends, your team is all around you. Though you may be a minority you are encouraged by their presence. Your church may be a minority in your town, but you have colleagues who are covered by the same insignia.
Elijah was alone. He had defeated the prophets of Baal, but then he had run away, and here beneath the Juniper tree he was all by himself, afraid and in despair. When he finally is confronted by God at Horeb, he is told, "I reserve 7000 in Israel - all whose knees have not bowed down to Baal." He is not alone. He is part of a team with a captain who cannot be defeated. Go to Spring Harvest or Keswick. Feel the strength of the team around you.
Fighting Mike Tyson must be one of the most intimidating things in the world. Evander Holyfield did it twice. He is the only man to have won the world heavyweight championship four times. Holyfield claims to be Christian. He has "I can do all things through Christ who strengthens me" embroidered on his fight dressing gown. As he trained for the fight he had sparring partners who mimicked Tyson's style. He was determined in his training.
We have to be determined in our training to live the Christian life. We have to abstain from sinful desires that war against our soul. We are waging a war against sin, not against sinners. Were it against sinners we would have to fight our friends, because the one criterion for becoming a Christian is to be a sinner. All those without sin need not apply. Christians are not defined by what they do not do. The reason we have something to say to the world is that we are sinners just like them. Our only difference is that someone has fished us out of the water. Those sitting wrapped in a blanket at the bottom of a lifeboat have no sense of superiority over those still in the sea. Our only plea is "Save them too!"
Not all desires are sinful. Sex is a wonderful gift from God. It is not sinful so long as it is confined to marriage and used to reinforce the structure of the family. It is a sin to misuse it. How destructive it can be when it is misused! To earn money is not a sin, even if you earn a great deal of it. But to use it to puff ourselves up and to oppress others is sinful. From him to whom much is given, much will be required. It is not a sin to live in a big house; but what an opportunity to give hospitality! Do you have a big car? The more people you can take to church.
Anne Atkins was wrong to expect the Tory candidate to live up to Christian standards unless she had been a Christian. People who live in the world of politics don't do God, said Tony Blair's presence on Earth, Alistair Campbell. We have no right to hold the world to account. The world will do worldly things. Being a member of the Church of England, Anne probably assumed that every English person is also a member unless specifically opted out. In that case they should behave like Christians. It is a delusion. We Christians are few in England today.
Our ambition should be to live such good lives among the pagans that, though they accuse us of doing wrong, they may see our good deeds. To what end? So that they may glorify God on the day that he visits us. To do that they will have to change before he returns for there is no mind changing after death.
Evander Holyfield claimed to be a Christian, but then it comes out that he had 5 kids out of wedlock with 4 different women; that he had been 'healed' by televangelist, Benny Hinn, who received an alleged $265,000 “donation” for the healing; that he has been linked to alleged usage of performance enhancing drugs; that his house is 54,000 square feet with 104 rooms and a bowling alley and that he has failed to pay child support for one of his 9 kids.
Live such good lives among the pagan...
Iain Dale was also wrong to assume that a Christian must be all forgiving. The offer of forgiveness is there from God. Sufficient grace is available. No more restitution needs to be made to God. No more bulls to be slaughtered or lambs killed. All that is needed is repentance. "Neither do I condemn you," said Jesus, "go and sin no more."
He wants a God who:
Shows complete, benevolent blindness
To our foibles.
Who does not notice when we err.
Forty-winks at deviation,
Falling short or reprobation.
Wouldn’t make a fuss
About us.
Because we stress the forgiveness of God, the world thinks that God doesn't mind sin. Because we stress the love of God, the world things that God is not also terrifying. Because Jesus told us in the Sermon on the Mount to "judge not that ye be not judged", the world thinks that it will not be judged on the last day.
We must expect the world to accuse us of doing wrong. How could it not when the world operates according to a different set of principles to us. We will not convince the Dawkins of this world by the force of our arguments. Few have been forced into heaven by the weight of logic. But many have looked at the likes of John Newton, William Wiberforce, Eric Liddell and others and asked, "What have they got in their lives that is missing from mine?"
We don't do good works to make us feel good, to repay the Lord for what he has done for us, to satisfy our conscience, to earn merit or to impress other Christians. We want to glorify God and have others do so too.
The problem is that the local Conservatives have selected a parliamentary candidate with a reputation. In 2005 she was in the newspapers having conducted an extra-marital affair with a Tory MP. Following this exposure she returned to her husband while the MP divorced his wife and has since remarried. Now, she has since been selected as a parliamentary candidate, but her selection has now been challenged on the grounds that she never told the selection committee of her former indiscretion. Since this is the first thing that comes up when you Google her name, one might argue that the omission was that of the selection committee rather than hers, but the bigger question is should it count against her that she has been an adulteress?
On Jeremy Vine's Radio 2 program, a discussion took place on the merits of the case between Iain Dale, a well known blogger and Anne Atkins, a well known columnist. These two come from widely different backgrounds. Dale is gay, and his stand is libertarian, Atkins is the wife of a Church of England vicar and stresses 'family values'. Should a Christian protest at the morality of our elected representatives? The argument is that if you can't trust them to keep a solemn vow made before God at their marriage, how could you trust them with their electoral promises? The counter argument is, shouldn't a Christian be willing to forgive an adulteress, just as Jesus did in John chapter 8?
