Saturday, October 31, 2009

Th17 cells

I can well remember when immunologists did not know what the lymphocyte did - our anatomy professor was certain that they turned into red cells. I remember the excitement when Roger Taylor and others set about separating lymphocytes into T cells and B cells. It wasn't long before T cells were divided into helper cells and cytotoxic cells. Then more recently T helper cells were separated into Th1 which helped the cellular immune response and Th which helped the antibody response.

I was sitting in a lecture 10-15 years ago when I heard Ethan Shivak explain that there was a regulatory T cell that was CD4+, CD25+ (and later FOXP3+). Well more recently three more types of T cells have been described: Th17, Tfh and Th. A recent review of T cells can be found here .

Th17s are cells that produce interleukin (IL) 17A, IL-17E and IL-17F. These are pro-inflammatory cytokines. They also produce IL-21 and IL-22. What are they for? They seem to be involved in fighting off certain unusual infections. For example, Th17 cells have been suggested to contribute to the resistance to Listeria, Salmonella, Toxoplasma, Cryptococcus, Leishmania and Francisella. A significant and specific role for the Th17 response has been shown for Klebsiella infection in the lung, intravenous Candida albicans infection, and infection of the natural rodent pathogen Citrobacter rodentium in the gut. In addition, the preferential production of IL-17 by T cells during infection with Bacteroides fragilis, Borrelia burgdoferi, Mycobacterium tuberculosis and fungal species suggests that Th17 responses are triggered by specific pathogens and are required for their clearance. Older readers may recognise that some of these these are important in immunodeficient individuals.

In addition to controlling infection, Th17 cells play an important role in autoimmunity. IL-17 expression has been associated with autoimmune diseases such as multiple sclerosis, Rheumatoid Arthritis, psoriasis and Inflammatory Bowel Disease, as well as with allergic responses. In particular, Th17 cells are critical for the development of experimental autoimmune encephalomyelitis and an experimental Rheumatoid Arthritis, whose development was originally attributed to Th1 cells before the discovery of Th17 cells.

How are Th17 cells produced? We know that TGF-β and IL-6 act together (and both are necessary) to commit naive T cells to develop into Th17 cells. and MyD88-dependent signaling, which proved to be IL-6. TGF-β alone tends to favor the production of Tregs but the addition of IL-6 redress that tendency and pushes the cells toward Th17 development.

IL-23 and IL-21 are cytokines shown to be important for Th17 differentiation. IL-23 is currently thought to be critical for promoting the survival and proliferation of differentiated Th17 cells. IL-23 uses one of the same chains as IL-12 and in some respects as reciprocal activity. It binds to the IL-23R complex composed of IL-12Rβ1 chain and a novel receptor chain (IL-23R) related to IL-12Rβ2 and gp130. Jak2/Tyk2-STAT1, 3, 4, and 5 are involved in its intracellular signal transduction. In contrast to IL-12, IL-23 predominantly activates STAT3, but not STAT4.

IL-21 is an IL-2 family member that was recently found to be highly produced by Th17 cells. IL-21 can substitute for IL-6 to induce Th17 cells along with TGF-β. IL-21-activated signaling pathways critical for Th17 differentiation and its biological function under physiological and pathological conditions remain to be established.

Retinoic acid-related orphan receptors (ROR) are the key transcription factors in Th17 differentiation.

Soon after the discovery of Th17 cell scientists wanted to know how it related to other Th cells. Based mostly on the studies in vitro, Th17 and iTreg were found to be mutually exclusive. Following activation in the presence of TGF-β, CD4 T cells differentiate into Foxp3-expressing iTreg without IL-17 expression. However, if IL-6 is also present, activated CD4 T cells deviate to Th-17 cells without Foxp3 expression. The mechanism of such a mutual exclusion could be owing to Foxp3 expression in iTreg and ROR-t expression in Th17 cells. It appears that high-level Foxp3 expression leads to the repression of ROR-t and thus Th17 differentiation, and ROR-t expression inhibits Foxp3 and prompts IL-17 production.

Recently, emerging evidence suggests that under certain conditions, seemingly committed T cells possess plasticity and may convert into other types of effector cells. Tregs can become Th17 cells in the presence of activated inflammatory Dendritic Cells through the action of IL-6. Seemingly fully differentiated Th17 cells were also shown to convert into Th1 cells in the absence of TGF-β.

I suggest a good read of the article I cited if you want to find out about Th9 and Tfh cells. indeed it will bring you up to date on T cells activity.

Falkirk Wheel

The year 2000 marked the end of the second millennium since the supposed date of the birth of Christ. The British government set aside money from the National Lottery for several engineering works to mark the year. The best known is the Millennium Dome in London's east end, but there are others. Today I came across one I had not heard about, The Falkirk Wheel . What I like about it is that it uses engineering principles from Archimedes and cost only $25 a day to run.

Wednesday, October 28, 2009

P53 explored

Of all the malign features of CLL, damage to the p53 pathway is the most serious. Most drugs used in CLL work by invoking the p53 pathway to destroy the CLL cells. A recent paper in Blood has examined the p53 pathway in patients entering the German CLL2H trial.

In this trial patients who required treatment but were refractory to at least one fludarabine containing regimen were treated with subcutaneous Campath. Tests were done to determine whether the patients had a loss of part of the short arm of chromosome 17 (where the p53 gene resides) or if the p53 gene was mutated or if the p53 was functionally intact by generating p21 after irradiation of the CLL cells.

The study asked two main questions: 1]what is the contribution or p53 pathway defects to fludarabine refractory CLL? and 2]what are the clinical implications of
p53 mutations in the setting of fludarabine refractory CLL treated with Campath?

The answer is that 36% of those with fludarabine refractory CLL do not have a defect in the p53 pathway. Only 32% of the patients had del 17p. 37% had mutations of the p53 gene. Most of these (68%) were in patients who had lost 17p, but the other third were in patients whose FISH test did not give any warning of fludarabine refractoriness. In other words looking for p53 mutations in patients who are refractory to fludarabine and will uncover another 12% who have a defect in the p53 pathway. Or put it another way, 18% of those who do not have del 17p will have a p53 mutation. Or if you like, 44% had a defect of p53. In addition, 19% had an 11q deletion, which leaves 36% with no obvious poor risk factor. (Note that the German CLL8 trial - which obviously came after this one - shows us that del 11q patients can be brought back into the standard risk fold by using FCR rather than FC).

So what happens to patients who are refractory to fludarabine when they are treated with Campath? Thew answer is that they don't do all that well. The average survival is about 18 months. This trial showed it to be worse for those with p53 mutations (13 months against 21 months) but this was not statistically significant - they would have needed to study more patients to be sure. Time to treatment failure was the same for both groups which tends to suggest that those without mutations will respond to something else for a while. What can be said is that despite all this, about a quarter of those with p53 mutations were still alive at 4 years.

Don't get confused; the mutations I am talking about in this article are nothing to do with the mutations of the IGHV genes that I normally write about.

My health once more

Sorry for the silence. We have been under the influence of the electrician who has been rewiring the house. There have been a few technical hitches that have needed sorting, but I trust that all is now working.

Our church has been holding an evangelistic outreach and on the last day I was interviewed on how I became a Christian, how I faced my cancer, and why bad things happen to Christians.

For those who haven't found how I became a Christian, you can read about it on this blog at .

When I first heard that I had got cancer I was shocked and frightened. I was also in considerable pain. My post-operative course was rocky and yet I was able to be content. a verse of Scripture cam to me "Thou wilt keep him in perfect peace whose mind is staid on thee." I put everything else out of my mind and just thought about what the Lord had done for me. There was a time when I thought that I would die in hospital, but that passed and I gradually recovered.

Because I had such a slow recovery from the post-operative ileus, the surgeon was keen to start chemotherapy as soon as possible. I think he half believed that it was the cancer that was stopping my bowel working properly. Perhaps I started too soon. The chemotherapy was difficult to bear. At first I thought that I would have a few days of ill health followed by a recovery period in which I would be able to live normally. In fact, although I was able to cope with nine courses of treatment, they came every second week and I had no time to recover before the next course was due. for much of the 20 weeks of treatment I was confined to the sofa, too sick to do very much. Even walking across the road left me breathless and exhausted.

