Arsenal's season over

A series of enthralling football matches, mostly involving Arsenal, has ended. There are three major competitions in British football (soccer, for my American readers). The oldest of these is the FA Cup, a knockout competition entered by almost every football club in the country, but almost always won by one of the 'big four', Arsenal and Chelsea (both from London), Liverpool and Manchester United. Then there is the Premier League, a series of 38 matches where everyone plays everyone twice (at home and away). The top four clubs (and yes it is the same four) get to play in the Champions' League the following season. This is a mixture of league and knockout matches played between the leading European clubs. This year, like last year, three of the four semi-finalists will be English clubs.

Until fairly recently all four clubs were possible winners of all three competitions. Arsenal were leading the Premier League by five points when they were drawn to play Manchester United (who were second in the league) in the FA Cup. It was a match that fueled expectations of high drama in the spectators. These two clubs undoubtedly play the most attractive football, possibly in the world. They are built around two very different personalities.

Sir Alex Ferguson, the Man U manager, is a Scotsman in his mid-sixties who played centre forward for Glasgow Rangers when he was young. He has been there for more than twenty years, having resurrected a club that had fallen on hard times since the glory years under Sir Matt Busby, the legendary manager at the time of the Munich air crash of 1958 that killed some of the greatest football talents that England has ever seen. In an era when television money has drawn the best footballers from around the world, Ferguson has attempted to keep an British backbone to his side, but even his team of the 1990s that included Beckham, Scholes, Giggs, Butt, Keane, Irwin, Pallister, Sheringham, Bruce and the Neville brothers was enlivened by such foreign stars as the sublime Frenchman, Eric Cantona, the ugly Dutchman Van Nistelrooy and the great Dane, Peter Schmeichel.

The Arsenal team that Arsene Wenger inherited a decade or so ago also had a British backbone. The back four of Dixon, Adams, Bould (or Keown) and Winterbourne were drilled like Grenadier Guards as they operated the offside trap. Arsenal were difficult to score against. The fans on the terraces would chant "One-nil to the Ars-en-al" to enshrine the defensive attitude - they were seldom scored against and only occasionally scored. Another touchline chat was "Boring Arsenal." The British backbone has long since disappeared and Wenger has filled his team with foreigners, especially Frenchman or players from former French colonies. Among Arsenal favourites have been Patrice Vierra, Robert Pires and Thiery Henry, but they represent another strand of Wenger's thinking; he sells players who reach the age of 30 and prefers to employ youngsters. One pundit's view, "Kids will never win anything," was belied by the 1999 team of Manchester United which won all three competitions. The influx or foreign players and Wenger's more intellectual approach has produced a game with quick interpassing, imaginative running off the ball, and the daring of the unlikely that is reminiscent of French Rugby.

The Man U v Arsenal cup-tie was eagerly awaited, not least because of the contrast in attitudes in the two clubs. In the event Manchester slaughtered them.

In many ways Arsene Wenger is an attractive character and Alex Ferguson an unattractive one. After a match between these two great teams there is seldom a touch of the hands between them as they studiously ignore each other. Wenger is more cerebral personality. His decisions are clearly thought through and he has been planning his team for a long time. He takes in consideration the need to build a new stadium and how that impacts on his ability to buy players on the open market.

Ferguson is more of a bully-boy. The famous incident where he threw a football boot at David Beckham and his well publicised spat with certain racehorse owners have not given a good impression. However, he is known as a disciplinarian and won't stand for misbehaviour from his young charges. On one occasion he burst in on a party organised by Lee Sharpe and attended by Ryan Giggs. Giggs was disciplined and Sharpe sacked (his career never recovered). Jap Stam was sold when he had harsh comments for Sir Alex in his autobiography. Beckham's lifestyle was inimical had he had to go, and when the Manchester youngsters organised a party recently which resulted in a (false) charge of rape, Sir Alex came down on them like a ton of bricks.

Contrast that with Wegner's attitude to his captain, William Gallas, after the match at Birmingham. With a minute to play Arsenal were leading but conceded a penalty from which Birmingham scored. TV replays afterwards indicated that this was a mistake by the referee. Gallas, instead of stationing himself on the edge of the penalty area in case of a rebound, marched to the centre circle and sat down in a colossal sulk that lasted until five minutes after the match had finished. Ferguson would have stripped him of the captaincy, Wegner, in complaining about the penalty, seemed to be saying, "Move over, William, I'll come and sulk alongside you."

Arsenal's season began to collapse. They had to play Chelsea and then Liverpool three times, once in the Premier League and twice in the Champion's League. In each game they took an early lead, but then bottled and lost. So the three English clubs in the Champions' semi-finals will be Man Utd, Liverpool and Chelsea. Arsenal's remaining chance of silverware this season, was to beat Manchester United yesterday.

For the first 25 minutes Arsenal dominated the game with Belorussian, Alexander Hleb, prominent and they should have scored, but attacker Adebayor was strangely out of touch, while Man U goalkeeper, Dutchman Van der Sar, had more difficulty keeping out deflections from his own defenders. At the other end United were creating chances for Wayne Rooney but out-of-favour German goalkeeper Jens Lehmann pulled off splendid saves. By half time there was no score, but shortly after the break, Adebayor headed home a goal for Arsenal. TV replays later showed that Adebayor had in fact slapped the ball in with his hand, but the referee missed that.

Although Arsenal were now ahead recent experience gave no confidence that they could hold on to a lead. Sure enough, five minutes later William Gallas conceded a penalty by handling the ball in his own penalty area. Player of the season Cristiano Ronaldo, the young Portuguese star, scored with a twice taken penalty and later Owen Hargreaves won the match for United with a well taken free-kick. United will be difficult to stop now, though they have to play Chelsea away and Chelsea could still catch them.

So what is wrong with Arsenal? With a name like Arsene, Wenger seems wedded to the club. He regards English players as overpriced and his team yesterday comprised two from France, two from the Ivory Coast, and one each from Germany, Spain, Cameroon, Togo, Holland, Belarus and Brazil. United on the other hand had six British players. While Sir Alex could bring international stars like Tevez, Anderson and Giggs on as substitutes, Arsene could only call on youngsters. Arsenal have been hit by injuries, but United have had their captain, Gary Neville out for 13 months and have seldom been able to call on the services of their French striker, Saha. Chelsea have similarly been deprived of major players through injury. The fact is that Arsenal do not have enough players of quality. Large squads run the risk of dissatisfaction among players who do not play regularly - Liverpool and Tottenham have found this to their detriment - but United seem to manage the rotation system better than any other team. Compared to their rivals, Arsenal have too small a squad.

In the last part of the season they have been at the butt end of many poor refereeing decisions, but in truth, these even themselves out during the course of a year. It's how you react to these that determines the long term outcome. Arsenal have reacted poorly. Even yesterday, Wenger was hinting at a conspiracy amongst referees against him, when as far as yesterday's match was concerned he was lucky that the Arsenal goal was not disallowed, and both the Arsenal infringements that led to United's goals were obvious and indisputable. Someone needs to say to him, "Get over it."

