We have come to rely on FISH to tell us about the chromosomes in CLL, but it is not a very satisfactory test. It will tell us about the abnormalities that we know exist in CLL - del 13q, del 11q, trisomy 12 and del 17p - but not about ones that we don't look for. In particular we know that isolated del 13q usually has a good prognosis, but unless we look at other chromosomes how do we know it is isolated.
The standard way of looking at chromosomes is to make cells divide, but in CLL this is very difficult. You need a mitogen and the standard mitogen is phorbol ester. Unfortunately although our lab gets over 80% of CLL cells to divide, nobocy else in the world can match our results. This has led other labs to experiment with cytokines to stimulate the CLL cells to divide.
In this month's Leukemia Research, a paper from Poland describes the use of a new mitogen, DSP30. DSP30 is a CpG-oligonucleotide (CpG-ODN). CpG-ODNs act as danger signals and stimulate the immune system. It induces proliferation
of both normal and leukemic B lymphocytes, stimulates production of cytokines, including IL-2 and TNF- , and regulates expression of surface antigens CD25 and CD86 in B lymphocytes. It also stimulates some other immune system cells, such as T lymphocytes, NK cells, dendritic cells and monocytes, to proliferate, secrete cytokines and/or differentiate.
Using DSP30, a sufficient number of metaphases suitable for analysis was obtained in 56/62 (90%) patients, and clonal chromosomal aberrations were detected in 42/56 (75%) patients. Normal karyotype was established in 14/56 (25%). In 9/14 (64%) cases with normal karyotype, aberrations were detected by FISH which revealed anomalies in 52/62 (84%) patients. Using DSP30 and/or FISH, aberrations were detected in 56/62
(90%) patients. DSP30 disclosed del 13q in only 10/56 (18%) cases, while FISH showed this anomaly in 41/62 (66%) subjects. Del 13q was cryptic and not detected by DSP30 in 28 patients. In those cases the presence of submicroscopic del 13q was confirmed by FISH on metaphases. In 4/41 (9.7%) patients del 13q were biallelic or concomitant monoallelic and biallelic. In 26/41 (63%) patients del 13q detected by FISH was a sole anomaly. Del 11q was detected by both FISH and DSP30 in 14 patients, whereas in two patients it was detected only by FISH due to an unsuccessful karyotyping. DSP30 enabled the detection of additional aberrations, especially translocations, in 7/14 (50%) patients with del 11q observed in FISH. DSP30 revealed cytogenetic anomalies which were not searched by FISH in 33/56 (59%) patients. The most frequently observed numerical aberrations were: monosomy 9 (n = 2), monosomy 10 (n = 2), monosomy 13 (n = 2), monosomy 14 (n = 2), monosomy 18 (n = 2) and loss of chromosome Y (n = 2).
It seems to me that complete karyotyping of CLL cells is now possible for all cytogenetics labs, and that it should be added to FISH for patients undergoing clinical trials.
Monday, July 18, 2011
Sunday, July 17, 2011
John 5:37-38
And the Father who sent me has Himself testified concerning me. You have never heard His voice nor seen his form, nor does His word dwell in you for you do not believe the one He sent.
Although John's gospel does not record the voice from heaven at Jesus' baptism, it would have been a well known occasion that didn't need setting down, when John was writing. Yet Jesus stresses that his listeners had not heard his voice. Moses had heard the voice from the burning bush; Elijah had heard the still, small voice; Jacob had seen his form; so had Abraham; and his word had dwelt in Joshua and the psalmists. Jesus was the word of God and the Jews of his time had no time for him. I am Jewish enough to have been vulnerable to Hitler and I weep for my ancestors.
We learn in the letter to the Hebrews that Jesus is 'the exact representation of His being'. The Jews who were his inquisitors were guilty of the one unforgivable sin - unbelief.
Although John's gospel does not record the voice from heaven at Jesus' baptism, it would have been a well known occasion that didn't need setting down, when John was writing. Yet Jesus stresses that his listeners had not heard his voice. Moses had heard the voice from the burning bush; Elijah had heard the still, small voice; Jacob had seen his form; so had Abraham; and his word had dwelt in Joshua and the psalmists. Jesus was the word of God and the Jews of his time had no time for him. I am Jewish enough to have been vulnerable to Hitler and I weep for my ancestors.
We learn in the letter to the Hebrews that Jesus is 'the exact representation of His being'. The Jews who were his inquisitors were guilty of the one unforgivable sin - unbelief.
Saturday, July 16, 2011
CS Lewis an evangelical?
Was CS Lewis an evangelical?
I think we can say categorically that he was not. Of course, he was a man of his generation. He denies being a fundamentalist, although he was accused of it because he refused to categorize any narrative as unhistorical because it contained miracles. Some people found miracles so hard to believe that they could not imagine any reason for CS Lewis to believe them other than a belief that every sentence of the Old Testament has historical or scientific truth. But this went much further than he would go. He was a creationist, but not a six-day creationist, but he also believed in purgatory (largely because he could not conceive that a sinner like him should be let into heaven without some serious scrubbing).
His profession was literary criticism and he applied his techniques to the Bible. His prejudice was that it was true, but he recognised different types of truth. Take the book of Job, for example. Along with Jean Calvin, he doubted whether it was historically true, rather than a work of fiction, like the Prodigal Son or the Good Samaritan, told to make an important point. He would not say it was not historical, but Job has no connection with any history or even legend, with no genealogy, living in an undescribed country, and the story is written as a storyteller would tell it.
He would accept that some early stories of Genesis come from an oral tradition and may have altered over time. We know that the Jews took inordinate means that the written text was preserved intact, though was there a time when alterations in the oral tradition could have been interpolated? But he also believed that the Holy Spirit took tremendous trouble to preserve his message in Scripture, through the agency of the church. This means that he has a greater respect for the Catholic church than we evangelicals might have. He says elsewhere that the differences between different branches of the church might turn out to be mere semantics when we get to heaven.