I spent a lot of the time in Bible study and prayer and I was encouraged by the hundreds of people from all over the world who sent messages of encouragement. I even managed to write a couple of hymns, although I couldn't have found the energy to rewire a plug.

Since the chemotherapy was completed a couple of months ago I have gradually improved. I have had some problem with my tummy, and of course, being a doctor, I have easily found symptoms to indicate that the cancer has returned. I presume that the symptoms have other causes since my weight is increasing and my appetite has improved. Gradually the symptoms are abating.

The worst problem has been the neuropathy caused by the Oxaloplatin. This mainly manifests as numbness and tingling in my hands and feet. There is some difficulty in doing up shirt buttons and tying shoelaces, but I manage. A less well recognised side effect is autonomic neuropathy. This means that the function of the nerves that go unnoticed is affected. My blood pressure has fallen. Previously I had to take blood pressure tablets, but even having stopped them my pressure is so low that in Germany (where low blood pressure is recognised as a disease) I would be given stimulants to raise it. The autonomic neuropathy also affects the temperature control of my hands so that I have to wear gloves on quite warm days, and it affects the motility of my bowels. It is this latter affect that can easily be confused with a return of the cancer. I have a CT scan again in a couple of weeks so this should give me an insight into whether I am right in my diagnosis.

In a couple of days I will make my first trip to London to examine a PhD. This will be a significant milestone for me.

Friday, October 23, 2009

BNP - the TV debate.

Last night on Question Time, Nick Griffin, leader of the British National Party, appeared for the first time. The audience was packed with his opponents, rent-a-mob besieged the BBC studio and four panelists appeared with him, all strongly opposed to his views.

Griffin is reputedly a fascist, yet his party won two seats at last year's European Elections and many councillors at local elections. I am not a BNP supporter.

As I have posted before, I supported the BBC in giving him the opportunity to present his views. In fact they had no choice. Their Charter demands that they be impartial and in the past they have given a voice to the Green Party, George Galloway's Respect Party and to UKIP, all of which are parties with a small and patchy following, that have won seats in Europe.

In the 1930s Oswald Moseley split from the Labor Party to form the British Union of Fascists, which allied with the Nazi Party in Germany and fought pitched battles on the streets of London with those on the Left. After the war, this brand of politics was taken up by the League of Empire Loyalists and then by the National Front. In the 1979 general election, the National Front polled 191,719 votes, 0.6% of the vote overall. Although it still exists, its current membership is 150. Nick Griffin is a former national organizer of the National Front and claims to be moving the British National Party in a more moderate direction. In the 2005 general election the BNP polled 0.7% of the total vote, but in 2008 got 5.2% of the votes in the London Mayoral election and in the same year had 2 MEPs elected and many local councillors to bring their total representation locally to 56 seats. The also have one of the 25 seats on the London Assembly. The BNP has increased its electoral influence despite well documented instances of racism, homophobia and antagonism to Islam. The general public has not been deterred from voting for them.

The rise of the BNP has been attributed to many factors. The scandal about MPs overclaiming expenses sowed distrust among voters for mainstream politicians, the recession has led to unemployment so that workers have become obsessed by immigrants 'taking our jobs', immigration has definitely increased leading to predictions that Britain's population will go from 60 to 70 million in the next 20 years, there is widespread discontent that even those illegal immigrants who are caught are seldom deported to their country of origin and the Labor government seems to keep no record of whether those on temporary visas (visitors of students) ever return to their own countries. Finally Europe is a dirty word to most Britons and many are angry that the promised referendum on the Lisbon Treaty never emerged, despite it being a Manifesto commitment by New Labor.

The TV program proved a disappointment. No political issues were discussed; instead the BNP was attacked for its previous statements (some of them mythical) rather than its present policies. Griffin was not a smart performer and some of his unpleasant beliefs were drawn out of him, but the atmosphere of intimidation was such that some will undoubtedly have felt sorry for him. One Afro-Caribbean member of the audience came over as a coherent and eloquent defender of Black Englishmen who was proud of his country and the same could be said of a South Asian who spoke with a London accent.

Griffin got in one barb at Jack Straw, the Labor Minister for Justice, by pointing out that Griffin's father had fought the Nazis in the RAF, while Straw's father (though part-Jewish) had registered as a conscientious objector. Had he wished to be nasty he could have had fun with Straw's previous views as a Marxist and with his son's conviction as a drug dealer. Griffin himself has been accused of inciting racial hatred but was not convicted of it when tried.

The only question that did not attack the BNP was "Is the rise of the BNP due to to government's handling of immigration?" The audience certainly thought so.

In summary, a debate on the BNP should certainly be held. There are issues which the main parties are afraid to approach for fear of being thought racist, homophobic or anti-Islamic. Many people are anxious about the loss of English cultural identity. Politicians are distrusted as self-serving crooks. A change of government is coming, but may be elected on a diminishing plebiscite which will allow minor parties undue influence.

Wednesday, October 21, 2009

The Crusades

When I was young I used to read about the Crusades in the way I used to read about Biggles. While Biggles was shooting down the Hun, Richard Coeur de Lion and Ivanhoe were cutting down the Infidel in Palestine. Revisionist historians have cast Biggles as a warmonger and Palestinian Muslims as victims. Just how correct are these recent pictures of what went on?

Were the Crusades the brainchild of an ambitious Pope or rapacious knights intent on booty? Hardly. They were a response to more than four centuries of conquests in which Muslims had already captured two thirds of the old Christian world. If you read about Paul's missionary journeys you will find that Christianity had spread from Jerusalem to Judea and Samaria, then on to Asia Minor and thence to Europe. It quickly dispersed throughout the Roman Empire. But here's the point: Christianity was not spread by armed force; it spread by word of mouth and the evidence of changed lives.

In contrast, Islam was born in war and grew the same way. From the time of Mohammed,
Muslim expansion was always by the sword. In a manner reminiscent of Hitler's Blitzkrieg, beginning shortly after the death of Mohammed, the warriors of Islam struck out against the Christians . Palestine, Syria, and Egypt - once the most heavily Christian areas in the world - quickly succumbed.

By the eighth century, Muslim armies had conquered all of Christian North Africa (where St Augustine had been bishop) and even into Spain. In the eleventh century, the Seljuk Turks conquered Asia Minor. Go to Capodocia in modern Turkey and see where the Christians were driven from their homes to live in caves. The Muslim invasion is sometimes regarded as just a fact of history while the Christian response is vilified as full of atrcoities, cannabalism and brutality. In my opinion this is a false antithesis. The Muslim invasion was brutal as were the Christian crusades; but many of the stories are exaggerated and some are entirely mythical.

At some point, European culture had to defend itself or be subsumed by Islam. The Byzantine Empire - the eastern half of the Holy Roman Empire was reduced until little more than Greece remained. In desperation, the Emperor in Constantinople sent word to the Christians of western Europe asking them to aid their brothers and sisters in the East. One factor that contributed to the decision in the West to respond to that request came from an incident in the year 1009, when the Fatimid Caliph al-Hakim bi-Amr Allah ordered the destruction of the Church of the Holy Sepulchre. In 1039 his successor, after requiring large sums be paid for the right, permitted the Byzantine Empire to rebuild it. Pilgrimages were allowed to the Holy Lands before and after the Sepulchre was rebuilt, but for a time pilgrims were captured and some of the clergy were killed. Destruction of the Holy Places and the murder of pilgrims gave an incentive that was not easily resisted.

The Muslim conquerors eventually realized that the wealth of Jerusalem came from the pilgrims and with this realization the persecution of pilgrims stopped. However, the damage was already done, and the violence of the Seljuk Turks became part of the concern that spread the passion for the Crusades. By the time the first crusaders arrived in Jerusalem persecution of pilgrims had long stopped but of course in those days there was no 24-hour news service.

In retrospect, we can see the slow corruption of the Christian church, which probably dates from the conversion of the Emperor Constantine, which led to the identification of the spiritual with the secular power. The church grew rich and powerful with positions of authority in the church being given to relatives of the secular rulers. The people were sold myths and bribed or frightened into obedience. People who are coerced into one faith can easily be coerced into a different one when the balance of power changes.