Most foreign players seem to be Roman Catholics. They cross themselves and touch the playing surface as the enter the arena, as if dedicating their performance to God. They then cheat. There are huge amounts of money at stake. These players often earn at least £40,000 a week and sometimes three times that. One practice has become so commonplace that no-one seems to take exception to it. When awarded a free kick, they throw the ball ten yards nearer the goal while the referee's back is turned. Yesterday Ces Fabregas, one of the best players in the world, was awarded a free kick in his own half. As the referee was running back, Fabregas threw the ball into his opponents' half and took the free kick from there. It was unnecessary because he didn't even kick the ball forward and he gained no advantage from it, but cheating has become so endemic in the game that players cheat even when there is no benefit to be gained.

A new page 1

What Fiona noticed first were his hands. They were not as she had remembered them. The fine, long fingers were calloused and grimy. His nails, once neatly manicured, were split and ragged, and as he took her hand she was conscious of how coarse and hardened were his palms.

“Fiona! How pleasant to see you!” His voice had not weakened, nor had that precise accent changed after ten years in the Somerset countryside. “You must come and have tea. I have some Darjeeling set by for just such an occasion.”

He was wearing a green check shirt and brown, baggy trousers drawn in at the waist by an MCC tie. His black rubber boots were caked with soil. A straw hat shedding raffia was pulled forward to shield his eyes from the glaring sun. As she observed his weather-burnt face and his watery blue eyes she began to suspect that she was on a fool’s errand. He was an old man!

Twenty years ago when she had first met him he had seemed a god. Neat and precise in his movement, in control and apparently knowing everything, he had surprised her by his friendliness and approachability. Later she came to recognise that this was no affectation put on by an older man to impress and possibly seduce a pretty young doctor, but his constant attitude to all students, whether teenage medics, visiting specialists in their fifties from Cairo, Baghdad or Buenos Aires, or, as she had been, registrars in their twenties.

In any case he was not an attractive man, in that sense, even then. His large hook nose and long face with receding hairline could be called distinctive but not handsome. As he led her inside the thatched cottage and hung his hat on a peg just inside the kitchen door she noticed that his hair had now completely gone apart from occasional single grey wires arising from a scalp with obvious solar keratoses and probable early squamous carcinomas. His ears had also increased in size since she has seen him last and his missing scalp hair appeared to have taken refuge there.

He flicked on the switch of the electric kettle. “Teapot in the left-hand cupboard. Tea on the shelf below it. You’ll find the cups on the dresser. The refrigerator is under the working surface. Don’t forget to warm the pot.” He took off his boots to reveal bright green, woollen socks, and left the kitchen by the door into the house.

Fiona busied herself making tea. She remembered that the professor liked it strong and with lemon. Her mind went back to the many occasions she had sat with him in his office, sharing the double-headed microscope, as he pointed out the taxonomic differences between the different leukaemias. Always such discussions would be preceded by a tea ceremony like this. It was a crazy conceit that she could solve her problem by going back to her roots and now she feared that this old man would be physically and mentally unable to invoke the past. Perhaps she had better make it a simple social call and reminisce about old times and old friends. They always said that you couldn’t go back. Time to stand on her own feet and stop leaning on a man.

School cheats

In today's papers there is outrage that a local council here in Dorset has spied on a family. The story is that this family was about to move house, but wanted their children to stay at the same school. Last September the youngest child was about to start school so they wrote to the council asking whether it would be possible for their younger daughter to attend the same school as her older sister. This was a question because they were intending to move a couple of miles out of the catchment area.

Schools are usually good about this sort of thing as they don't like to disrupt the continuity of children's schooling if it can be avoided and like to accommodate parent's wishes not to deliver their children to different schools in the mornings The local school authority agreed that it would be fine if they had not moved before the school term began.

So they delayed their move until the following January and the children both went to the same school as agreed. However, the parents now complain that the council sent investigators out to ensure that they really were living at the address that they had given. "1984!" the cry. "Big Brother!" Most newspaper readers seem to agree with them.

But if it were social benefit cheats who were detected by such snooping the newspapers would praise the effort of local authorities to curb unnecessary spending. It is not the snooping that is the issue, but the presence of poor schools that parents want to avoid and feel that they must cheat to avoid. These particular parents were exonerated. they should be grateful; without the snooping they might not have been.

Locks and Islam

In an industrial museum in the Midlands I watched a locksmith at work. He asked this question, "What are locks for?"

My reply was what most people would answer, "To keep people out."

"No," he countered, "walls are to keep people out, locks are to let people in."

I remembered this as I was thinking about the Wilders film that I posted about yesterday. I have to reconcile what that film showed with my knowledge of my many friends who are Muslims.

A few years ago I took a trip to Turkey and apart from visiting Ankara and Istanbul, I went into the rural interior. Among the intellectual elite there was full espousal of secularism; Western clothes, Western attitudes, Western science and a strong social conscience. I was sponsored by the British Council and asked to make a report on what I saw. I told them that I was impressed by the energy and hard work of the doctors there and, though there were enormous challenges, I thought that in time Turkey would make a good candidate for assimilation into the EU.

Even in the cities, though, there was a huge uneducated conglomerate of people. The ER of the pediatric hospital in Ankara was besieged every morning with 200 sick kids who had everything from polio to leukemia. They had often walked or travelled by horse-drawn cart many miles from the countryside and were just waiting their turn. Many were sent away at the end of the day. If you couldn’t get to the city then medical care was negligible.

Today, I wouldn't bet tuppence on Turkey's chances of EU entry. The rise of militant Islam, the large numbers of Turkish 'guest workers' in Germany, the continuing conflict in Cyprus, the enmity with Greece, the human rights issues with the Kurds; all make it highly unlikely that the EU will accept Turkey. And if the EU, that most PC of all institutions, demurs on Turkey, what price relations with Lebanon, Egypt, Iran, Syria, the Palestinians and points east?

When I went into the Turkish interior it wasn’t Islam that held sway, but superstition. You could buy lucky charms from any village store. Visitors are familiar with the Mediterranean coastline but even Ankara is little visited and much of the Turkish countryside is bleak and underpopulated. There are some remarkable things to see in Capadocia (see picture) but as we visited village after village it was clear that things had changed little from the days of the Hittites.

Under the Ottoman empire Turkey had become lazy, fat and corrupt and following WWI the secular reforms of Kemal Ataturk were necessary. There have been Islamist reawakenings recently, but these are not yet similar to those of Pakistan or Afghanistan.

We make a great mistake to lump all Muslims together. Islam is at least as diverse as Christianity. It differs in having no central authority. The local mosque is independent. Sure, individual imams have influence, but many congregations take as much notice of the Jihadists as I would of Jimmy Swaggart or Ian Paisley. Because of this independence it is hard to get sensible Muslims to act together to condemn the extremists.

You don’t have to be uneducated to fall for the Jihadists message; a lot of very clever people followed Adolf Hitler and Lenin. But a clever speaker can recruit the masses in their millions and it’s difficult to get that genie back in the bottle. I think the danger from militant Islam is at least as great as from Nazism or Leninism and perhaps greater, since for Germans and Russians death was something of a deterrent. Not so for many Iranians.

We can do little to stem the tide of these people streaming out of the Middle East and the subcontinent with their murderous intent. The current trials in London show that the security services are doing a good job, but they have to succeed every time and the terrorists only once. We can target aid towards people in these places who think like we do, but we have to rely on the ‘good’ Muslims to exert more influence. In this respect I was drawn to this site by an article in today's BMJ entitled "Radical Muslim doctors and what they mean for the NHS". The article stresses that the authority of a doctor in modern Islam surpasses even that of an imam. They are expected to be experts on theology as well as medicine. It tells us that most of the world's Muslims are neither fundamentalists nor followers of radical sharia but many Muslim doctors and other professionals are attracted to an ideology that projects a solution to all human problems in a fundamentalist interpretation of Islam, along with a demand for exclusive governance that is based on the radical Wahhabi and related forms of religious law or sharia. You can download the full document here.