I would not be too quick to criticize other Christians and the grounds of semantics.
I quote from Reflections on the Psalms. "We may observe that the teaching of Our Lord Himself in which there is no imperfection, is not given us in that cut-and-dried, fool-proof, systematic fashion we might have expected or desired. He wrote no book. We only have reported sayings, most of them uttered in answer to questions, shaped in some degree by their context. And when we have collected them all, we cannot reduce them to a system. He preaches but he does not lecture. He uses paradox, proverb, exaggeration, parable, irony; even the 'wisecrack'. He utters maxims which like popular proverbs, if rigorously taken , may seem to contradict one another. His teaching therefore cannot be grasped by the intellect alone, cannot be 'got up' as if it were an academic subject. If we try to do that with it, we shall find Him the most elusive of teachers. He hardly ever gives a straight answer to a straight question. He will not be pinned down. The attempt is like trying to bottle a sunbeam."
I take this to mean that Lewis thinks that the Scripture is much more dynamic than we evangelicals take it to be. It is more open to interpretation guided by the Holy Spirit and that there are still truths to emerge that are not in the commentaries.
I think he would say that the New Testament characters acted in just this way. For example with the two on the road to Emmaus Jesus taught what it said about Himself from the Pentateuch and the prophets. Before Jesus much of what he revealed would have been interpreted differently by the Jewish teachers. Undoubtedly there are Messianic passages , but would the suffering servant have been seen as Messianic? Probably not.
But we have Phillip opening up Isaiah 53 directly with Jesus in mind to the Ethiopian eunuch. Before that passage in Acts, the suffering would have been thought of as referring to the nation of Israel itself. Jesus identified himself with the sufferer in Psalm 22 (My God, My God, why hast thou deserted me ... ) He asks how Christ could be both David's son and David's lord identifying himself as 'my Lord' in Psalm 110. He applied Psalm 91:11-12 to himself (He shall give his angels charge over thee ... that thou hurt not thy foot against a stone.) Psalm 118:22 (neither shalt thou suffer thy Holy One to see corruption) is appropriated as a prophesy of the resurrection in Acts 2.
Most have difficulty with uncertainty. With Scripture, I am afraid that we have to live with uncertainty. Even the most convincing commentater will admit to pasages with alternative explanation. No systematic theology is entirely convincing on every point. Lewis is vaguer than most and leaves many points undetermined, yet what he is sure about he puts beautifuly clearly. There has been too much Lewis worshipping for my taste and he would have hated it. He regarded himself as an amateur theologian and a professional student of literture, especially teh ancient literature of many traditions. He brought that studen's eye and insight into his studies of Scripture and he was always open to another interpretaion. I admire his intellect and his writing style, but I know he could sometimes be profoundly wrong.
I think we can say categorically that he was not. Of course, he was a man of his generation. He denies being a fundamentalist, although he was accused of it because he refused to categorize any narrative as unhistorical because it contained miracles. Some people found miracles so hard to believe that they could not imagine any reason for CS Lewis to believe them other than a belief that every sentence of the Old Testament has historical or scientific truth. But this went much further than he would go. He was a creationist, but not a six-day creationist, but he also believed in purgatory (largely because he could not conceive that a sinner like him should be let into heaven without some serious scrubbing).
His profession was literary criticism and he applied his techniques to the Bible. His prejudice was that it was true, but he recognised different types of truth. Take the book of Job, for example. Along with Jean Calvin, he doubted whether it was historically true, rather than a work of fiction, like the Prodigal Son or the Good Samaritan, told to make an important point. He would not say it was not historical, but Job has no connection with any history or even legend, with no genealogy, living in an undescribed country, and the story is written as a storyteller would tell it.
He would accept that some early stories of Genesis come from an oral tradition and may have altered over time. We know that the Jews took inordinate means that the written text was preserved intact, though was there a time when alterations in the oral tradition could have been interpolated? But he also believed that the Holy Spirit took tremendous trouble to preserve his message in Scripture, through the agency of the church. This means that he has a greater respect for the Catholic church than we evangelicals might have. He says elsewhere that the differences between different branches of the church might turn out to be mere semantics when we get to heaven.
I would not be too quick to criticize other Christians and the grounds of semantics.
I quote from Reflections on the Psalms. "We may observe that the teaching of Our Lord Himself in which there is no imperfection, is not given us in that cut-and-dried, fool-proof, systematic fashion we might have expected or desired. He wrote no book. We only have reported sayings, most of them uttered in answer to questions, shaped in some degree by their context. And when we have collected them all, we cannot reduce them to a system. He preaches but he does not lecture. He uses paradox, proverb, exaggeration, parable, irony; even the 'wisecrack'. He utters maxims which like popular proverbs, if rigorously taken , may seem to contradict one another. His teaching therefore cannot be grasped by the intellect alone, cannot be 'got up' as if it were an academic subject. If we try to do that with it, we shall find Him the most elusive of teachers. He hardly ever gives a straight answer to a straight question. He will not be pinned down. The attempt is like trying to bottle a sunbeam."
I take this to mean that Lewis thinks that the Scripture is much more dynamic than we evangelicals take it to be. It is more open to interpretation guided by the Holy Spirit and that there are still truths to emerge that are not in the commentaries.
I think he would say that the New Testament characters acted in just this way. For example with the two on the road to Emmaus Jesus taught what it said about Himself from the Pentateuch and the prophets. Before Jesus much of what he revealed would have been interpreted differently by the Jewish teachers. Undoubtedly there are Messianic passages , but would the suffering servant have been seen as Messianic? Probably not.