Recently the war in Yugoslavia saw a sort of re-enactment of the crusades. The Roman Catholic Croatians were set against the Greek Orthodox Serbs, who clashed with the Muslim Bosnians; yet as was stated by a UN general on the spot; racially they are all Serbs.

Jesus never endorsed war of any physical kind. "My Kingdom is not of this world," he said, "If it were, my servants would fight." He repudiated Peter's sword thrust to take off the Temple servant's ear. "All who draw the sword will die by the sword." Yet he realised that his message would lead to battles. "Do not suppose that I have come to bring peace to the earth. I did not come to bring peace but a sword." His message would set people against people. Because some would reject his message there would inevitably be conflict. In preparation for that conflict he advised his disciples "If you don't have a sword, sell your cloak and buy one." Yet when the disciples volunteered, "See, Lord, here are two swords," he was quick to reply, "That is enough."

I interpret that as his saying my kingdom is to be spread by word of mouth, not by violence, but such will be the opposition from unbelievers that you will need to defend yourselves. The Apostle Paul, gives us an example of someone who uses the secular law to protect himself when as a Roman citizen he is arrested in Philippi and when brought before the Roman authorities in Jerusalem he appeals to Caesar (who as he tells us in the letter to the Romans, 'bears the sword' for the protection of those who have not broken any law).

Pope Gregory VII struggled with reservations about the doctrinal validity of a holy war and the shedding of blood for the Lord and had, with difficulty, resolved the question in favour of justified violence, especially given the fact that the pilgrims to the Holy Land were being persecuted. Saint Augustine of Hippo, Gregory's intellectual model, had justified the use of force in the service of Christ in The City of God, and a Christian "just war" in defence of the sacred sites in Palestine might well be contemplated. As it happened it was Gregory's successor who initiated the First Crusade.

Looking back we can see other considerations that may have weighed with the papacy, though how much is difficult to be sure of at this distance. The Christianization of the Vikings, Slavs, and Magyars, had produced a large class of armed warriors whose energies were misplaced fighting one another and terrorizing the locals. The Christian princes of northern Iberia had been fighting their way out of the mountains of Galicia and Asturias, the Basque Country and Navarre, with increasing success, for about a hundred years. The fall of Moorish Toledo to the Kingdom of León in 1085 was a major victory and an obvious sign that the Muslims could be defeated. The Norman adventurer Robert Guiscard had conquered Calabria in 1057 and was holding what had traditionally been Byzantine territory against the Muslims of Sicily. The maritime states of Pisa, Genoa and Catalonia were all actively fighting Islamic strongholds in Majorca and Sardinia, freeing the coasts of Italy and Catalonia from Muslim raids. It appeared the tide was turning and there seemed to be a possibility of ending the schism between the eastern and western Christian church.

However, trying to apportion blame for the Crusades is a lost cause. Just try reading the Wiki article and then click on the areas that are disputed. At the time of the crusades many of the cities of Palestine, such as Antioch, had a mainly Christian population. The stories of atrocities cannot be referenced to first-hand sources and have the stench of propaganda about them. Undoubtedly there were atrocities on both sides and no Geneva convention applied. It is futile to look at past wars through the eyes of Amnesty International.

The end of the Crusades at the end of the fifteenth century did not signal the end of bloodshed. France and England had already given up crusading and were fighting each other and after the Turks were held back at the gates of Vienna, Muslims went back to fighting each other too. Religious wars continued, pitching Catholic against Protestant and Sunni against Shiite.

The word 'Crusader' has perjorative overtones for Muslims but quite the opposite for Christians. To say the crusades, a multi-century initiative by Europe, was either "good" or "bad" raises the question of "for whom?" Without the Crusades, Europeans might still being counting using Roman numerals! We might have lost Aristotle for another few centuries. The Crusades prevented further Muslim expansion into Christian territory (on as great a scale as had previously been seen) for hundreds of years; good for Christians: bad for Muslims. It is too simple to sum up with "good" or "bad". Any historian who does so is almost automatically biased.

Tuesday, October 20, 2009

What gives offence.

Following on from the last post, I have tried to imagine what sort of things I would like people arrested for because they have offended me. Here is a random list.

Bad language - not only the words employed to describe sexual and excretory functions but particularly "Jesus" and "Christ" used as expletives, and when I am in a bad mood, grammatical solecisms, misplaced apostrophes and interpolated aitches at the beginning of the word 'aitch'.

Homosexual activity in public places. Come to think of it, heterosexual activity in public places. No snogging in church!

Bullying, particularly racist bullying, whether it be white on black or black on white or black on Asian. But not just racism. Bullying of girls by boys, women by men, the old by the young, the poor by the rich, the ugly by the beautiful, workers by management, homosexuals by heterosexuals, red-haired people by those with other hair colors, and vice-versa for all of these categories, since we should never assume that bullying is always one-way.

Cheating. I am offended by those who dissemble to obtain benefits that they are not entitled to as well as those who fail to pay their taxes; by those who call a ball 'out' when it is 'in' at tennis, who feign injury in football, who claim a catch in cricket when they know it had already hit the ground before it ended up in their hands, who land low-blows in boxing, who use hands in the ruck in rugby, by card sharps, hucksters, charlatans, scientific frauds, adulterers and advertisers of face creams (no, you're not worth it).

Arrogance. This is a major temptation in everyone who is powerful including politicians, physicians and preachers.

Rudeness. In a way this is a form of bullying. You can either be rude back which is bad manners or you can cower under it, which means you are being bullied. In Western culture it is rude to hide your face in public. Whether you are wearing one of those all-over crash helmets, a balaclava or a niqab, it is impolite to wear one in Western society unless you are riding a motor cycle or robbing a bank. It is only because correcting people in public is regarded as rude that you haven't be told before.

In religion I am offended by baptismal regeneration, papal infallibility, the idea of Mary's immaculate conception or bodily assumption, the idea of priests as a separate category of Christians, drawing attention to yourself by waving your hands in the air, the prosperity gospel, denying the communion table to anyone who is not a member of your group, denial of the existence of either hell or heaven, lack of generosity, the idea that you can work your way to heaven, the denial of the deity of Christ, the creation of sainthood as a special category of 'super Christians', the worship of many gods, atheism, deism, denial of the resurrection of Christ, deliberate distortions of the Trinity, female circumcision, jihads and suicide bombers.

You might think I am easily offended.

Free speech

There is a row in the UK at the moment about freedom of speech. Two incidents have triggered it. The first was the decision of the BBC to invite Nick Griffin, the leader of the British National Party, to appear on their flagship political program, Question Time, and the second was an article in the Daily Mail about the death of a pop singer.

The British National Party (BNP) is the spiritual descendant of Oswald Moseley's pre-war fascists. They wish to preserve Britain from immigration, particularly from those whose skin is of a darker hue. They draw their support from the white working classes who have traditionally supported the Labor Party.

Overt racism is, of course, denigrated in Britain and the BNP have tried to distance themselves from that charge. Recent mass immigration to Britain has come from Poland, the Baltic countries, Romania and Bulgaria, all countries with white populations (though Romanian gypsies, a persecuted people in their own country, are somewhat swarthy). There are certainly racists among BNP members, though their electoral support - they have two members of the European Parliament and many local councillors - does not imply more than a million racists in England. They have been campaigning on the dilution of British "Christian" heritage and the intrusion of traditions from other countries, particularly Muslim countries.

Certainly a large number of immigrants have entered Britain, putting strain on the NHS and education system. Many of the immigrants have been illegals - Commonwealth citizens outstaying their visitor or student visas, Afghan and Iraqi men hitching a lift under trucks on ferries and trains from France, Chinese peasants packed 57 deep into secret compartments in trucks, and many foreign nationals taking part in fake marriages to British citizens. Although the number of black and Asian immigrants does not constitute anything like the proportion of non-whites to be found in America, being less than 10% of the population, they tend to be concentrated in certain areas, particularly in London, around Manchester and in midland industrial towns like Leicester.

With the recession it has been fairly easy to blame the immigrants for difficulties in finding a house, large classes in schools where few speak English, loss of jobs, and long waiting times in hospitals. The Unions are in decline and the Labor Party is in disarray. Consequently, many of the white working classes find the BNP an attractive home.