Stephen Schwartz, the author of the report, testifies to his attitude to radical Islam thus: "I stopped going to mosques in my home town after 9/11 – as many other Muslims did in their quiet manner without seeking public attention – and severed relations with “official” Islam and its spokesmen who are the most egregious practitioners of bigotry with their hate-filled language that fuels violence.
The cost for me was liberating as I distanced myself from folks who preach a war-mongering ideology masquerading as a religion."

Within Britain we must free ourselves from the conviction that we may not criticize people with dark-colored skin. Our reticence in this respect has allowed us to be exploited. We have to get over it. If people act in an unacceptable manner they must not be allowed to deflect criticism with the cry "Racial prejudice!"

As far as immigration is concerned we must, like Israel, build bigger fences, but these barriers must have sophisticated locks to allow entrance to people we would like to come in. If such a system of lock and key requires what they call impertinent questions into life and lifestyle, so be it. People don't have to come if it offends them.

Fitna

If you haven't yet seen the controversial 15 minute short film Fitna by Geert Wilders you should. I am not endorsing it nor using it to condemn Islam, but it is a wake up call to what many people are doing in the name of Islam.

Were people doing this in the name of Christianity I should be shouting from the rooftops in condemnation of them. The Muslims that I know are friendly, house-trained Westerners, yet I know that there are British Muslims who think it is a righteous thing to do to incinerate men women and children in tube trains, buses and aeroplanes. There are Imams in British Mosques preaching death to homosexuals, adulterers, Muslims who convert to Christianity, cartoonists, novelists and Muslim soldiers in the British military. I don't know how strong this movement is, but it is prominent enough to have scared a lot of people.

Wilders' film shows passages from the Koran, then an Imam preaching, then one of the many atrocities that act out the jihad. It does not make easy viewing. Network Solutions, which originally hosted the video is apparently seeking to censor its content following complaints from Muslims. The film is certainly inflammatory, but not because of any shrillness or propaganda. The content is factual. It would be easy to draw the conclusion that all Muslims are like this and that immigration is to blame.

In the Guardian today, Timothy Garton-Ash writes against censorship, but still criticises the film - clearly he come from a different political perspective to Wilders.

Similar passages may be found in the Old Testament, and one misunderstood passage in Romans Chapter 1 in the New Testament, but you would be hard put to find a Jewish or Christian preacher preaching that these verses should be put into practice, and you don't find Christian terrorists blowing themselves up in city metros. Indeed, when a 'Christian' assassinated a doctor who performed abortions it was roundly condemned by almost every Christian on the planet, even those who are passionately against abortion.

My message therefore to Muslims is, "These people are desecrating your religion. Make them stop. If you don't people will assume that this is what Islam is like."

Aphorisms

When you hear the beat of hooves think of horses not zebras.

You can do anything you like as long as you don’t want the credit for it.

If you only find one disease in an old person, you’re missing something.

Capitalism makes it possible for some people, sometimes, to do things that the collective does not want done; that's what makes it so unacceptable.

A gentleman is someone who never picks his nose even when he is alone.

An aphorism is a witty response thought up the day after it was needed.

It’s terrible to get old but the alternative is worse.

Don't let your worries get the best of you; remember, Moses started out as a basket case.

Many folks want to serve God, but only as his advisers.

If you see someone without a smile, give them one of yours.

Coincidence is when God chooses to remain anonymous.

Until you come to terms with your own death you can’t talk to anyone else about theirs.

Every journey begins with a single step; every cancer begins with a single cell.

Great love and great achievements involve great risk.

Keep no record of wrongs; there can be no forgiving without forgetting.

I cannot write long books; I leave that for those people who have nothing to say.

In an autocracy, one person has his way; in an aristocracy, a few people have their way; in a democracy, no one has his way.

CD20 and trisomy 12

In advice that I have been giving over the past 5 years I have been stressing that CD20 is brighter in patients who have trisomy 12. Indeed we noticed some time ago that trisomy 12 CLL was rather different from other types of CLL [1]. Today, published in the British journal of Haematology comes mathematical confirmation of our observation, from Michael Keating's group [2].

In patients with trisomy 12 there were 23,603 CD20 antigenic sites per cell compared with 10,781 for del 13q, 9,341 for del 17p, 8,828 for those with negative FISH and 5,886 for those with del 11q. The figures for trisomy 12 and del 11q patients were statistically significantly different.

Does this matter? Yes, because rituximab targets CD20. In the same paper the MDACC group report that the combination of rituximab and GM-CSF produced responses in93% of patients with trisomy 12, 73% in patients with negative FISH, del 13q or del 17p, and 50% in patients with del 11q.

References

1] Trisomy 12 defines a group of CLL with atypical morphology: correlation between cytogenetic, clinical and laboratory features in 544 patients. Matutes E, Oscier D, Garcia-Marco-J, Ellis J, Copplestone A, Gillingham R, Hamblin T, Lens D, Swansbury GJ, Catovsky D. Brit J Haem 1996 92: 382-8

2] Chronic lymphocytic leukaemia CD20 expression is dependent on the genetic subtype: a study of quantitative flow cytometry and fluorescent in situ hybridization in 510 patients. Tam CS, Otero-Palacios J, Abruzzi LV et al. Brit J Haem 2008 141: 36-40.

TWENTY MILLION POUNDS

Do you get those messages telling you that some widow of an important person has twenty million pounds (dollars, euros, whatever) in the Ivory Coast (Nigeria, Sierra Leone, perm any of 168 countries) that she can't get out of the country, but needs to use your bank account details to do so? Of course you do (unless your spam filter strains them out). The amazing thing is that some people must fall for it, otherwise they would stop sending them. I wonder, though, if they are pitching the figure correctly for their market? Is there a figure that would be more tempting? 200 million? 2 billion? Or perhaps there is a figure that would be more believable? 2,792 pounds, perhaps? Or 27,920?

BBC: more propaganda.

"Global temperatures this year will be lower than in 2007...This would mean global temperatures have not risen since 1998, prompting some to question climate change theory. But experts have also forecast a record high temperature within five years, probably associated with another episode of El Nino"
Arch-global warming reporter's original piece on the BBC website

A little later this had changed to "Global temperatures will drop slightly this year...This would mean global temperatures have not risen since 1998, prompting some to question climate change theory. But experts say we are still clearly in a long-term warming trend -- and they forecast a new record high temperature within five years.The WMO points out that the decade from 1998 to 2007 was the warmest on record. Since the beginning of the 20th Century, the global average surface temperature has risen by 0.74C. While NASA, the US space agency, cites 2005 as the warmest year, the UK's Hadley Centre lists it as second to 1998. Researchers say the uncertainty in the observed value for any particular year is larger than these small temperature differences. What matters, they say, is the long-term upward trend."

Shortly later it appeared thus, "... experts say we are still clearly in a long-term warming trend -- and they forecast a new record high temperature within five years.The WMO points out that the decade from 1998 to 2007 was the warmest on record. Since the beginning of the 20th Century, the global average surface temperature has risen by 0.74C. While NASA, the US space agency, cites 2005 as the warmest year, the UK's Hadley Centre lists it as second to 1998. Researchers say the uncertainty in the observed value for any particular year is larger than these small temperature differences. What matters, they say, is the long-term upward trend."