But we have Phillip opening up Isaiah 53 directly with Jesus in mind to the Ethiopian eunuch. Before that passage in Acts, the suffering would have been thought of as referring to the nation of Israel itself. Jesus identified himself with the sufferer in Psalm 22 (My God, My God, why hast thou deserted me ... ) He asks how Christ could be both David's son and David's lord identifying himself as 'my Lord' in Psalm 110. He applied Psalm 91:11-12 to himself (He shall give his angels charge over thee ... that thou hurt not thy foot against a stone.) Psalm 118:22 (neither shalt thou suffer thy Holy One to see corruption) is appropriated as a prophesy of the resurrection in Acts 2.
Most have difficulty with uncertainty. With Scripture, I am afraid that we have to live with uncertainty. Even the most convincing commentater will admit to pasages with alternative explanation. No systematic theology is entirely convincing on every point. Lewis is vaguer than most and leaves many points undetermined, yet what he is sure about he puts beautifuly clearly. There has been too much Lewis worshipping for my taste and he would have hated it. He regarded himself as an amateur theologian and a professional student of literture, especially teh ancient literature of many traditions. He brought that studen's eye and insight into his studies of Scripture and he was always open to another interpretaion. I admire his intellect and his writing style, but I know he could sometimes be profoundly wrong.
John 5:36. The testimony of miracles.
I have testimony weightier than that of John. For the very work that the Father has given me to finish, and which I am doing, testifies that the Father has sent me.
Water into wine, healing the official's son, healing the paralytic; you don't see things like that every day. If you imagine that these things can be done without the intervention of a higher authority, you are more gullible than the ordinary Joe. They couldn't move against Jesus without a better explanation. There will be more impressive works than these to come.
Water into wine, healing the official's son, healing the paralytic; you don't see things like that every day. If you imagine that these things can be done without the intervention of a higher authority, you are more gullible than the ordinary Joe. They couldn't move against Jesus without a better explanation. There will be more impressive works than these to come.
Cell phones
Steven King wrote a novel about cell phones called Cell. Everyone who was using their phone at a particular time was turned into a zombie. I believe it's true. I've seen them on the train from London. "Hello. I'm on the train. I'm shouting in case anyone else in the carriage can't hear me!"
Now a major storm has arisen over cell phone hacking. I have a confession. I own a cell phone. Early in its life I managed to press a button which stopped it ringing and it hasn't rung since. I have no idea how to restore its ring nor any interest in doing so. It has become an out-only phone; very useful for carrying in the car in case of a breakdown.
Apparently, it is possible to listen to the voice-mail of other people's cell phones. All you do is ring the number when no-one is available and you get switched to voice mail. Then you enter the manufacturer's default number and the phone gives you access to previous voice mail. It is easily guarded against by simply changing the default code to one you have made up. Journalists have known about this for many years and so have most members of the public like me, who know very little else about cell phones. Some years ago the England football manager was discovered to be having an affair with a TV weather girl. It was by this sort of phone hacking that the newspaper (I think the Daily Mail) found out about it. I'm surprised it still goes on when the remedy is so obvious, but apparently it does.
This simple activity has just brought down a major newspaper and severely affected an important industry. The News of the World was the largest selling British Newspaper. Its forte was exposing the sexual peccadillo's of Church of England clerics. I learned to read at the age of 2 by looking at the football results in the News of the World. Sad to see it go. Although this newspaper was the greatest offender in the phone hacking stakes it was by no means the only one. Indeed the Trinity Mirror Group (which owns the Daily Mirror) and the Associated Newspapers Group (which owns the Daily Mail) have been more involved in phone hacking than the News International Group (which owns the News of the World and the Sun). You might ask why this has all redounded on News International.
The answer is complex. First, the people who were affected by phone hacking are the sort of people who nobody cares about; buffoons like John Prescott and bimbos like Sienna Miller (I can hear you asking 'who she?').
Second, because nobody really cared, the police dragged their heels over the affair; worse than that they were in a cosy relationship with journalists, accepting illegal payments for information and not asking too many questions.
Third a particular episode of phone hacking surfaced at a murder trial. It appears that the phone of missing schoolgirl, Millie Dowler, was hacked and voice mail removed to unblock a full phone. This gave the impression that Millie was still alive - much to the distress of her parents. This discovery led to the discovery that other victims had been in similar situation, touching on the two little girls murdered at Souham, soldiers killed in Afghanistan and even victims of 7/7 and 9/11. The public may not care about buffoons and bimbos, but they certainly do about murder victims, shot soldiers and victims of atrocities.
Fourth, Rupert Murdoch is a hate-figure in left-wing circles. At the last general election he changed sides. His newspapers had been supporting his friend Tony Blair previously, but he switched to supporting his new friend David Cameron. Betrayal is a common feature of left-wing politics (read about Stalinist USSR) and this campaign has been driven by the Guardian and the BBC. They are even angry that Tony Blair was seduced by Murdoch in the first place - but would he have won three elections without Murdoch?
I expect that when the Judicial Enquiry reports we shall see that all red-top newspapers were equally at fault and there will be some rearrangement of the deck chairs. Probably the police will carry the can. The Press Complaints Commission will have new staff and a slightly different remit. The Parliamentary Lobby system will change and politicians will find more underhand ways to get into bed with journalists.
Now a major storm has arisen over cell phone hacking. I have a confession. I own a cell phone. Early in its life I managed to press a button which stopped it ringing and it hasn't rung since. I have no idea how to restore its ring nor any interest in doing so. It has become an out-only phone; very useful for carrying in the car in case of a breakdown.
Apparently, it is possible to listen to the voice-mail of other people's cell phones. All you do is ring the number when no-one is available and you get switched to voice mail. Then you enter the manufacturer's default number and the phone gives you access to previous voice mail. It is easily guarded against by simply changing the default code to one you have made up. Journalists have known about this for many years and so have most members of the public like me, who know very little else about cell phones. Some years ago the England football manager was discovered to be having an affair with a TV weather girl. It was by this sort of phone hacking that the newspaper (I think the Daily Mail) found out about it. I'm surprised it still goes on when the remedy is so obvious, but apparently it does.