Another factor has been the pushing of political correctness by New Labor. To be blunt, the working man has been given to making offensive jokes against foreigners, homosexuals, vicars and Manchester United supporters ever since I worked in a factory some 50 years ago and probably before that. I honestly don't believe he meant any harm by it. Anybody from the Indian subcontinent was called "Paki" to his face, any Afro-Caribbean individual was called "Darkie", any Scot "Jock", any Welshman "Taffy" and any Irishman "Paddy". Though not that common, anyone from Eastern Europe was known as "Boris". These were terms of affection. I realise that in other strata of society these words may be offensive, but to be culturally sensitive you have to be sensitive to all cultures including that of the white working class. It is this neglect of this political base by New Labor that has allowed the BNP to flourish.

Apparently the singer from Boyzone was in a homosexual relationship. He died at a very young age on a Spanish holiday island from pulmonary edema. This is very unusual, though one does see it in young athletes because of an unsuspected cardiac condition. Given the reputation of pop singers one would immediately suspect that drugs might have been involved and as I understand it the toxicology report is not in yet. The Daily Mail columnist, Jan Muir has caused offence by suggesting that the man's lifestyle precipitated his early death. I have no idea whether she is right as I know nothing about his lifestyle. He does not seem to have died from AIDS or hepatitis, two diseases commoner among homosexuals, and I have no idea whether he fitted into the stereotype of people in his profession in overindulging in drugs and alcohol. However, writing an article in Britain's most popular daily newspaper that besmirches the reputation of a popular entertainer who has just died was, as Sir Humphrey used to put it on 'Yes Minister', courageous.

Stephen Fry, the comedian and presumed polymath, who himself has had an irregular lifestyle, has orchestrated a protest on Facebook to try and get Jan Muir dismissed (though the Daily Mail is probably revelling in her notoriety). Some 21,000 letters of protest have been received. Peter Hain, ex-minister in the Labor government who came to fame as a protester against Apartheid in South Africa, and himself forced to resign over financial irregularities, has been campaigning to get the BNP uninvited from Question Time. It would be surprising if either of them succeeded. The principle is one of free speech. In the UK no-one is prevented from speaking their mind unless they incite violence. Even minor violence is tolerated (viz. the recent occupation of a coal-fired power station by green campaigners). It is generally thought that unsavoury people will condemn themselves out of their own mouths.

One of the tenets of the politically correct is that a racist or homophobic remark is regarded as such if the object of the jibe feels offended by it. This is such utter nonsense as to be untenable. People take offence at imagined slights. There are many things that offend me but no-one is prosecuted. One law for one section of society and a different law for another? It won't do.

Friday, October 16, 2009

The Wire

What does a retired university professor do with his time? He certainly spends a lot of time on the Internet reading the newspapers and his favorite blogs. He answers the telephone and fends off people who want to sell him insurance, double glazing, new kitchens and magazine subscriptions. He goes supermarket shopping with his wife. He has a break for coffee mid-morning and a break for tea mid-afternoon. He does at least 6 crosswords a day with his wife. He tries to write something on his blog. He listens to some music - keen on adagios at the moment. He puzzles over Bayesian statistics. He sporadically polishes brass doorhandles and fits new toilet seats. He edits his journal. He reads. Currently, in various degrees of the partially read are Planet Narnia, Terry Pratchett's Unseen Academicals, Keller's The Reason for God, My Grammar and I, The Saga of the Sydney Opera house, CS Lewis's The Discarded Image, David Wilkerson's Man Have I Got problems, FF Bruce's Men and Movements in the Primitive Church, Alec Moyter's Look to the Rock and Assist Me to Proclaim, the Life and Hymns of Charles Wesley.

And he watches television. My purpose in this blog is to review The Wire.

Claimed by some to be the best show on television for a decade or more, most Christians would avoid this show like the plague. The language is revolting and there are lurid sex scenes that would be a temptation for many. So this series comes with a health warning.

That said, I have watched all five seasons with the subtitles turned on, mainly because the African-American patois was unintelligible to me, but also because you need to know what is being said to follow the plot.

On the other hand this work of fiction is extremely moral. It teaches us that the heart of man is desperately wicked. Corruption permeates every element of society. It begins by showing how drugs have wormed their way into the fabric of society, so much that for portions of the community drugs represent the basic way of making a living. The drug culture is steeped in crime with murders and beatings being the commonplace consequence of imagined slight. The cops have the closest contact with the drug world, and guess what the cops are corrupt, indeed all branches of law enforcement: judges, lawyers, prosecutors, prison staff are all corrupt. The ordinary working man in the docks is corrupt; he also drinks too much. The church is corrupt. The schools are corrupt, the politicians are corrupt, the newspapers are corrupt.

There are some people who honestly want to make a difference. We see a couple of policemen who have been sidelined because they were incorruptible. We see a politician who really cares about his community. We see a police lieutenant who wants to police the city correctly, we see a newspaper man who not only understands the rudiments of grammar but also believes in the truth. But what happens is you either play the game or you die (or at very least are demoted). An ex-killer starts a boxing gym to attract young blacks away from drugs. He is kneecapped for his trouble. A teacher wants to befriend his pupils in order to teach them the basics of reading, writing and arithmetic. He is bullied into teaching to the test, supplying them with model questions and answers that will closely resemble the test. A honest editor wishes to expose a reporter who is fabricating stories; he is demoted. A senior policeman cuts crime by isolating the drug trade to a deserted area and turning a blind eye to drug supply to addicts. It allows social workers to get into help the addicts. The politicians find out and he is demoted, losing pension. Two honest cops game the system to get funds they have been denied to catch multiple murders. Politicians and senior policemen, themselves up to their elbows in muck discipline the cops and then take personal credit for the success. The DA cuts a crooked deal with a crooked defence lawyer to allow the prosecution of murderers to go ahead.

We are left with a straight policeman who is already compromised by youthful indiscretion and by an adulterous affair resigning from the force rather than join in the morass of decay.

The acting and production values are superb, but how people need a savior!

Thursday, October 15, 2009

New ways of doing trials

I met Eli Estey on a trip to MD Anderson in Houston. I found him to be a charming and thoughtful guy. He has now moved to the 'Hutch' in Seattle and has penned an interesting article entitled "Do commonly used clinical trial designs reflect clinical reality?" in the journal Haematologica.

We normally rely on randomized phase III clinical trials which compare two treatments using endpoints like overall survival, progression-free survival or time to next treatment. We rely heavily on p<0.05 which means that there is less than a 1 in 20 chance that any difference between the two could have occurred accidentally. In other words we are pretty sure that any positive result is not a false positive. In leukemia trials there is a tradition, which comes from St Jude's Memphis, that we inch forwards in our improvements. Childhood ALL is curable in the majority of cases. Treatment involves the use of several drugs in a particular order over a couple of years. Successive trials made small changes to the protocol that gave small improvements in survival. In order to be sure that these small improvements were not false positives the trials needed to utilize large numbers of patients so that a 'p' value of <0.05 could be obtained. Childhood ALL trials started with drugs that gave a high rate of complete remissions (vincristine and prednisone) so there was a good chance that adding more chemotherapy would improve things, but not by much. Hence, it was necessary to be certain that adding these new drugs did make a difference and were not false positives.

With adults, the problem is not that we are doing pretty well already, but that we don't cure very many at all. Therefore, our problem is not that we have too many false positives; it is that there may be drugs out there that help, but we reject them because we have too many false negatives.

The cure rate for CLL and adult AML is so poor that we are not really interested in drugs that make a small difference - we want agents that make a big difference - we should be willing to accept a higher risk of a false positive.

When trials are designed the numbers needed in each arm are partially determined by the power calculation. Traditionally an 80% power is required. What does this mean? It is actually the false negative rate. It means that one trial in five is discarding a treatment incorrectly because the negative answer was a false one.

Estey argues that this way of doing things is not clinically relevant. On the contrary there have been quite massive improvements in adult leukemia that did not come from these sorts of trials at all. He cites the value of imatinib in CML, CDA in hairy cell leukemia, arsenic trioxide and ATRA in acute promyelocytic leukemia and high-dose ara-C for core-binding factor AML as examples where the effect was so large that it didn't need an enormous trial to detect its value.