None of the updates was signified by a change to the 'last update stamp'.

Why were these changes made? because of pressure from author and climate alarmist Jo Abbess. Read all about it at American thinker.

Nevertheless, the global conspiracy about climate change seems to be falling apart.

No more Mr Nice Guy

Tony (we don't do God) Blair has spoken about the importance of religion in a lecture at Westminster Cathedral. His lecture, among other things, deals with the question of how different faiths should relate to each other in today's global culture. He pleads for tolerance and the avoidance of extremism. Here is the key passage

I don't think there is much to disagree with there. We are all a bit sick of the Spanish Inquisition and Hindu violence against Christians in India and most of all of Islamic Jihad, but how does all that gel with Nehemiah chapter 13?

Remember that Nehemiah had been given permission to leave his job as Royal wine-taster to return from exile and rebuild the walls of Jerusalem. with God's enabling he overcame the difficulties and the walls were successfully rebuilt and Judaism re-established in the city. Job done he returned to his job in Babylon, but some time later he asked permission and came back to Jerusalem. He found everything had gone to pot. His long-term enemy, Tobiah, had finagled a room in the Temple. The Levites had been denied the tithes and offerings and had gone back to work their fields for a living and many young men and women had married foreigners so that their children could not longer speak Hebrew and could not therefore understand the word of God.

Nehemiah's attitude was to lose his temper and get violent. Verse 25, "I rebuked them and called curses down on them. I beat some of the men and pulled out their hair"

The question is where does zeal end and intolerance begin? We should not tolerate the intolerable. However, violence must be a very rare occurrence. Vengeance in mine, says the Lord, I will repay.

There are those Christians who hate Islam and tell us that the violence and oppression are part and parcel of the faith; it is there in the Koran. On the other hand I have friends who are Muslims as well as Hindus, Sikhs and atheists. They are cultured, humane individuals who would no more think of blowing up a bus than I would.

I absolutely believe that as Jesus said, "No man comes to the father, but by me." but once I have explained the gospel, the best witness I can be is by living a life of love and self-sacrifice. Belief in God is a personal choice. You do not become a believer by inheritance or by force. We are saved by faith and this is itself a gift of God. It cannot be coerced by zealots.

CLL: New agents

A whole range of new therapeutic agents is in development, some of which are already in the clinic. Lenalidomide [163] might act by interfering with the tumour/stroma interaction. Ofatumumab is a fully humanised CD20 monoclonal antibody with reputed advantages over rituximab because of a slower off-rate.[164] Lumiliximab—a primatised anti-CD23—is entering clinical trials in patients with chronic lymphocytic leukaemia.[165] Chronic lymphocytic leukaemia cells with deletions at 11q23 seem to be especially sensitive to the orally available poly (ADP-ribose) polymerase inhibitor 4-amino-1,8-naphthalamide.[166] ATM-deletion-mediated drug resistance might also be overcome with Nutlin 3a.[167] Finally, acadesine seems to be a new chemotherapeutic agent capable of killing chronic lymphocytic leukaemia cells yet leaving T cells unharmed.[168]

References

163 A Chanan-Khan, KC Miller and L Musial et al., Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study, J Clin Oncol 24 (2006), pp. 5343–5349.
164 JL Teeling, WJ Mackus and LJ Wiegman et al., The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20, J Immunol 177 (2006), pp. 362–371.
165 BD Cheson, Monoclonal antibody therapy of chronic lymphocytic leukemia, Cancer Immunol Immunother 55 (2006), pp. 188–196.
166 HE Bryant and T Helleday, Inhibition of poly (ADP-ribose) polymerase activates ATM which is required for subsequent homologous recombination repair, Nucleic Acids Res 34 (2006), pp. 1685–1691.
167 K Kojima, M Konopleva, T McQueen, S O'Brien, W Plunkett and M Andreeff, Mdm2 inhibitor Nutlin-3a induces p53-mediated apoptosis by transcription-dependent and transcription-independent mechanisms and may overcome Atm-mediated resistance to fludarabine in chronic lymphocytic leukemia, Blood 108 (2006), pp. 993–1000.
168 C Campas, JM Lopez and AF Santidrian et al., Acadesine activates AMPK and induces apoptosis in B-cell chronic lymphocytic leukemia cells but not in T lymphocytes, Blood 101 (2003), pp. 3674–3680.

Drug-resistant chronic lymphocytic leukaemia

After successful induction therapy, relapse is almost inevitable if no consolidation takes place and is still possible if consolidation has been done. After long remissions, patients will usually respond again to the same type of treatment, but relapse after short-lived remissions and primary refractory disease needs a different approach.

In the relapsed and refractory setting,[157] and [158] fludarabine, cyclophosphamide, and rituximab can produce high response rates (73%) and complete remissions (25%). In a comparison with historical controls, results suggested that fludarabine, cyclophosphamide, and rituximab is superior to fludarabine plus cyclophosphamide or to fludarabine alone. However, although the multivariate analysis included concentrations in serum of β2 microglobulin, interphase cytogenetics and IGHV mutational status were not studied.

No phase III data on this comparison has yet been published, although the REACH trial is currently being evaluated. The first interim analysis early in 2008 did not react its projected end point and a final analysis will take place later this year.

Most effective treatments for chronic lymphocytic leukaemia need an intact TP53 pathway. Patients with advanced refractory chronic lymphocytic leukaemia treated with high-dose prednisolone had an overall response rate of 77%.[159] Alemtuzumab also produced high levels of response in TP53-deleted chronic lymphocytic leukaemia.[160] The combination of these agents gave a 100% response with 60% complete remission in a few patients with TP53 defects.[161]

The use of these agents in combination is very immunosuppressive and reactivation of CMV is a constant hazard. It is necessary to screen for this on a weekly basis, and to institute treatment with gancyclovir before symptoms occur is reactivation is seen.

Flavopiridol, a cyclin-dependent kinase inhibitor, has proved a very effective killer of TP53-deleted chronic lymphocytic leukaemia cells in vitro, but it was almost completely ineffective in vivo because it was so highly bound to human serum albumin. By altering the infusion schedule, partial remissions of long duration have been obtained in 42% of chronic lymphocytic leukaemias with TP53 deletions.[162]

Lenalidomide, is a derivative of thalidomide that is effective in the treatment of myeloma and myelodycplastic syndrome, especially cases with del 5q. It has been used in the treatment of CLL with moderate efficacy. Its mode of action is not completely clear, but it is believed to interfere with interactions between stromal cells and CLL cells in the tissues. Consequently it might have activity in patients with disease that is resistant to standard therapy.

The original phase II study from Roswell Park [163] reported on 45 patients with relapsed or refractory disease treated with 25mg/day for 21 days of a 28 day cycle. 9% achieved CRs and 38% PRs. 10 of the patients had ATM deletions and 6 p53 deletions. The response rate in those with ATM deletions was the same as in other cases, but they do not report what happened in patients with p53 deletions.