This simple activity has just brought down a major newspaper and severely affected an important industry. The News of the World was the largest selling British Newspaper. Its forte was exposing the sexual peccadillo's of Church of England clerics. I learned to read at the age of 2 by looking at the football results in the News of the World. Sad to see it go. Although this newspaper was the greatest offender in the phone hacking stakes it was by no means the only one. Indeed the Trinity Mirror Group (which owns the Daily Mirror) and the Associated Newspapers Group (which owns the Daily Mail) have been more involved in phone hacking than the News International Group (which owns the News of the World and the Sun). You might ask why this has all redounded on News International.
The answer is complex. First, the people who were affected by phone hacking are the sort of people who nobody cares about; buffoons like John Prescott and bimbos like Sienna Miller (I can hear you asking 'who she?').
Second, because nobody really cared, the police dragged their heels over the affair; worse than that they were in a cosy relationship with journalists, accepting illegal payments for information and not asking too many questions.
Third a particular episode of phone hacking surfaced at a murder trial. It appears that the phone of missing schoolgirl, Millie Dowler, was hacked and voice mail removed to unblock a full phone. This gave the impression that Millie was still alive - much to the distress of her parents. This discovery led to the discovery that other victims had been in similar situation, touching on the two little girls murdered at Souham, soldiers killed in Afghanistan and even victims of 7/7 and 9/11. The public may not care about buffoons and bimbos, but they certainly do about murder victims, shot soldiers and victims of atrocities.
Fourth, Rupert Murdoch is a hate-figure in left-wing circles. At the last general election he changed sides. His newspapers had been supporting his friend Tony Blair previously, but he switched to supporting his new friend David Cameron. Betrayal is a common feature of left-wing politics (read about Stalinist USSR) and this campaign has been driven by the Guardian and the BBC. They are even angry that Tony Blair was seduced by Murdoch in the first place - but would he have won three elections without Murdoch?
I expect that when the Judicial Enquiry reports we shall see that all red-top newspapers were equally at fault and there will be some rearrangement of the deck chairs. Probably the police will carry the can. The Press Complaints Commission will have new staff and a slightly different remit. The Parliamentary Lobby system will change and politicians will find more underhand ways to get into bed with journalists.
Friday, July 15, 2011
John 5:33-34. Whose testimony?
You have sent to John and he has testified to the truth. Not that I accept human testimony, but I mention it that you may be saved.
Jesus is playing with them. He is teasing them. He is concerned that they may be saved and by reminding them of John's testimony he wonders if they may have listened to him since only believing in Jesus will save them. But he has better testimony that John's.
Jesus is playing with them. He is teasing them. He is concerned that they may be saved and by reminding them of John's testimony he wonders if they may have listened to him since only believing in Jesus will save them. But he has better testimony that John's.
Who should have prognostic markers done and when?
Why should I get my prognostic markers done? Many people have decided not to get their markers tested for very good reasons. They just want to get on with their lives and the future will come soon enough. However, just like we watch the weather forecasts many of us do want to know something about the future so we can plan for it.
I think it goes without saying that anyone who needs treatment should have his TP53 status established. Response to conventional drugs in CLL is severely impaired in TP53 deficient patients and why suffer the toxicity of fludarabine if it isn't going to work? Generally this means a FISH test for del 17p. In my opinion knowing that you are del 13q, or trisomy 12 isn't going to give you any extra information and unless these come as a cheap package, I wouldn't bother with them at this stage.
The other markers that matter of IGHV mutations, CD38, ZAP-70, beta2M and del 11q. These will not affect the response to treatment, at least not when judged by rate of CR and PR, though they might affect MRD negativity. What they do affect is length of remission and overall survival. The IGHV mutation status affects these things from the time of diagnosis, and ZAP-70 expression done by the Crespo method or the Orchard method is a close correlate of that. ZAP-70 done by the Rassenti method is an independent prognostic factor and when done by commercial labs is so unreliable as not to be recommended.
CD38 is changeable, so at diagnosis it may be low but as the disease progresses it tends to increase. The same is true to some extent of Beta2M.
A lot of thought is spent on whether to choose FR or FCR, or between FCR and PCR and even if Bendamustine might not be a better bet, but what influences outcome most is not which treatment is chosen but whether or not the IGHV genes are mutated or unmutated. This does not change during the course of disease and only needs to be done once, at diagnosis.
In about a third of cases the markers are uniformly bad and in about a third they are uniformly good. It is the middle third where confusion lies. In my experience these patients have an intermediate prognosis. This is often because the CD38 is low and will be raised later in the course of the disease, but sometimes it is because the CLL cell has found another way of signaling through to second messengers in the cell that by-pass the B-cell receptor's usual pathway.
Del 11q was always thought of as a poor prognostic marker, but the addition of rituximab to therapeutic mixtures has meant that remissions have been just as long as for those without del 11q. However, a caveat: on the grapevine I hear that this may not remain true as the trials become more mature. We wait and see.
This is what I recommend for patients who have CLL.
Group 1. Those patients with MBL and those who truly do not want to know, do not do any but the diagnostic markers (CD5, CD19, CD20, CD23, CD79b, surface Ig, FMC7).
Group 2. Those who do want some idea of the future, IGHV mutations, Beta2M and CD38. In certain circumstances (if you are lucky enough to be under a Consortioum Center) ZAP-70. Don't be content with just the mutated/unmutated result; ask which gene is being used and whether it belongs to one of the stereotypes.
Group 3. If you have unmutated IGHV genes and low CD38 and Beta2M, get these measured every year. There is no need to repeat the IGHV mutations; these will not change.