I raise this problem for CLL recently in this way. John Byrd recently reported that there are 107 different agents being studied at teh preclinical and clinical level for teh treatment of CLL. The typical phase III trial in CLL requires 800+ patients. There are simply not enough patients to test all those agent singly let alone in combination. WE must find a better way of doing things.

The better way that Estey proposes is the use of Bayesian statistics. Thomas Bayes (c. 1702 – 17 April 1761) was a British mathematician and Presbyterian minister, known for having formulated a specific case of the theorem that bears his name: Bayes' theorem, which was published posthumously. I have read the paper several times but I am none the wiser. Would someone please explain Baysian statistics to me.

The Bridesmaids

Monday, October 12, 2009

Living Stones - 1 Peter 2:4-8

Have you ever had that sinking feeling when something really valuable goes missing? You have mislaid your wedding ring and as you think back over all your movements you become convinced that it has gone into a waste bin. You have already riffled through the waste-paper baskets so now you must tackle the garbage bin. You empty the bin on your lawn and pull everything apart but it's not there and you begin to curse yourself that you didn't take care of it because your mind was on something else.

I remember the time when I was left minding my young son on a beach. My wife and her sister had taken my daughter for an ice cream and I was supposed to watch the toddler. I was engrossed in a book so I didn't see him wander off. When the women returned they noticed him missing. We ran up and down the beach looking for him. Had he run down to the sea and drowned? Had he been abducted by some childless woman or even worse a pedophile? We were panicking but eventually someone found him crying half a mile up the beach.

But they had not just mislaid the cornerstone - they had actually rejected it.

This wasn't just a mistake of the moment like when the computer asks you, "Are you sure you want to delete the whole PhD thesis?" and you click on "yes". This was a deliberate, well thought out decision. Nor was it a decision made out of ignorance. Years ago I was treating patients with a very expensive drug called IL-2. Sometimes we had to slow down the drip because of side effects with the result that it went past its sell-by date while there was still drug left in the syringe. The nurses, knowing that they could no longer give it to a patient through it away, whereas I knew I could still use it for laboratory experiments and was very cross. It wasn't the nurses' fault, they did not know better.

A politician has the answer to the current global financial crisis. You listen to him. His arguments are plausible. It means you have to change your ways. You have to give up some of the privileges that you have. But his arguments are cast iron and you know that the present approach is not working. Yet the past is familiar. You like your privileges. You don't want to change and in any case the fellow is probably a charlatan. You have heard some whisperings against him so you reject him. Then three days later, he rises from the dead.

That is the closest analogy that I can come up with. The Prime Minister tells us that we must continue to print money or the recovery will falter; we can start repaying the debt in a couple of years. The Leader of the Opposition says, "No, the debt is so large we need to start repaying it straight away." Who is right? It's a political decision. You might choose one way or the other. But if Gordon Brown had emphasized his views by walking on water that he had turned into wine you would tend to favor what he said about anything. (Not that I think Gordon Brown is the Messiah - far from it!)

The rejection of Jesus was a deliberate act by the rulers of the Jews. They had all the evidence they needed to accept him; their rejection was willful and wicked.

The IL-2 that the nurses rejected was precious to me and the stone that the builders rejected was precious to God. Diamond prospectors in Sierra Leone find a grubby stone that they chuck it away. The laborers don’t recognize it for what it is, but the foreman sees it and knows that it can be polished up and cut into a precious stone. Jesus uses this image of a stone to refer to himself and quotes from Psalm 118 in the parable of the tenants in Matthew 21:33-46 and Peter in his speech before the Sanhedrin in Acts chapter 4 explicitly states that Jesus is the stone "YOU" builders rejected who has become the capstone. In both passages, the first parabolically, the second explicitly, the Jews are being told that they have rejected the ruler of the Universe and that they too will be rejected. There is a play on words in Psalm 118 in the original Hebrew, which does not come through in any of the translations. The word we have as 'capstone' or 'cornerstone' could refer to the stone that holds an arch together or the stone that anchors and aligns adjacent walls as it is placed at the corner of a building. But in Hebrew the word for corner is used as a metaphor for the chief ruler. Jesus not only identifies himself as the Son who is sent as a final gesture to the wicked tenants – surely they will listen to him – but also as the chief ruler of the Universe.

Middle class areas like Bournemouth can't hope to support very good football clubs, so in recent years AFC Bournemouth has been near to bankruptcy. They had a new stadium built, which didn't help their finances. The stadium might be finished one day but at the moment there is seating on three sides, but the other end is a pile of rubble and is known locally as the Brighton Beach end. This is a jibe against the other large south coast resort. Whereas Bournemouth has seven miles of golden sands for a beach, our rival Brighton is all stones. Stones may be good for building with, but they are hopeless as a beach.

The passage we are studying today refers to us as living stones.

As you come to him, the living Stone — rejected by men but chosen by God and precious to him — you also, like living stones, are being built into a spiritual house to be a holy priesthood, offering spiritual sacrifices acceptable to God through Jesus Christ. For in Scripture it says: "See, I lay a stone in Zion, a chosen and precious cornerstone, and the one who trusts in him
will never be put to shame." Now to you who believe, this stone is precious. But to those who do not believe, "The stone the builders rejected has become the capstone," and, "A stone that causes men to stumble and a rock that makes them fall." They stumble because they disobey the message—which is also what they were destined for.

The message in this short passage is plain: [1] Jesus is the Living Stone, the cornerstone of our faith. [2] We are being transformed to be like him. [3] If we acknowledge this and obey the divine plan we will not be put to shame, but if we disobey we will come a cropper.

Have you seen the movie “The 300”? The legend has it that a visiting potentate asked to see the walls of Sparta – but Sparta had no walls. Instead the King pointed to his warriors, “These are our walls.” If you have been reading Bernard Cornwell’s books about Saxon Britain at the time of King Alfred you will have heard of the term ‘shield wall’. The warriors locked their shields together to form an impenetrable wall. If one man fell then one from the second rank immediately took his place. The British Square was made on similar lines. All have in common a united front – each individual subjecting himself to the common cause – each individual acting as one whole.

There never was a Good Samaritan. It was just a story Jesus told. But it was a story with a message. Had he been following Dawkin’s rules he would have preserved his own DNA, but he had a fellow feeling for someone who was his traditional enemy. We hear of soldiers in Afghanistan being killed by a second bomb when they went back to rescue a fallen comrade. Why did they do it despite the danger? It is because the teaching of Jesus has so permeated our culture. As living stones we are locked together in the walls of a Holy Temple held together by the mortar of love.

Not just walls; we are a Holy Priesthood. What does a Priest do? He speaks to God and he offers sacrifices. In the theocracy of Israel certain individuals were set aside to be priests, but the New Testament has nothing of this. We have one High Priest (after the order of Melchizedek who has made sufficient sacrifice for every sin) but no other intermediary is needed. Nowhere in the New Testament is a holder of a church office designated a priest. All Christians are priests and Holy Priests at that. Holy in the sense that we have been set apart for God, and priests in that we may speak to Him with no-one having to make fresh representations on our behalf.

But what are the sacrifices that we must make? Not the blood of lambs or bulls as in the days of old, but Spiritual Sacrifices acceptable to God. What can I give him poor as I am? wrote Christina Rosetti. “Give my heart” was the answer. Not just the anatomical heart, but my total commitment. Were the whole realm of nature mine, that were a present far too small, wrote Isaac Watts. Love so amazing, so divine, demands my soul, my life, my all.

I like cricket. There was a time when I would spend hours in the sun listening to the thwock of leather on willow punctuated by a splattering of polite applause, but my time is more precious now. Giving up playing the game was painful; giving up watching is worse. But first things must come first.

Every element of a Christian’s life must reflect his commitment. The Christian life is not just a hobby, to be fitted in when you have a spare moment, but communion with the Holy Spirit pervades the very warp and woof of existence. For me to live is Christ.

‘Now to you who believe this stone is precious’ is an incorrect translation; the NIV has interpolated words that are not in the Greek. ‘Now to you who believe is honor’ would be more accurate – it is the honor due to Jesus bestowed upon us. But to those who do not believe…

Stones that are not incorporated into a building can trip us up. They can do worse; they can fall on us and crush us. Let’s not strain the metaphor too far. If you disobey the message then there is no ultimate honor or joy.