A second study from MD Anderson Cancer Center [163a] included a dose escalation phase, begining at 5mg/every day for 28 days, rising to a maximum of 25mg. 44 relapsed or refractory patients were studies. The CR rate was 7% and the PR rate 25%. Given the rather lower dose some patients received, this was in line with the Roswell Park findings. The response rate among del 11q patients was 39%, but among 8del 17p patients, only one responded. Lenalidomide is being touted as a useful drug in TP53 deleted patients; there is very little evidence to support this.

157 W Wierda, S O'Brien and S Wen et al., Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia, J Clin Oncol 23 (2005), pp. 4070–4078.

158 W Wierda, S O'Brien and S Faderl et al., A retrospective comparison of three sequential groups of patients with recurrent/refractory chronic lymphocytic leukemia treated with fludarabine-based regimens, Cancer 106 (2006), pp. 337–345.

159 PD Thornton, E Matutes and AG Bosanquet et al., High dose methylprednisolone can induce remissions in CLL patients with p53 abnormalities, Ann Hematol 82 (2003), pp. 759–765.

160 NC Osuji, I Del Giudice, E Matutes, AC Wotherspoon, C Dearden and D Catovsky, The efficacy of alemtuzumab for refractory chronic lymphocytic leukemia in relation to cytogenetic abnormalities of p53, Haematologica 90 (2005), pp. 1435–1436.

161 AR Pettitt, E Matutes and D Oscier, Alemtuzumab in combination with high-dose methylprednisolone is a logical, feasible and highly active therapeutic regimen in chronic lymphocytic leukaemia patients with p53 defects, Leukemia 20 (2006), pp. 1441–1445.


162 JC Byrd, TS Lin and JT Dalton et al., Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia, Blood 109 (2007), pp. 399–404.

163 A Chanan-Khan, KC Miller and L Musial et al., Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study, J Clin Oncol 24 (2006), pp. 5343–5349.

163a A Ferrajoli, L Bang-Ning, EJ Schlette et al. Lenalidomide induces compltee and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood (2008) published on-line March 11 doi:10.1182/blood-2007-12-130120

Bendamustine: Hype or Hope?

A lot of fuss is being made about bendamustine (also known as Treanda). Because it is an alkylating agent with some of the properties of purine analogues and because it is reputed to work in fludarabine refractory cases there has been a lot of chatter about it. So is it all hype or is it justified?

In August 2007 Cephalon, Inc. announced that the U.S. Food and Drug Administration (FDA) Office of Orphan Products Development granted orphan drug designation for the company's investigational therapy, TREANDA(R) (bendamustine HCl), for the treatment of chronic lymphocytic leukemia (CLL). Orphan drug status is granted by the FDA to promote the development of products that demonstrate promise for the treatment of rare diseases affecting less than 200,000 Americans annually. The orphan drug designation would entitle Cephalon to a seven-year period of marketing exclusivity in the United States for TREANDA, if approved by FDA for the treatment of CLL. Note that the drug is out of patent and there are no development costs to pay for. What Cephalon decide to charge for it should simply compenate them for the costs of bringing it to market. So if it costs more than, say $500 a course, we are being seriously ripped off.

Cephalon’s blurb states that TREANDA is the first rationally designed purine analog / alkylator hybrid, combining the moieties of an antimetabolite and an alkylator. Preclinical data show that TREANDA induces rapid, sustained single- and double-strand DNA damage, which results in apoptosis, or programmed cell death in the tumor. TREANDA also induces mitotic checkpoint inhibition, which results in non-apoptotic cell death. These novel dual-action, anti-tumor effects of TREANDA may be attributed to its unique chemical design.

Cephalon holds exclusive rights to market and develop TREANDA in the United States. TREANDA is licensed from Astellas Deutschland GmbH. Bendamustine is marketed in Germany by Astellas' licensee, MundiPharma International Limited, under the trade name RIBOMUSTIN(R). In Germany, RIBOMUSTIN is indicated as a single-agent or in combination with other anti-cancer agents for indolent NHL, multiple myeloma, and CLL. SymBio Pharmaceuticals Ltd holds exclusive rights to market and sell bendamustine HCl in Asia.

Bendamustine is one of the few drugs to emerge from a Communist country period. It was first synthesized in 1963 in the German Democratic Republic. It is chemically related to the alkylating agent chlorambucil, with the benzene ring in the chlorambucil molecule replaced by a 1-methyl-benzimidazole moiety. The mechanisms of action of bendamustine have been under investigation since the early 1960s, and its first use was as a treatment for multiple myeloma in 1969. It has three active moieties: an alkylating group, in common with the nitrogen mustard family; a benzimidazole ring, which may act as a purine analog; and a butyric acid side-chain – see figures at the top of the article. The drug undergoes extensive first-pass metabolism. However, unmetabolized bendamustine accounts for about 45% of the total drug recovered in urine. The main transformation product is a cytotoxic hydroxy metabolite (beta-hydroxybendamustine). Bendamustine was originally synthesized with the intention of producing an antineoplastic agent with low toxicity and both alkylating and antimetabolic properties. However, it has been shown that, at least at high concentrations, it acts primarily as an alkylating agent.

Bendamustine is certainly a different drug that has activity in a number of tumor types. Our concern must be is it a useful addition to our armory for fighting CLL?
A paper in the Journal of Cancer Research and Clinical Oncology from East Germany in 2001 reported the use of bendamustine in a phase II study of 23 patients with advanced CLL. 13 were chemotherapy naïve, others were called refractory or relapsed, but I don’t have evidence of what that means – and it is certainly critical. The treatment-related mortality was 13%. The overall response rate was 65% and the CR rate was 26%.

A second phase I/II study was published in Haematologica in 2005. This is a rather better journal. The level pf peer review is similar to that of Blood. 16 patients were studied, all had relapsed or refractory disease. Now this needs to be precisely defined. All patients had to be either Binet stage B or C with active disease. They needed to have had at least 1 prior treatment with either chlorambucil or fludarabine – in fact only 2 had had just 1 prior treatment, four had had 2, three 3, four 4, two 5, and one 6. Refractory disease meant relapse within 6 months of previous treatment and they had to have this or relapsed or progressive disease. In fact 13 were resistant to chlorambucil and 4 to fludarabine (there is some overlap but two were apparently not resistant to either).

This was a dose finding study and while they started at 100 mg per square meter twice a month, they had to reduce to 70mg per square meter to find a dose with acceptable toxicity for such patients. The toxicities were mainly hematological. Lymphoma patients can tolerate a higher dose, but they are less likely to have bone marrow impairment.

6 patients were withdrawn from the study because of toxicity. Of the remaining 10, there were 2 CRs, 1 nPR and 4 PRs. The conclusion of this study is that bendamustine is an active agent in CLL and that the safe dose in multiply treated patients is 70 mg/square meter, twice a month. It seems to have activity in patients who do not respond well to chlorambucil, It should be noted that these patients included one patient who had del 11q, but in the majority FISH studies were not available.
I guess the excitement about bendamustine stems from a report at ASH in 2007. A randomized phase III study compared bendamustine with chlorambucil in previously untreated patients. The plain outcome measures appeared impressive: Overall response rate was 69% for bendamustine and 39% for chlorambucil. CR rate was 30% and 2%. Median progression-free survival was 21.7 months and 9.3 months respectively.
But it is important to look at the fine detail in these trials. The dose of bendamustine was 100 mg/sq m on days 1 and 2 and the dose of chlorambucil 0.8 mg/kg on days 1 and 15.