Group 4. If you are about to start treatment either for the first or subsequent time you must have FISH for Del 17p and preferably at the moment for Del 11q. At the moment there is no need to test for trisomy 12 or del 13q, but if these are available in a cheap package you may as well since I do believe that as more knowledge accumulates they will be useful. With del 13q it is likely to be the size of the deletion that is important. It is always better to get the markers done at research labs rather than at commercial labs, because they often obtain more information than you pay for and as time passes that information becomes useful. I am still waiting to see what becomes of the information that those with trisomy 12 often have trisomy 16 and sometimes 18 or 19 as well. They may all belong to a single stereotype.
There is evidence that mutated and unmutated respond equally well to PCI32765 and CAL101. Yes, but they respond equally well to fludarabine. It is length of remission and overall survival where things differ.
I think it goes without saying that anyone who needs treatment should have his TP53 status established. Response to conventional drugs in CLL is severely impaired in TP53 deficient patients and why suffer the toxicity of fludarabine if it isn't going to work? Generally this means a FISH test for del 17p. In my opinion knowing that you are del 13q, or trisomy 12 isn't going to give you any extra information and unless these come as a cheap package, I wouldn't bother with them at this stage.
The other markers that matter of IGHV mutations, CD38, ZAP-70, beta2M and del 11q. These will not affect the response to treatment, at least not when judged by rate of CR and PR, though they might affect MRD negativity. What they do affect is length of remission and overall survival. The IGHV mutation status affects these things from the time of diagnosis, and ZAP-70 expression done by the Crespo method or the Orchard method is a close correlate of that. ZAP-70 done by the Rassenti method is an independent prognostic factor and when done by commercial labs is so unreliable as not to be recommended.
CD38 is changeable, so at diagnosis it may be low but as the disease progresses it tends to increase. The same is true to some extent of Beta2M.
A lot of thought is spent on whether to choose FR or FCR, or between FCR and PCR and even if Bendamustine might not be a better bet, but what influences outcome most is not which treatment is chosen but whether or not the IGHV genes are mutated or unmutated. This does not change during the course of disease and only needs to be done once, at diagnosis.
In about a third of cases the markers are uniformly bad and in about a third they are uniformly good. It is the middle third where confusion lies. In my experience these patients have an intermediate prognosis. This is often because the CD38 is low and will be raised later in the course of the disease, but sometimes it is because the CLL cell has found another way of signaling through to second messengers in the cell that by-pass the B-cell receptor's usual pathway.
Del 11q was always thought of as a poor prognostic marker, but the addition of rituximab to therapeutic mixtures has meant that remissions have been just as long as for those without del 11q. However, a caveat: on the grapevine I hear that this may not remain true as the trials become more mature. We wait and see.
This is what I recommend for patients who have CLL.
Group 1. Those patients with MBL and those who truly do not want to know, do not do any but the diagnostic markers (CD5, CD19, CD20, CD23, CD79b, surface Ig, FMC7).
Group 2. Those who do want some idea of the future, IGHV mutations, Beta2M and CD38. In certain circumstances (if you are lucky enough to be under a Consortioum Center) ZAP-70. Don't be content with just the mutated/unmutated result; ask which gene is being used and whether it belongs to one of the stereotypes.
Group 3. If you have unmutated IGHV genes and low CD38 and Beta2M, get these measured every year. There is no need to repeat the IGHV mutations; these will not change.
Group 4. If you are about to start treatment either for the first or subsequent time you must have FISH for Del 17p and preferably at the moment for Del 11q. At the moment there is no need to test for trisomy 12 or del 13q, but if these are available in a cheap package you may as well since I do believe that as more knowledge accumulates they will be useful. With del 13q it is likely to be the size of the deletion that is important. It is always better to get the markers done at research labs rather than at commercial labs, because they often obtain more information than you pay for and as time passes that information becomes useful. I am still waiting to see what becomes of the information that those with trisomy 12 often have trisomy 16 and sometimes 18 or 19 as well. They may all belong to a single stereotype.
There is evidence that mutated and unmutated respond equally well to PCI32765 and CAL101. Yes, but they respond equally well to fludarabine. It is length of remission and overall survival where things differ.
Thursday, July 14, 2011
John 5:32. Who is the other witness?
There is another who testifies in my favor, and I know that his testimony about me is valid
We know that the 'another' is the Father, but Jesus is not revealing this just yet. He will go on to list other witnesses, but from what has preceded this, we know he must mean the Father.
We know that the 'another' is the Father, but Jesus is not revealing this just yet. He will go on to list other witnesses, but from what has preceded this, we know he must mean the Father.
Praise
Here's a wake up call to any medical teachers out there; do you praise your fellows?
Eddie Blackburn, who was Professor of Haematology at Sheffield, used to make a habit of writing a letter praising the authors of papers that he read in the British Journal of Haematology.
William Mayo, the founder of the Mayo Clinic used praise to encourage young doctors.
One of them said, "You'd read a paper at a staff meeting and afterwards he'd see you in the lift or the hall, and would shake your hand and put his hand on your shoulder with a quiet, 'Good work,' and a straight warm look that made you think he meant it. Or perhaps a day or two later you'd get a note from him, just a short one saying something like, 'Dear -------, I learned more about ------- from that paper of yours the other night than I ever knew before. It was a good job.' Believe me, a fellow prized those notes."
Eddie Blackburn, who was Professor of Haematology at Sheffield, used to make a habit of writing a letter praising the authors of papers that he read in the British Journal of Haematology.
William Mayo, the founder of the Mayo Clinic used praise to encourage young doctors.
One of them said, "You'd read a paper at a staff meeting and afterwards he'd see you in the lift or the hall, and would shake your hand and put his hand on your shoulder with a quiet, 'Good work,' and a straight warm look that made you think he meant it. Or perhaps a day or two later you'd get a note from him, just a short one saying something like, 'Dear -------, I learned more about ------- from that paper of yours the other night than I ever knew before. It was a good job.' Believe me, a fellow prized those notes."
Wednesday, July 13, 2011
John 5:31. Many witnesses.
If I testify about myself, my testimony is not valid.