Have you ever been in a maze? Sometimes you will hit upon a system; such as always turn right at the first opportunity, which will take you a long way. You may seem to be making progress – you are on a broad highway to success, but suddenly you come upon a dead end. There is no way out. Even worse you may stumble into a deep pit from which there is no escape.

The trouble with wrong turnings is that they are not labeled ‘wrong turning’ and they may well seem the easiest way to go. The more people who take it the broader the path will be. Following the crowd does not guarantee it’s the right way. Remember the film ‘The Poseidon Adventure’? Most people were following the authority figure the wrong way, but they would not turn back.

We would be in a proper pickle had not God revealed Himself in the Bible. We may look at the creation and be sure that there is a God. We might look at the laws of physics and know that He is a God of order, but without the Bible we should not know that he is a God of love.

The Living Stone is both salvation and danger; to those who believe salvation; to those who reject it destruction. They stumble because they disobey the message. That is their human responsibility, they bring destruction on themselves. ‘Which is also what they were destined to do’; God is not taken by surprise. He knows that some will reject the message; He even knows who. Why some are not rescued is a matter for God’s sovereignty. Destined for destruction? I cannot fathom why, but the last person with the temerity to ask God face to face was met with the answer “Where were you when I laid the earth’s foundation?” I would not dare to outguess God.

Transplants - a conclusion

So, what is the conclusion? Who should have a transplant and when. As usual, the best results are achieved in people who don't need one, and transplanters delight in doing these because it makes their results look good. However, all transplants have a risk of killing the patients, and the procedure is not so safe that it should be performed if it is not necessary.

Perhaps the most obvious group to benefit are patients without co-morbidities who need treatment but have del 17p. Even in this group there is probably a need to debulk the disease before the transplant and how to do this is controversial.

The second group is for patients who have failed to respond to a fludarabine containing regimen or relapsed following treatment with one within 12 months.

The only other sensible advice is not to muck around with other regimes like PCR, cladribine or various experimental treatments. If a transplant is necessary it should be performed as soon as the criteria are met.

There is no information about which reduced conditioning regime should be used, but almost certainly a non-ablative treatment is preferable to an ablative one. T depletion is still in the melting pot. Almost certainly it is better to go to an experienced unit that has performed many previous transplants in CLL (not one that has specialised in other diseases).

Sunday, October 11, 2009

Specific transplant problems in CLL

Transplants are more likely to be rejected in CLL than in other conditions. The rejection rate in follicular lymphoma is between 3 and 6%. For CLL it may be as high as 20%. One study from Nebraska showed that the the graft failed to take completely in 35% of cases. This particularly a problem with T-depleted grafts - rejections of close to 20% compared with less than 10% with unmanipulated grafts. Factors that might play a part in this are the level of CLL infiltration in the marrow and a deficiency of host dendritic cells.

Another specific factor for CLL transplants is prior immunodeficiency. 60% of non-relapse deaths are due to infection. Patients who have had prior fludarabine or alemtuzumab are particularly susceptible.

For patients with mixed chimerism (both donor and graft cells are present in blood or marrow) and especially if there is evidence of persistent disease, donor lymphocyte infusions are indicated, though they are usually ineffective in progressive disease. Graft-versus-host disease is of course a risk of DLI and they have found greater favor with units using T-depleted grafts.

Another particular feature of CLL transplants is the occurrence of late relapses. One possible reason for this seems to be the existence of the CLL in sanctuary sites that do not communicate with blood or marrow - blood and marrow being the sites that are tested for minimal residual disease. Imaging studies for lymph node involvement are therefore necessary post transplant before declaring cure.

Saturday, October 10, 2009

What are the alternatives to transplantation?

In patients who are fludarabine refractory or have a p53 dysfunction the available treatments are limited. The first drug that comes to mind is alemtuzumab (Campath). Although Campath does not require intact p53 to kill CLL cells, it is very poor at eliminating bulky disease. Why this should be is unclear, since in the first |Lancet paper on the treatment of two patients with CLL with Campath, bulky disease was not a problem. However, Campath is made differently now and it may be that the new system is not as good at attaching sugars to the molecule. Hence the new alemtuzumab may be ineffectively glycosylated. A new version of Campath is being developed.

Another drug that deals with p53 deficient CLL cells is high dose steroids (either methylprednisolone or dexamethasone). These drugs also deal with bulky disease, but they are likely to produce severe steroid side effects, such as high blood pressure, fluid retention, alteration in body shape (a melon on cocktail sticks), thin skin, thin bones, diabetes and most important in this context, immunodeficiency.

This is why many doctors are reluctant to combine high dose steroids with alemtuzumab. Fungal, viral and bacterial infections are all likely and must be guarded against. Prophylactic cotrimoxazole (either Bactrim or Septrin) is needed to prevent pneumocystis, aciclovir (or similar) to prevent herpes simplex and zoster, and one of the many antifungals to prevent candida and aspergillus. Twice weekly screening for reactivated CMV is also necessary.

However, in my experience, when used in specialized centers this is the most effective treatment available.

There are advocates for high dose steroids with rituximab and some evidence that this combination may also be effective in bulky fludarabine resistant disease. We await a head to head comparison.

Lenalidomide (Revlimid) is reported to be effective in drug resistant CLL though the numbers of drug resistant and p53 defective patients treated in clinical trials is still very few. The other agent with this property is Flavopiridol, but this is notoriously difficult to administer and available in very few centers.

Clinical trials of other drugs that may be useful, like acadesine, are continuing, but as yet treatment for this difficult problem remains uncertain.

wedding pictures

The happy couple should be returning home today.

There were one or two intruders on the party

Some of them making real pigs of themselves.

One last look at the venue.

Friday, October 09, 2009

Transplants: ablative or non-ablative?

Continuing from yesterday. Should one go for an ablative or non-ablative transplant? Ablative means using sufficient chemotherapy to destroy as much of the leukemia as possible, while not worrying about how much bone marrow is destroyed because it is going to be replaced by the graft anyway; non-ablative means using immunosuppressive drugs to enable the marrow to engraft and relying on graft-versus-leukemia to destroy the tumor.

The paper in Blood has looked at the results on ablative transplants published by the European Bone Marrow Transplant Registry (EBMTR) and the International BMTR. The long term overall survival was 46% and another 46% died of the treatment (the remaining 8% died of relapsed leukemia). The best results came from the Dana Farber at Boston with only 24% treatment related mortality and 55% overall survival at 6 years. However, none of the Boston patients had fludarabine refractory disease. The median age at transplant ranged between 39 and 48 at different centers.

In the total experience from Europe and America, if an unrelated donor was used, the results were less good, with only 33% overall survival at 5 years.

Non-ablative transplants can be used in older patients - up to 72 years of age, with a median age of between 50 and 57. This type of transplantation is fairly recent, but we do have 7 reports of studies from different units (Seattle, Houston, Boston, Germany, Spain and the UK) on both sides of the Atlantic involving 346 patients.

The degree of myeloablation and immunosuppression varied between centers with Seattle being least for both, Spain being the most myelosuppressive and the UK the most immunosuppressive. Only Seattle has 5-year follow up and they report 23% treatment-related mortality and 50% overall survival similar to Boston's figures on ablative transplants, but 87% of the Seattle patients were refractory to fludarabine and the patients were older. The other studies are less mature, but treatment-related mortality ranged from 16% to 34% and overall survival from 48% to 72%. One suspects that these figures will deteriorate as time passes.

I have interpreted these figures a little. Generally they don't talk about treatment-related mortality, but non-relapse mortality to take account of the fact that some patients commit suicide, others have heart attacks and others are run-down by Greyhound buses. However, most non-relapse deaths are caused by the treatment - even suicides.

One of the reasons that patients commit suicide is that they can't live with chronic graft-versus-host disease. This was least common in those groups treated with more immunosuppressive drugs like alemtuzumab (in the UK) and ATG (in Germany). The worry is that more immunosuppression means more relapses. The data are not mature enough to be sure of this.

So far my conclusions are that about half of CLL patients can expect to be cured by a transplant. Reduced intensity conditioning extends our ability to transplant patients who are older - up to the early seventies - and have co-morbidities. The exact form of conditioning that should be used is still being used, but even among survivors there is a high risk of both acute and chronic graft-versus-host disease which may be very unpleasant.