So this is pretty well the maximum dose of bendamustine and a suboptimal dose of chlorambucil. It is not the usual way of reporting chlorambucil doses, but this works out at about 6mg a day for 14 days for an average person, whereas my usual dose is 10mg per day. If we compare the results of the chlorambucil arm in this trial with that of the LRF CLL4 trial that was taking place at the same time. The overall response rate for CLL4 was 72% and the CR rate 7%. The median PFS was 18 months. Now we know that FC is considerably better than chlorambucil, even at the higher dosage, so the real test for bendamustine would be how it compares with FC.

Bendamustine is given as an intravenous infusion, whereas both fludarabine and cyclophosphamide can be taken orally. There are suggestions that bendamustine kills cells by different pathways from those used by other alkylating agents, but as far as I can discover they all require p53, so there is no evidence that it will supplant alemtuzumab in p53 depleted cases.

So at the moment I think it is hype rather than evidence.

Water: How the intellectuals get it wrong

"A magnificent film... Unforgetably touching the heart - Salman Rushdie.

"Utterly beautidul... A dazzling, stirring, marvelous film." Film Review.
Acadamy Award Nominee 2007.

A film by Deepa Mehta, it gained high plaudits from the critics, though in India and Pakistan it was banned. Some Indian critics felt the acting was poor, the main stars being chosen for their good looks rather than their acting ability.

The story is set in 1938 and depicts the plight of Hindu widows in India then. They had three choices - marry their husband's younger brother, throw themselves on his funeral pyre (this had been outlawed by the British) or live celibate lives of quietness in a widows retreat. Women were regarded as worthless, a drag on the household economy and a dowry was needed if you wanted to marry them off. An alternate choice was to marry your female children off at a very young age to an old man who was reasonably rich. When he died the young girl - in this film aged only 8 - is deposited in a widow's retreat.

Who funds these retreats? They were self funding. Young attractive widows were hired out as prostitutes. In this story, one of these young women and a young Brahmin lawyer, who is a follower of Gandhi, fall in love. They plan to marry, but on a visit to his home she discovers that his father was one of her former clients. Bereft, she kills herself.

Now that's a good plot. But the film is just dreadful. It was so slow. After an hour of nothing happening we turned it off and watched an episode of The Good Life. You can have teh dialogue in either Hindi or English. but the English is incomprehensible and there are no subtitles. Don't waste your time.

CLL: Consolidation therapy

Consolidation of remission aims to eliminate all detectable disease from the patient. In assessing the success of such attempts, the sensitivity of the method used to detect minimal residual disease is crucial. Unlike, many other haematological cancers, there is no characteristic chromosomal translocation to detect. Detection methods use either PCR to identify a unique tumour-associated sequence or flow cytometry to find an exclusive set of tumour antigens. The most sensitive assay uses PCR to detect a specific clonotypic sequence. This technique can ascertain 1 in 100 000 cells,[138] but the IGHV gene needs to have been sequenced before treatment. Use of consensus primers to detect monoclonal immunoglobulin is much less sensitive, being only able to identify 1 in 1000 cells.[139] Rawstron and colleagues [140] have developed a four-colour flow technique capable of detecting 1 in 50 000 cells, and this method has been refined further by an international group for use when anti-CD20 form part of the treatment strategy.[141]

Remissions are traditionally consolidated with high-dose chemotherapy, sometimes with autologous stem-cell rescue. With this approach, a German research group could eliminate minimal residual disease and produce prolonged remissions in patients whose chronic lymphocytic leukaemia had mutated IGHV genes; however, for those with unmutated IGHV genes, molecular relapse was inevitable, and clinical relapse almost so, by 4 years' follow up.[142] However, even this less-than-encouraging outcome might be better than what is achievable with conventional chemotherapy, according to findings of a comparison in matched historical controls.[143] Moreover, stem-cell harvest is only possible in about two-thirds of patients with chronic lymphocytic leukaemia, and there is a worryingly high prevalence of secondary myelodysplastic syndrome.[144] and [145]

Stem-cell allografts have been used in an attempt to capitalise on the graft-versus-leukaemia effect to eliminate minimal residual disease. In a largely elderly population, myeloablative conditioning leads to high treatment-related mortality of 40–50%.[145], [146] and [147] To combat this toxic effect, allotransplantation with reduced intensity conditioning, often followed by donor lymphocyte infusion, has become popular. Early results do not yet show an improvement in event-free survival compared with myeloablative transplants.[148], [149] and [150] In every series, a high frequency of chronic graft-versus-host disease is noted. Nevertheless, in patients with poor-risk prognostic markers, and especially those with 17p13 deletions, sustained remissions without molecular relapse are achievable.[151]

Potentially less hazardous are attempts to consolidate remission with monoclonal antibodies. Alemtuzumab is especially suited because it can kill chronic lymphocytic leukaemia cells in a caspase-independent manner that is not inhibited by loss of TP53 protein [152] and is, therefore, able to eliminate chemotherapy-resistant cells.[153] In a study of 91 previously treated patients,[154] 44 of whom were refractory to purine analogues, complete remissions as defined by the US National Cancer Institute [121] were achieved in 32%. In these individuals, a four-colour flow technique for detection of minimal residual disease did not identify disease in 56%.[140] Patients who became negative for minimal residual disease had significantly longer treatment-free and overall survival than those who did not.

In a prospective phase III study in Germany,[155] patients were randomly allocated either no treatment or alemtuzumab 30 mg intravenously three times a week for 12 weeks, beginning a median of 67 days after the last dose of induction chemotherapy (fludarabine with or without cyclophosphamide). Although recruitment to this trial was halted at 21 patients because of severe infections in the alemtuzumab group, those allocated alemtuzumab had significantly longer progression-free survival than those assigned no treatment. Using a very sensitive PCR-based assay with sequence-specific primers to detect minimal residual disease, five of six patients tested became negative for minimal residual disease. Findings of a phase II study156 of alemtuzumab given in doses of 10 mg subcutaneously three times a week for 6 weeks, beginning not less than 8 weeks after discontinuation of fludarabine induction chemotherapy, proved that this regimen was safe and able to turn partial remissions into complete remissions. A PCR technique with consensus primers (a less sensitive method than that used in the phase III study) was used to detect minimal residual disease; patients with mutated IGHV genes were more likely to become negative for minimal residual disease than were those with unmutated IGHV genes. Reactivation of cytomegalovirus happened in 53% but was successfully treated with oral ganciclovir. 53% of patients successfully underwent autologous stem-cell transplantation, but no follow-up information is available. At present, immunological consolidation with alemtuzumab after chemotherapy seems safer than with allogeneic transplantation, but we await a comparison of efficacy.