No-one likes someone who blows their own horn. Jesus had a 'sign' ministry. The miracles spoke for themselves. Had he just worked on the Sabbath or made what were considered blasphemous statements about himself the the Jews would have felt very safe in stoning him. But the signs were there or all to see. They would later accuse him of doing these miracles by devilish means, but while the people were behind him their hands were tied.
Jesus would go on to develop the theme that there were yet other witnesses to who he was.
No-one likes someone who blows their own horn. Jesus had a 'sign' ministry. The miracles spoke for themselves. Had he just worked on the Sabbath or made what were considered blasphemous statements about himself the the Jews would have felt very safe in stoning him. But the signs were there or all to see. They would later accuse him of doing these miracles by devilish means, but while the people were behind him their hands were tied.
Jesus would go on to develop the theme that there were yet other witnesses to who he was.
Tuesday, July 12, 2011
T-cells are important in CLL
Nick Chiorazzi's group have published a paper in Blood that shows a method that enables mature CLL cells to grow in a mouse model. They use a nonobese diabetes/severe combined immunodeficincy/gammacnull mouse into which they introduce precursors of human hematopoietic and mesenchymal lineages. It had been previously found that in order for CLL cells to fail to be rejected by a mouse, it has to be very immuno-incompetent indeed. A NOD/SCID mouse lacks the IL-2 family common cytokine receptor gamma chain gene rendering the animal completely deficient in lymphocytes including NK cells. In addition, CLL cells require the support of T cells, monocytes and monocyte-derived nurse-like cells and stromal cells.
They established that autologous CD3+, CD4+ T cells were necessary for CLL engraftment and proliferation, whereas murine stroma and monocyte-derived lineages are quite sufficient to support growth. Another human cell type that facilitated growth in this model was allogeneic antigen presnting cells (either CD14+ or CD19+). This suggests that activation of T cells in necessary for the facilitation of CLL growth to occur.
It may be that the effectiveness of T-cell toxic drugs like fludarabine and Campath derives from their ability to kill T cells. Possibly the importance of T/B interactions is reflected in some of the epiphenomena of CLL such as second malignancies, immunodeficiency and autoimmunity.
They established that autologous CD3+, CD4+ T cells were necessary for CLL engraftment and proliferation, whereas murine stroma and monocyte-derived lineages are quite sufficient to support growth. Another human cell type that facilitated growth in this model was allogeneic antigen presnting cells (either CD14+ or CD19+). This suggests that activation of T cells in necessary for the facilitation of CLL growth to occur.
It may be that the effectiveness of T-cell toxic drugs like fludarabine and Campath derives from their ability to kill T cells. Possibly the importance of T/B interactions is reflected in some of the epiphenomena of CLL such as second malignancies, immunodeficiency and autoimmunity.
JE Trapnell RIP
John Eliot Trapnell, consultant surgeon, has died aged 81. John was my mentor in surgery. I first met him as a medical student when he was a registrar in Bristol. He was born a Bristolean and was educated at Clifton College, the famous Public School where the highest score in cricket was made in Victorian times (Arthur Collins scored 628 not out over four afternoons in June 1899 when he was 13 years old).
John graduated BA from Trinity College Cambridge in 1951 and MB.BChir in 1954, having done his clinical training at the Middlesex Hospital. He achieved a Cambridge MD in 1966. House jobs at the Middlesex and Central Middlesex were followed by junior doctor training at Leicester and then service with the Church Missionary Society in Maseno in Kenya
Between 1960 and 1968 he was a Registrar and Senior Registrar on the Bristol rotation, which for him included a year in Philadelphia on a Fulbright Scholarship.
When I met John, he had a formidable reputation as a surgeon of the old school. He knew his own mind and was quite sure that he as a surgeon knew better what needed to be done than any mere physician. I remember as a house surgeon being asked to remove dead muscle from the leg of a man with end-stage cirrhosis. John was of the opinion that the leg needed to be amputated. He watched over me while I nibbled away at the ischemic leg. When I had finished he said, "Now they will believe me when I say it needs to be amputated."
John became consultant surgeon in Bournemouth in 1968 and had been here for 4 years before I came down as a Senior Registrar in Hematology. He always watched over me and was kind to me as my career progressed.
Shortly after I was converted he came and preached at my house at a meeting we held for those aged 20-40. I remember he preached on Exodus 15:22-27: the waters of Marah and Elim. For a long while he was an Anglican Lay Reader, but under the ministry of Harry Kilbride he was baptized as an adult believer, which upset some people. He later preached regularly at Anglican, Methodist, Baptist and Evangelical churches throughout Hampshire and Dorset and beyond.
As Senior Surgeon in Bournemouth he was hugely influential, affecting many changes while he was Chairman of the Medical Staff. He was greatly beloved of his patients though his colleagues sometimes required more patience with him. He could be forthright. His patients remember the kind way he always phoned up the spouse of the person he had just operated on to tell him or her that all was well.
He became a world authority on pancreatitis and cancer of the pancreas, publishing over 70 scientific and medical papers and 10 text-book chapters. He received many honors including the EK Frey Prize Medal of the German and Austrian Intensive Care Society. He held a Hunterian Professorship of the Royal College of Surgeons in 1969. He traveled widely as a visiting Professor in America, Europe and Asia and lecturer and examiner worldwide. He worked tirelessly to help foreign medical graduates in Africa and from behind the iron curtain obtain first class higher surgical training.
He retired at the age of 60 and had 21 years of retirement at his beautiful house on the edge of the New Forest. He died peacefully in his sleep in Cambridge following a reunion at Trinity College. He is survived by his wife Sandy and his four daughters from an earlier marriage.
John 5:30. A plethora of grace.
By myself I can do nothing; I judge only as I hear, and my judgement is just, for I seek not to please myself but him who sent me.