Transplantation in CLL may justifiably be referred to as a work in progress.

Weddings again

Why is the price to dry clean a wedding dress seven times the price to dry clean an exactly similar ballroom gown?

Are there gangsters involved?

Any suspicious characters among this lot?

Butter wouldn't melt in their mouths.

Thursday, October 08, 2009

wedding pictures

My mother eventually arrived.

There weren't really 29 pages to my speech. This was just to scare them!

Who needs a transplant?

I think another article about bone marrow transplants is due. A paper has appeared in Blood detailing the European experience in CLL, so it is timely to review this and to reacquaint readers with the issues.

First off, we don’t call it ‘bone marrow transplantation’ anymore, because we quite often take the graft from the blood. We tend to talk about stem cell transplants, though this is confusing now that infusions of embryonic stem cells are being used for some neurological diseases. The authors entitle their paper “Allogeneic hematopoietic cell transplantation for chronic lymphocytic leukemia: ready for prime time?”

Note the ‘allogeneic’. 25 years ago when I started in transplantation, we used to think that autografting; taking the donated marrow from the patient him (or her) self; would avoid the nasty complications of rejection and graft-versus-host disease. However, nobody is cured by an autograft. Tom McCune, who for a long time was thought to be the one patient to be cured in this way, has relapsed. I had a patient who went 13 years after an autograft and died of something else without relapsing, but I suspect he would have relapsed over time if he hadn’t got lung cancer.

So, let’s be clear, the purpose of allografting is to cure. How does it cure? Well, it’s not by allowing us to give more chemotherapy and then rescuing the damaged marrow with a graft. We used to think that was what we were doing, and the superiority over autografting was because the autograft would always be contaminated by residual disease; hence the fashion for laundering the marrow with monoclonal antibodies. However, allografts are also superior to transplants from identical twins whose marrow was completely clean.

No, it turns out that the efficiency of an allograft depends on its ability to mount an immune attack on the leukemia – the so-called ‘graft-versus-leukemia’ effect. This being so there was no longer any need to give the whopping doses of chemotherapy or radiotherapy, just enough immunosuppression was needed to ensure the graft would take. These days most transplants use ‘reduced intensity conditioning’ and because of this we can do them in increasingly older people. I used to joke that my ambition was to get so old that nobody would think of doing a transplant on me. I have a way to go as they are done routinely up to the age of 70 and exceptionally in people who are older. This is good news for patients with CLL since the median age of presentation is 72, and though some patients present at an earlier age (my youngest is 21) and older patients can often be managed to the end of their natural lifespan with palliative chemotherapy, nearly 50% of patients fall within the age when a transplant is feasible.

So who should have a transplant? I guess the answer is that bit is a judgement issue, since there are no randomized clinical trials to give us an answer. Even reduced intensity conditioning allografts are hazardous. So like matrimony, transplantation is not to be enterprized, nor taken in hand, unadvisedly, lightly, or wantonly, to satisfy man’s carnal lusts or appetites, like brute beasts that have no understanding; but reverently, discreetly, advisedly, soberly and in the fear of God, duly considering the causes for which transplants were ordained.

Transplantation should be reserved for patients with poor-risk disease, among them, those who are fludarabine refractory. The outlook for these patients is dismal. Before the availability of monoclonal antibodies, the overall response rate for the first salvage therapy after relapse from a fludarabine-induced remission was only 22% with a median overall survival (OS) of 10-12 months, and even though alemtuzumab is licensed for fludarabine-refractory patients, the response rate is only 33% and the median OS is only 16 months. FCR will produce a higher response rate in fludarabine refractory patients (58%), but the length of remission is probably not very long. I say probably because the paper does not tell us, though the more intense regimen of OFAR gives an overall survival of less than a year in this situation.

Define ‘fludarabine refractory’. This means that there was no PR or CR following treatment with standard doses of fludarabine or that if there was a response, progression occurred within 6 months of stopping treatment.

The major reason for failing to respond adequately to fludarabine is loss of p53 activity. p53 is a protein discovered more than a quarter of a century ago by Richard Lane at Dundee in Scotland. It is called the ‘guardian of the genome’. Its function is to detect damage to DNA and assess whether the damage is reparable. If it is, then damage repair is initiated, if it is not, then p53 starts up a program that results in cell death. Most anti-cancer drugs (including fludarabine, chlorambucil and bendamustine) use p53 induced apoptosis (programmed cell death) to kill tumor cells. We can detect that p53 has gone missing with FISH, since the p53 gene resides on the short arm of chromosome 17. The technical term for those who have lost it is del 17p.

Don’t we have two chromosome 17s? Isn’t the gene for p53 on the other chromosome 17 sufficient? In some cases it may be. We have certainly seen some del 17p patients who have a benign disease; these usually have mutated IGHV genes and do not require treatment according to the IWCLL guidelines. However, whenever a patient with del 17p requires treatment according to the IWCLL guidelines, the other chromosome 17 carries a p53 gene that codes for a disabled p53 molecule. Such patients are refractory to fludarabine and almost always refractory to FCR.

In clinical trials around 5-7% of patients presenting for treatment for the first time have del 17p, but in trials of patients presenting for salvage treatment following relapse, the incidence of del 17p is about 30%.

So who needs a transplant? Anyone aged 70 or under without significant co-morbidities who needs treatment and had del 17p or who is refractory to fludarabine.

Tuesday, October 06, 2009

Monday, October 05, 2009

The Wedding

As if my cancer weren't enough, calamity piled on calamity as we prepared for my daughter's wedding. Her main preoccupation was writing her thesis for her PhD. She was up writing for the whole night on the Thursday before the Saturday ceremony and I had to deliver it for binding during Friday lunchtime.

Early in the week I walked into the tailgate of my car and scarred my beautiful facial features which would have made the photographs even worse than we expected them to be (I will post them later). The weather was holding up though; we have had an Indian summer this September. The dresses for bride and bridesmaids seemed to be going well and the flowers to decorate both the reception and the church were being assembled according to plan. The wedding suits were another matter. In order for all the suits to be co-ordinated, the groom had gone to Moss Bros who have branches in every large town. However, something didn't work with the communication and as the ushers and groom's family turned up at various branches of the company, nobody knew anything about the order. Even on the final day one of the ushers had striped trousers instead of plain black. The correct uniform had to be couriered in from another branch. The problem is that Moss Bros have no competition nationally and their management has become slack. Tesco should branch out and compete with them.

We were watching the weather forecast carefully. After high pressure had been sitting over the British Isles for most of the month, a depression was inching in from the Atlantic. 60 mph winds were forecast with rain moving in from the north. Since the main charm of the venue for the reception was the riverside aspect with swans, ducks and geese, this did not bode well.

Then a supermarket delivery truck took off my wing mirror as it tried to negotiate a narrow street. What else could go wrong?

On the Saturday morning the skies were blue with just a little cloud. The bridesmaids look delightful in their ivory colored frocks with burgundy sashes. My suit seemed to fit. My wife looked charming in her new outfit. The cars appeared. These were replica Model A Fords with running boards. I half expected to see gangsters with Tommy-guns appear.

We loaded my four granddaughters into their limousine together with my wife and daughter and watched them depart. The weather was still dry though a little windy. My daughter then came out. Dressed in ivory with a silver headdress imported from America she looked like a queen. We were early as we boarded the second car, so the driver took us on a long route via the sea front. Passers-by waved at the strange wedding car ands we waved back. At the church the little bridesmaids aged 6 to 11 lined up behind us and the doors opened before us. We glided down the aisle to the strains of the Pachelbel Canon in D played on the flute.

The service opened with "Love Divine", then my grandson Alex, aged 14, read from Philippians 4:4-8.

Rejoice in the Lord always: and again I say, Rejoice.
Let your gentleness be known to all men. The Lord is at hand.
Do not be anxious about anything, but in everything, by prayer and petition, with thanksgiving, present your requests to God. And the peace of God, which passes all understanding, shall guard your hearts and minds in Christ Jesus.
Finally, brothers and sisters, whatever is true, whatever is noble, whatever is right, whatever is pure, whatever is lovely, whatever is admirable—if anything be excellent or praiseworthy—think about these things.