References

138 A Noy, R Verma and M Glenn et al., Clonotypic polymerase chain reaction confirms minimal residual disease in CLL nodular PR: results from a sequential treatment CLL protocol, Blood 97 (2001), pp. 1929–1936.
139 S Bottcher, M Ritgen and C Pott et al., Comparative analysis of minimal residual disease detection using four-color flow cytometry, consensus IgH-PCR, and quantitative IgH PCR in CLL after allogeneic and autologous stem cell transplantation, Leukemia 18 (2004), pp. 1637–1645.
140 AC Rawstron, B Kennedy and PA Evans et al., Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy, Blood 98 (2001), pp. 29–35.
141 AC Rawstron, N Villamor and M Ritgen et al., International standardized approach for flow cytometric residual disease monitoring in chronic lymphocytic leukaemia, Leukemia 21 (2007), pp. 956–964.
142 M Ritgen, A Lange and S Stilgenbauer et al., Unmutated immunoglobulin variable heavy-chain gene status remains an adverse prognostic factor after autologous stem cell transplantation for chronic lymphocytic leukemia, Blood 101 (2003), pp. 2049–2053.
143 P Dreger, S Stilgenbauer and A Benner et al., The prognostic impact of autologous stem cell transplantation in patients with chronic lymphocytic leukemia: a risk-matched analysis based on the VH gene mutational status, Blood 103 (2004), pp. 2850–2858.
144 DW Milligan, S Fernandes and R Dasgupta et al., Results of the MRC pilot study show autografting for younger patients with chronic lymphocytic leukemia is safe and achieves a high percentage of molecular responses, Blood 105 (2005), pp. 397–404.
145 JG Gribben, D Zahrieh and K Stephans et al., Autologous and allogeneic stem cell transplantations for poor-risk chronic lymphocytic leukemia, Blood 106 (2005), pp. 4389–4396.
146 M Michallet, B Corront and D Hollard et al., Allogeneic bone marrow transplantation in chronic lymphocytic leukemia: 17 cases—report from the EBMTG, Bone Marrow Transplant 7 (1991), pp. 275–279.
147 S Paneesha and DW Milligan, Stem cell transplantation for chronic lymphocytic leukaemia, Br J Haematol 128 (2005), pp. 145–152.
148 P Dreger, R Brand and D Milligan et al., Reduced-intensity conditioning lowers treatment-related mortality of allogeneic stem cell transplantation for chronic lymphocytic leukemia: a population-matched analysis, Leukemia 19 (2005), pp. 1029–1033.
149 JR Brown, HT Kim and S Li et al., Predictors of improved progression-free survival after nonmyeloablative allogeneic stem cell transplantation for advanced chronic lymphocytic leukemia, Biol Blood Marrow Transplant 12 (2006), pp. 1056–1064.
150 J Delgado, K Thomson and N Russell et al., Results of alemtuzumab-based reduced-intensity allogeneic transplantation for chronic lymphocytic leukemia: a British Society of Blood and Marrow Transplantation Study, Blood 107 (2006),
151 D Caballero, JA Garcia-Marco and R Martino et al., Allogeneic transplant with reduced intensity conditioning regimens may overcome the poor prognosis of B-cell chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy-chain gene and chromosomal abnormalities (11q- and 17p-), Clin Cancer Res 11 (2005), pp. 7757–7763.
152 AP Mone, C Cheney and AL Banks et al., Alemtuzumab induces caspase-independent cell death in human chronic lymphocytic leukemia cells through a lipid raft-dependent mechanism, Leukemia 20 (2006), pp. 272–279.
153 G Lozanski, NA Heerema and IW Flinn et al., Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions, Blood 103 (2004), pp. 3278–3281.
154 P Moreton, B Kennedy and G Lucas et al., Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival, J Clin Oncol 23 (2005), pp. 2971–2979.
155 CM Wendtner, M Ritgen and CD Schweighofer et al., Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission: experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG), Leukemia 18 (2004), pp. 1093–1101.
156 M Montillo, A Tedeschi and S Miqueleiz et al., Alemtuzumab as consolidation after a response to fludarabine is effective in purging residual disease in patients with chronic lymphocytic leukemia, J Clin Oncol 24 (2006), pp. 2337–2342.

Fracture and Harry Potter

This new movie starring Tony Hopkins and Ryan Gosling is not so much a "Who dunnit" as a "How did he do it?". On this basis I should have a job in the DA's office because I spotted it very early on. Hopkins keeps changing accents, which is was disconcerting. Was it deliberate? Was he trying to add mystery to his character? Was it just lazy? In a sort of sub-Lecter character Hopkins acts everyone else off the screen, but it's still a lazy performance; it's too easy for him. So what's wrong with the film? The love interest with Rosamund Pike is pointless and without chemistry - probably there to introduce her father. The final twist was telegraphed long before it needed to be. The business with the confusion over the cell phones was put in as a heavy hint when most people would have solved the puzzle, but the main problem was Gosling. He just can't carry a film. I've not seen him before in anything. He is apparently Canadian, so he can't be all bad, and he was nominated for an Oscar for Half Nelson, which I haven't seen. Perhaps it's unfair to play him alongside Hopkins, but even a lazy Hopkins makes him look like an amateur. He reminds me of Edward Norton. In a famous Master Class on acting, Michael Caine emphasized the importance of being still for the camera. Both these young actors seem to have taken this on board. They have thin-lipped expressionless faces that hardly move during a performance.

I absolve David Strathairn from criticism. He was the only other convincing actor in the movie.

Daniel Radcliffe is what is wrong with the latest Harry Potter film. He is so wooden that he must have thought he was playing the part of his wand rather than Harry Potter himself. This franchise is getting to the darker end of the books; there's not much humor in this one. The supporting acting is generally excellent. Imelda Staunton, once again astonishes with her range, Michael Gambon looked much more of a Dumbledore than last time, Robbie Coltrane still convinces as Hagrid, an ageing Rober Hardy plays Fudge, but then there are Emma Thompson, David Thewlis, Richard Griffiths, Fiona Shaw, Helena Bonham-Carter, Ralph Feinnes, Brendan Gleeson, Gary Oldman, Mark Williams, Maggie Smith, Julie Walters, Jason Isaacs and Alan Rickman. A special mention for David Bradley. This veteran actor has been playing villains, tramps and petty criminals for many years, and has been able to construct the horrible Filch in all the films. No-one does loathsome better.

Emma Watson may have a career after Harry Potter. The jury is still out on Rupert Grint. As for Daniel Ratcliffe - take the money and run.

CLL: Immunochemotherapy

Rituximab—the chimeric monoclonal anti-CD20—is only moderately active as a first-line agent in chronic lymphocytic leukaemia,[131] with an overall response rate of 51% and a complete remission rate of only 4%. However, when it is added to fludarabine or fludarabine plus cyclophosphamide, impressive responses have been reported. In a randomised phase II study,[132] rituximab added to fludarabine produced higher responses when given concurrently than when given sequentially. When compared with historical selected controls in a multivariate analysis controlling for pretreatment characteristics (but not for modern prognostic markers), addition of rituximab seemed to enhance significantly progression-free and overall survival.[133]

The combination of fludarabine, cyclophosphamide, and rituximab has been tested in first-line and relapsed and refractory settings (see also section on Drug-resistant chronic lymphocytic leukaemia). As first-line therapy,[134] overall response rates of 95% and complete remission rates of 70% were reported. In historical controls treated with fludarabine plus cyclophosphamide, the same research group recorded overall response rates of 88%, with 35% complete remission. However, only 33% of patients treated with fludarabine, cyclophosphamide, and rituximab were Rai stage III and IV, compared with 50% of those given fludarabine plus cyclophosphamide, and no modern prognostic markers have been reported for either patients or historical controls. In another phase II study, addition of mitoxantrone to fludarabine, cyclophosphamide, and rituximab seemed to add only toxic effects rather than increased efficacy.[135] Phase III comparisons of fludarabine, cyclophosphamide, and rituximab and fludarabine plus cyclophosphamide are currently underway, and these findings should be reported in 2008 or 2009.