Shall not the judge of all the earth do right? asked Abraham as the LORD prepared to judge Sodom. So it shall be on that day of final judgement. There will be no side or bias to the judge of all the earth. Remember that if any man be in Hell it will be the result of human responsibility; if any man be in Heaven it be because of divine sovereignty. My only resort is to cast myself on the mercy of the court; but there is plenteous mercy available and free. In the midst of condemnation we swim in a plethors of grace.
Shall not the judge of all the earth do right? asked Abraham as the LORD prepared to judge Sodom. So it shall be on that day of final judgement. There will be no side or bias to the judge of all the earth. Remember that if any man be in Hell it will be the result of human responsibility; if any man be in Heaven it be because of divine sovereignty. My only resort is to cast myself on the mercy of the court; but there is plenteous mercy available and free. In the midst of condemnation we swim in a plethors of grace.
Monday, July 11, 2011
John 5:28-29.The marks of the saved
Do not be amazed at this, for a time is coming when all who are in their graves will hear his voice and come out—those who have done what is good will rise to live, and those who have done what is evil will rise to be condemned.
All will face judgement. I guess these verses put an end to those who say that all will be saved or those who say when we die we rot.
Note that it is men's doings that are judged. Calvin himself notes that the Lord is not speaking of the cause of salvation, which is the finished work of Christ, but the marks of the saved. It is good doing that distinguishes the elect from the reprobate. Otherwise we must believe that belief is work.
All will face judgement. I guess these verses put an end to those who say that all will be saved or those who say when we die we rot.
Note that it is men's doings that are judged. Calvin himself notes that the Lord is not speaking of the cause of salvation, which is the finished work of Christ, but the marks of the saved. It is good doing that distinguishes the elect from the reprobate. Otherwise we must believe that belief is work.
Sunday, July 10, 2011
Chukka weekend
We have had a busy weekend. Our son, David and girlfriend Charlotte have been staying with us. They have been exhibiting with their company, Chukka, at the British Beach Polo Championships at Sandbanks. It was a pukka event watched by a lot of rich people. The alcohol was flowing which lubricated their wallets.
It was not our sort of event, but the sun was shining with a cooling onshore breeze and some beach volleyball to watch as well. No William and Kate though.
David has also helped me to water-blast my dirty patio and restored the water feature in the garden where the pump had burnt out.
We also took their dog down on the beach at Hengistbury Head. I have found the weekend very tiring. I no longer have the strngth and stamina that I once had. I have to pace myself.
It was not our sort of event, but the sun was shining with a cooling onshore breeze and some beach volleyball to watch as well. No William and Kate though.
David has also helped me to water-blast my dirty patio and restored the water feature in the garden where the pump had burnt out.
We also took their dog down on the beach at Hengistbury Head. I have found the weekend very tiring. I no longer have the strngth and stamina that I once had. I have to pace myself.
John 5:27. Judged by our peer.
And he has given him authority to judge because he is the Son of Man
A man should be judged by his peers. Jesus was tempted in every way as we are. He was subject to the same privations, deficiencies, cruelties, psychological strain, and more so. He does not judge from some lofty plain but in his common humanity.
A man should be judged by his peers. Jesus was tempted in every way as we are. He was subject to the same privations, deficiencies, cruelties, psychological strain, and more so. He does not judge from some lofty plain but in his common humanity.
John 5:26. The Son has life in himself.
For as the Father has life in himself, so he has granted the Son to have life in himself.
The moon, the planets and, as we have seen from space exploration, the earth itself, have only reflected light from the sun. So it is with life on earth; we human beings together with every creature whether plant or animal or microbe only have life because of being created by one with life in himself. The Father has it and so does the Son.
Some theologians talk about the 'eternal generation of the Son'. It all depends what they mean by this, but it should imply that this granting of life to the Son was not something that began at the the incarnation, since John has already told us that 'all things were created by him.'
I like JC Ryle on this: The privileges of a true Christian are greatly underrated by many... One of a true Christians's treasures is the 'presentness' of his salvation. It is not a far distant thing which he has to have at last, if he does his duty and is good. It is his own in title the moment he believes. He is already pardoned, forgiven and saved - though not in heaven.
Another of his treasures is the 'completeness' of his justification. His sins are entirely removed, taken away and blotted out by Christ's blood. He may look forward to judgement without fear. He shall stand without fault before the throne of God.
The third treasure is the entire change in his relation and position towards God. He is no longer as one dead before him - dead legally, like a man sentenced to die, and dead in heart. He is alive unto God. He is a new creature. Old things are passed away and all things are become new.
The moon, the planets and, as we have seen from space exploration, the earth itself, have only reflected light from the sun. So it is with life on earth; we human beings together with every creature whether plant or animal or microbe only have life because of being created by one with life in himself. The Father has it and so does the Son.
Some theologians talk about the 'eternal generation of the Son'. It all depends what they mean by this, but it should imply that this granting of life to the Son was not something that began at the the incarnation, since John has already told us that 'all things were created by him.'
I like JC Ryle on this: The privileges of a true Christian are greatly underrated by many... One of a true Christians's treasures is the 'presentness' of his salvation. It is not a far distant thing which he has to have at last, if he does his duty and is good. It is his own in title the moment he believes. He is already pardoned, forgiven and saved - though not in heaven.
Another of his treasures is the 'completeness' of his justification. His sins are entirely removed, taken away and blotted out by Christ's blood. He may look forward to judgement without fear. He shall stand without fault before the throne of God.
The third treasure is the entire change in his relation and position towards God. He is no longer as one dead before him - dead legally, like a man sentenced to die, and dead in heart. He is alive unto God. He is a new creature. Old things are passed away and all things are become new.
Saturday, July 09, 2011
Praising God
One of the criticisms that Richard Dawkins has of the Christian God is that he is always demanding praise. the Psalms are particularly demanding in this respect. "Praise the Lord", "O praise the Lord with me", "Praise him".
This gels poorly with the English character which believes in public modesty. We despise the millionaire or celebrity of sportsman who always demands assurance of his own importance.