The vows were made - a mixture of old and new. She didn't promise to obey, but she did vow to submit to her husband (a better translation). As soon as we got to 'who gives this woman?' I could sit down - very welcome because my legs were swelling up. We sang "Amazing Grace".

Our Pastor, Chris Kelly gave the address. He was excellent - putting people at their ease with tact and humor but not neglecting to explain the gospel. 10 rules for wives from the 1950s cause amusement and some indignation from the women present only for them to be mollified by 12 more PC rules from the 1990s. But from the reading Chris gave the couple just three instructions: Be Joyful, be gentle and be thankful.

The we sang "Guide me O thou great redeemer" before we trooped out to sign the register.

The bride and groom marched out to Jeremiah Clark's Trumpet Voluntary played on the Allen organ. The congregation of about 170 snapped us with their phones and cameras as we processed.

The gangster-cars took us out to Sopley Mill. We were the 52nd wedding party that they had catered for this year. The grounds are their chief feature but unfortunately the weather was closing in. We had hoped that our guests could wander around the grounds in the sunshine, and examine the menagerie of rabbits, guinea pigs and rare breeds of fowl, but it was getting too cold.
So instead we guided the 86 of them up the stairs to a champagne reception on the first floor. In the meantime my son David arranged for select groups to go down and be photographed on the lawn. This was all working well until we noticed that my 89-year old mother was missing. Apparently, they had missed a turning and the 10-minute journey from church to reception had so far lasted 70 minutes. Thankfully, they had a mobile phone and David was able to guide them to Bournemouth airport and go and collect them from there.

So to the meal of smoked salmon, lamb shank, and strawberry cheesecake, which was well received and then to the speeches. As father of the bride I went first. Here is what I said:

For those who don’t know me, my name is Terry. Diane and I would like to welcome you all to Angela and Stuart’s wedding.

We would especially like to welcome Alec and Sheila, Stuart’s parents as well as his brothers and the rest of his family and friends. We know that you have come a long way and we trust that you will enjoy your time on the south coast. Welcome also to members of our family, to Angela’s friends from school and work, and to our friends from church.

I want to thank all those who have helped to make this day special for Stuart and Angela, particularly Chris who took the service, Rosa the Registrar and Mary who did the flowers in the church. Thanks also to Best Man Gavin, Hannah, Amelia, Evie and Charlotte who were beautiful bridesmaids, Alex who read so well, and Peter, Jack and Richard who with Alex acted as ushers.

We have also to thank Sopley Mill who have put on this splendid spread. Elizabeth of Southbourne who made the dresses for bride and bridesmaid, and Alison Florists of Charminster Road who did the flowers that decorate the room here. For anyone who wants an idea for a start up business, I recommend that they go into dress suit hire. There is clearly a gap in the market. Your only competitor would be Moss Bros, whose management is so poor that they would fold if they had any competition.

One of my proud duties is to commend Angela to you. I hardly know how to begin. When she achieved the top First Class Honours degree from Oxford it was the culmination of a brilliant academic career at school and university. Angela has always won prizes. When she was very little she won an art prize. Grade 8 and a performance certificate for both piano and clarinet, it seemed an insult when music was the only GCSE that she didn’t get an A star for. She was also Dorset long jump champion and Dorset young scientist of the year when she was at school. Now here she is looking very beautiful in white like someone out of Lord of the Rings (no, not Gandalf, nor Gollum – I was thinking more of Galadriel – the part played by Cate Blanchett). When Stuart put the ring on her finger, I half expected that she would disappear!

Angela is a very determined person. If she sets her heart on something she is sure to get it. When she thought about getting married she put an advert in the local paper saying, “Husband wanted” She had 117 identical replies all from women saying, “Please take mine!”

Fortunately, that was not necessary as she met Stuart. We welcome Stuart into our family. Stuart is a great sailor. I believe they are going on a boat for their honeymoon. Just, please be careful as you go round Cape Horn. So he won’t get bored on board I have leant him my complete collection of Patrick O’Brien’s Master and Commander books. Seventeen volumes, I think.

October 3rd is a very auspicious day for getting married. On October 3rd 1899 The Boer War began. On this day 1928 the Chicago Taxicab War started with two Yellow Cabs being blown up. In 1942 the Germans launched the first V2 rocket on October 3rd and ten years later on the same date the first British atom bomb was exploded. In 1968 there were street riots in Mexico City and in 1975 it was the Thriller in Manilla when Muhammed Ali fought Smoking Joe Frazier, then in 1993 it was Black Hawk Down – the first Battle of Mogidishu in Somalia started.

It is hardly surprising that the first SOS was sent on October 3rd 1906.

I was despairing in finding anything about marriage until I came up with October 3rd in 1995 OJ Simpson was acquitted of killing his wife.

Then at last a successful marriage: In 1990 East and West Germany were reunited!

My next task is to give sage advice on the subject of marriage to the happy couple garnered from 42 years of experience.

This is what I have learnt. Marriage is the place where you get forgiven even when you don’t deserve it.

So Stuart, here is my advice: Apologise – even when you don’t know what you have done. There is no point in denying it. ‘Fess up straight away. Getting forgiven is much better than fighting, and what are you going to do if you win?

Ogden Nash put it well: To keep your marriage brimming; With love in the loving cup; Whenever you’re wrong admit it; Whenever you’re right, shut up.

Marriage is to a man’s advantage. Married men live longer than single ones, (no it’s not true that it just seems longer) but married women have shorter (though more exciting) lives than their single sisters.

Marriage is a wonderful institution. But who wants to live in an institution?

Shakespeare gave us the best description:

Let me not to the marriage of true minds
admit impediments. Love is not love
which alters when it alteration finds,
or bends with the remover to remove:
Oh, no! It is an ever-fixed mark.
That looks on tempests and is never shaken;
it is the star to every wandering bark,
whose worth's unknown, although his height be taken.
Love's not Time's fool, though rosy lips and cheeks
within his bending sickle's compass come;
love alters not with his brief hours and weeks,
but bears it out even to the edge of doom.
If this be error and upon me proved,
I never writ, nor no man ever loved.

Finally, to get back to Angela – as some of you know she wants to be a haematologist, and one of the main concerns of haematologists these days is the stem cell. I’m not sure that I approve of embryonic stem cells when it seems that you can obtain from the bone marrow stem cells that can be coaxed into turning into whatever kind of tissue you want for a spare part – whether it is kidney, heart, liver or brain. I am sure that this was what God had in mind when He took a bone from Adam to make Eve.

But where should he take the bone from? He could have taken it from the skull, but that would have given the impression that he wanted Eve to rule over Adam, He could have taken in from Adam’s heel – but that would give the impression that she could be trampled underfoot. So he took a rib. From his side to show that they were equals, from under his arm, so that he would protect her, and from next to his heart to be loved by him.

Ladies and Gentlemen Please raise your glasses to toast the Bride and Groom.

We finally finished about 8-30 pm. I was too tired to watch the football on television.

The rain stayed away until this morning, but then it poured.

My health

A lot of people have been asking about my health. I continue to improve after stopping the chemotherapy. Remember, before the operation I had no symptoms. I lost 21 pounds after the operation and the chemo, which lasted together with the recovery time after the operation a full 6 months, laid me so low that I could hardly get out of my chair some days. I have now regained 12 of the 21 pounds and to look at me you would think I was very well.

I managed to survive the wedding very well, although I was very tired yesterday. I still have some odd aches and pains - especially at the site of my line insertion. I continue on the warfarin. I managed to catch my forehead on the tailgate of my car and inflicted a large cut. This bled profusely and covered my face with gore. Scalp wounds always bleed but the anticoagulants enhanced it. The wedding photographer will have to PhotoShop all the pictures.

The peripheral neuropathy is slowly improving but I can't pick up banknotes from the floor and I didn't notice that my favorite shoes were letting in water.

My major problem is swelling of the ankles. This has been investigated in the past and no cause found. Since my autonomic neuropathy gave me postural hypotension I have stopped my blood pressure tablets and one of those was a thiazide diuretic. I took a furosamide yesterday and lost 3 pounds. Obviously, I was concerned about recurrent lymph nodes or extension of my DVT. but the quick response to a diuretic makes these unlikely.

All in all, I feel about 90% as well as I did when all this started and when I get down the gym I should make up the last 10%.