In 1 Peter 2 verse 11, the apostle begins to tell us how we should live in the world we are in. He writes to Christians, not to pagans. He tells us that we are aliens and strangers in the world. "Dear Friends" as the NIV translates it is too weak. "Dear loved ones" would be nearer. He is assigning us to the team made up of those for whom Christ has died. And though we are loved by Christ we are not playing at home; we are the away team. We are aliens and strangers in the world.
Go to any Premier division football match and you will understand what this means. Among a crowd of 50,000 you may be among 1000 cramped in the visitors' enclosure. Even the word 'enclosure' makes you sound like an animal in a zoo. You are certainly treated like one. The majority in the crowd sing their chants at you, mocking you and making you feel small. They are trying to intimidate you. But minority that you are, you are still part of a team. You sing back, determined not to be silenced. Imagine yourself to be the one Spurs supporter sitting among the Arsenal fans. You would certainly keep quiet. When they sang "You're not singing any more!" it would be true for you. But here in the visitor's enclosure you are among friends, your team is all around you. Though you may be a minority you are encouraged by their presence. Your church may be a minority in your town, but you have colleagues who are covered by the same insignia.
Elijah was alone. He had defeated the prophets of Baal, but then he had run away, and here beneath the Juniper tree he was all by himself, afraid and in despair. When he finally is confronted by God at Horeb, he is told, "I reserve 7000 in Israel - all whose knees have not bowed down to Baal." He is not alone. He is part of a team with a captain who cannot be defeated. Go to Spring Harvest or Keswick. Feel the strength of the team around you.
Fighting Mike Tyson must be one of the most intimidating things in the world. Evander Holyfield did it twice. He is the only man to have won the world heavyweight championship four times. Holyfield claims to be Christian. He has "I can do all things through Christ who strengthens me" embroidered on his fight dressing gown. As he trained for the fight he had sparring partners who mimicked Tyson's style. He was determined in his training.
We have to be determined in our training to live the Christian life. We have to abstain from sinful desires that war against our soul. We are waging a war against sin, not against sinners. Were it against sinners we would have to fight our friends, because the one criterion for becoming a Christian is to be a sinner. All those without sin need not apply. Christians are not defined by what they do not do. The reason we have something to say to the world is that we are sinners just like them. Our only difference is that someone has fished us out of the water. Those sitting wrapped in a blanket at the bottom of a lifeboat have no sense of superiority over those still in the sea. Our only plea is "Save them too!"
Not all desires are sinful. Sex is a wonderful gift from God. It is not sinful so long as it is confined to marriage and used to reinforce the structure of the family. It is a sin to misuse it. How destructive it can be when it is misused! To earn money is not a sin, even if you earn a great deal of it. But to use it to puff ourselves up and to oppress others is sinful. From him to whom much is given, much will be required. It is not a sin to live in a big house; but what an opportunity to give hospitality! Do you have a big car? The more people you can take to church.
Anne Atkins was wrong to expect the Tory candidate to live up to Christian standards unless she had been a Christian. People who live in the world of politics don't do God, said Tony Blair's presence on Earth, Alistair Campbell. We have no right to hold the world to account. The world will do worldly things. Being a member of the Church of England, Anne probably assumed that every English person is also a member unless specifically opted out. In that case they should behave like Christians. It is a delusion. We Christians are few in England today.
Our ambition should be to live such good lives among the pagans that, though they accuse us of doing wrong, they may see our good deeds. To what end? So that they may glorify God on the day that he visits us. To do that they will have to change before he returns for there is no mind changing after death.
Evander Holyfield claimed to be a Christian, but then it comes out that he had 5 kids out of wedlock with 4 different women; that he had been 'healed' by televangelist, Benny Hinn, who received an alleged $265,000 “donation” for the healing; that he has been linked to alleged usage of performance enhancing drugs; that his house is 54,000 square feet with 104 rooms and a bowling alley and that he has failed to pay child support for one of his 9 kids.
Live such good lives among the pagan...
Iain Dale was also wrong to assume that a Christian must be all forgiving. The offer of forgiveness is there from God. Sufficient grace is available. No more restitution needs to be made to God. No more bulls to be slaughtered or lambs killed. All that is needed is repentance. "Neither do I condemn you," said Jesus, "go and sin no more."
He wants a God who:
Shows complete, benevolent blindness
To our foibles.
Who does not notice when we err.
Forty-winks at deviation,
Falling short or reprobation.
Wouldn’t make a fuss
About us.
Because we stress the forgiveness of God, the world thinks that God doesn't mind sin. Because we stress the love of God, the world things that God is not also terrifying. Because Jesus told us in the Sermon on the Mount to "judge not that ye be not judged", the world thinks that it will not be judged on the last day.
We must expect the world to accuse us of doing wrong. How could it not when the world operates according to a different set of principles to us. We will not convince the Dawkins of this world by the force of our arguments. Few have been forced into heaven by the weight of logic. But many have looked at the likes of John Newton, William Wiberforce, Eric Liddell and others and asked, "What have they got in their lives that is missing from mine?"
We don't do good works to make us feel good, to repay the Lord for what he has done for us, to satisfy our conscience, to earn merit or to impress other Christians. We want to glorify God and have others do so too.
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