Even worse is the silly pagan bargaining that says we weill praise him if he does something for us. "Keep me alive because I can't praise you when I'm dead"
It is easy to be grateful to God, to be reverent towards him and obedient to him, but a continual cacophony of praise? Isn't that gilding the lilly?
We read elsewhere that He is worthy to be praised. And that is true. Even inanimate objects are sometimes thought to be admirable. We admire a landscape or a picture. We praise a TV program or a play. In fact we make ourselves look insensitive or obtuse if we don't The man who does not praise a wonderful piece of music or a good book or a bright morning or the love of a good woman or even an exciting cricket match is lacking in some way.
So it is with God. What he has created, the way he has dealt with his creation and above all the atoning sacrifice of Jesus, demands praise. Not in any creepy sense or from any vain desire. Indeed in Psalm 50 the Lord says, "If I were hungry, would I tell you?" If such an absurd thing could be contemplated why should he turn to us for supply?
For praise is a human reaction to excellence and we do it by sharing our approval with others. To start to applaud is to invite others to join in. Somehow the praise completes the enjoyment. The chief end of men is to glorify God and enjoy him forever. Not for his sake, but for ours.
This gels poorly with the English character which believes in public modesty. We despise the millionaire or celebrity of sportsman who always demands assurance of his own importance.
Even worse is the silly pagan bargaining that says we weill praise him if he does something for us. "Keep me alive because I can't praise you when I'm dead"
It is easy to be grateful to God, to be reverent towards him and obedient to him, but a continual cacophony of praise? Isn't that gilding the lilly?
We read elsewhere that He is worthy to be praised. And that is true. Even inanimate objects are sometimes thought to be admirable. We admire a landscape or a picture. We praise a TV program or a play. In fact we make ourselves look insensitive or obtuse if we don't The man who does not praise a wonderful piece of music or a good book or a bright morning or the love of a good woman or even an exciting cricket match is lacking in some way.
So it is with God. What he has created, the way he has dealt with his creation and above all the atoning sacrifice of Jesus, demands praise. Not in any creepy sense or from any vain desire. Indeed in Psalm 50 the Lord says, "If I were hungry, would I tell you?" If such an absurd thing could be contemplated why should he turn to us for supply?
For praise is a human reaction to excellence and we do it by sharing our approval with others. To start to applaud is to invite others to join in. Somehow the praise completes the enjoyment. The chief end of men is to glorify God and enjoy him forever. Not for his sake, but for ours.
Friday, July 08, 2011
Is O-FC as good as FCR?
The MDACC lot have published the results of a phase 2 trial of FC with Ofatumumab in 61 previously untreated CLL patients. The question we all want to know is whether O-FC is likely to be an improvement on FCR.
The problem with a phase 2 study is that there is no comparison that is valid. All you can do is look at other phase 2 studies and make a rough judgement.
So what is the competition like? The CALGB 9712 trial reported at CR rate of 47% and an OR rate of 90% for FR. The MDACC FCR response rate was 72% CR and 95% OR. The Spanish FCM-R rates were 82% CR and 93% OR. But the German CLL8 study reported a more realistic 44% CR rate and 95% OR, All these studies were in relatively young and fit patients.
However, the O-FC study was a bit more stringent in some respects, though not all. The patients were still young with a median age of 56, but they included 13% with a del 17p and 16% with del 11q. 64% had a Beta-2M level greater than 3.5. 47% were unmutated and 20% had a raised CD38. Of particular note was the OR of 63% and CR rate of 13% in del 17p patients.
The overall incidence of toxicity and failure to complete treatment was similar to the MDACC experience with FCR.
The FC was given in standard doses but the O was given as either 500 or 1000 mg (not per sq m). The OR rate was 77% and 73% for the two doses respectively (ie not statistically different) but the CR rate was 50% for the higher dose and 32% for the lower (not statistically different, though because of small numbers). By univariate analysis the factors determining response were completion of sufficient courses of treatment and the Beta-2M level.
What can we say then, is O-FC as good as FCR? This small study is unable to say more than it might be. We shall have to await head to head comparisons.
The problem with a phase 2 study is that there is no comparison that is valid. All you can do is look at other phase 2 studies and make a rough judgement.
So what is the competition like? The CALGB 9712 trial reported at CR rate of 47% and an OR rate of 90% for FR. The MDACC FCR response rate was 72% CR and 95% OR. The Spanish FCM-R rates were 82% CR and 93% OR. But the German CLL8 study reported a more realistic 44% CR rate and 95% OR, All these studies were in relatively young and fit patients.
However, the O-FC study was a bit more stringent in some respects, though not all. The patients were still young with a median age of 56, but they included 13% with a del 17p and 16% with del 11q. 64% had a Beta-2M level greater than 3.5. 47% were unmutated and 20% had a raised CD38. Of particular note was the OR of 63% and CR rate of 13% in del 17p patients.
The overall incidence of toxicity and failure to complete treatment was similar to the MDACC experience with FCR.
The FC was given in standard doses but the O was given as either 500 or 1000 mg (not per sq m). The OR rate was 77% and 73% for the two doses respectively (ie not statistically different) but the CR rate was 50% for the higher dose and 32% for the lower (not statistically different, though because of small numbers). By univariate analysis the factors determining response were completion of sufficient courses of treatment and the Beta-2M level.
What can we say then, is O-FC as good as FCR? This small study is unable to say more than it might be. We shall have to await head to head comparisons.
John 5:25. Waking the dead.
I tell you the truth, a time is coming and has now come, when the dead will hear the voice of the Son of God and those who hear will live
The expression relates to the future, when at the end time the voice of Jesus will wake the physically dead in a call to judgement AND to the present when the voice of Jesus will wake the spiritually dead.
The expression relates to the future, when at the end time the voice of Jesus will wake the physically dead in a call to judgement AND to the present when the voice of Jesus will wake the spiritually dead.
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