Another purine analogue, pentostatin, has been assessed in combination with cyclophosphamide and rituximab in a phase II trial of previously untreated patients with chronic lymphocytic leukaemia.[136] This trial is valuable in that the prognostic markers IGHV gene mutations, CD38 expression, ZAP70 expression, and interphase cytogenetics were reported. The overall response rate was 91%, with 41% complete remission. Patients with TP53 anomalies had poor responses. The researchers claim that this regimen is less toxic than fludarabine, cyclophosphamide, and rituximab.

Although not yet published, even in abstract form, the Roche website has this statement concerning the German/French CLL8 trial: The pivotal CLL8 trial, initiated by the German CLL study group, successfully met its primary endpoint, by showing that patients treated with MabThera in combination with the current standard chemotherapy achieved a significant improvement in progression free survival, compared to patients treated with chemotherapy alone.

This result became apparent following the first interim analysis in January 2008. An abstract is being prepared for ASH 2008.

Alemtuzumab seems to be one of the few agents capable of killing chronic lymphocytic leukaemia cells with mutated or deleted TP53 genes. The drug has been used as first-line therapy in a phase III trial, in which it was compared with chlorambucil at a dose of 40 mg/m2 per month. Overall response rates and progression-free survival were significantly better for alemtuzumab than for chlorambucil.[137]

Unfortunately, Alemtuzumab seems to be incapable of penatrating large tumor masses and is regarded as contraindicated if lymph nodes have a diameter of greater than 5 cm. However, when used in combination with high dose methylprednisolone (another drug that is effective in CLL lacking p53 function) in a small phase II study, teh overall response rate was 100% with a 60% CR rate. [161]

References

131 JD Hainsworth, S Litchy and JH Barton et al., Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network, J Clin Oncol 21 (2003), pp. 1746–1751.

132 JC Byrd, BL Peterson and VA Morrison et al., Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712), Blood 101 (2003), pp. 6–14.

133 JC Byrd, K Rai and BL Peterson et al., Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011, Blood 105 (2005), pp. 49–53.

134 MJ Keating, S O'Brien and M Albitar et al., Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia, J Clin Oncol 23 (2005), pp. 4079–4088.

135 S Faderl, WG Wierda and S O'Brien et al., Fludarabine, cyclophosphamide, mitoxantrone plus rituximab (FCM-R) as frontline therapy for CLL: results of a phase 2 study, Blood 108 (2006), p. 2836.

136 NE Kay, SM Geyer and TG Call et al., Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia, Blood 109 (2007), pp. 405–411.

137 P Hillmen, AB Skotnicki and T Robak et al., Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia, J Clin Oncol 25 (2007), pp. 5616–5623.

161 AR Pettitt, E Matutes and D Oscier, Alemtuzumab in combination with high-dose methylprednisolone is a logical, feasible and highly active therapeutic regimen in chronic lymphocytic leukaemia patients with p53 defects, Leukemia 20 (2006), pp. 1441–1445.

The Illusionist

After 'The Prestige' now comes 'The Illusionist'. Oscar nominated for Cinematography it was another period piece about conjurers. Less difficult than the Prestige and the trick more easily guessed. After Star Trek we are used to both teleportation and holograms. "Even if we escaped he would hunt us down until we are dead" says the Duchess and that is the clue. In a way, the human interest story was more accessible than that of the Prestige, but the tricks were not explained - the sword in the stone in particular when he would have had no apparatus to make it work.

The Prestige was much darker, with Hugh Jackman playing against type and Christian Bale apparently sacrificing his queen. I certainly never spotted the Tessler answer until it was revealed, but I did guess the twin. Of the two, my wife preferred the Illusionist, but I preferred the Prestige.

CLL Treatment: Purine analogues

With the introduction of purine analogues, a class of drug better able to achieve complete remission in chronic lymphocytic leukaemia, the possibility has arisen of treating the disease in a similar way to other leukaemias—eg, with induction chemotherapy to achieve complete remission followed by consolidation treatment to eliminate minimal residual disease. Progress towards this end has been limited for several reasons. Complete remission in chronic lymphocytic leukaemia allows for up to 30% of chronic lymphocytic leukaemia cells to remain in the bone marrow;[121] many patients live long and symptom-free lives without achieving complete remission; and most are elderly and are not candidates for more intensive treatments. Purine analogues cause profound suppression of T-cell immunity [122] and can trigger autoimmunity.[123] If the induction-consolidation strategy is not to be followed, these hazards could outweigh the benefits.

The purine analogue fludarabine, alone or in combination, has become the standard of care in most countries other than the UK. Researchers in a meta-analysis [124] looked at five trials of 1838 patients randomly allocated either an alkylator-based regimen or a purine analogue. Individuals treated with purine analogues had significantly higher overall and complete response rates and longer progression-free survival than did those treated with alkylator-based regimens, but overall survival did not differ between treatment groups. Three further large trials had not been assessed at the time the meta-analysis was undertaken, and a difference in overall survival could yet arise as further data accumulate. However, because patients who fail one regimen can respond very well to another, this question might never be resolved. Because of this factor and because the natural history of chronic lymphocytic leukaemia is so long, researchers doing clinical trials have adopted progression-free survival as a surrogate for overall survival as the primary endpoint. However, such a strategy can be misleading.[125]

Findings of a trial in which a higher monthly dose of chlorambucil (70 mg/m2) was compared with fludarabine showed that response rates and median progression-free and overall survival did not differ between groups. Furthermore, fewer toxic effects arose in the chlorambucil group—ie, neutrophil counts lower than 1×109/L, admission for more than 1 day, and grade 1 and 2 diarrhoea. The frequency of autoimmune haemolytic anaemia was similar in both groups but seems to have been more severe in the fludarabine group than in the chlorambucil group, since two patients treated with fludarabine died from the complication.[126]

Combinations of purine analogues and alkylating agents have been tested in three randomised trials. In an Intergroup trial,[127] a fludarabine plus chlorambucil regimen had to be abandoned as too toxic. Workers on a German CLL4 trial compared fludarabine plus cyclophosphamide with fludarabine alone as first-line therapy in 375 patients younger than age 66 years,[128] and a similar comparison was undertaken in a British CLL4 trial [126] in 390 patients without age restriction. Findings of both CLL4 studies showed the combination was significantly better than fludarabine alone in terms of overall and complete response rates and progression-free survival, but overall survival did not differ between groups. Moreover, the combination was significantly more toxic than fludarabine alone in terms of neutrophil counts lower than 1×109/L, admission to hospital for more than 1 day, grade 3 and 4 nausea and vomiting, grade 1 or 2 alopecia, and grade 1 or 2 diarrhoea. However, autoimmune haemolytic anaemia was significantly less frequent with the combination. In Intergroup trial E2997,113 complete response rates were reported as 24·6% for fludarabine plus cyclophosphamide and 5·3% for fludarabine alone. Median progression-free survival was 33·5 months and 19·9 months, respectively. Both these differences were statistically significant.

Another purine analogue, cladribine, has been assessed in a three-way, randomised phase III study.[129] Researchers compared the agent alone and in combination with cyclophosphamide or cyclophosphamide plus mitoxantrone. The three-drug combination produced significantly more responses and complete remissions at the expense of more bone-marrow toxic effects. Progression-free and overall survival did not differ between groups. Mitoxantrone has also been used in combination with fludarabine plus cyclophosphamide in a phase II trial in relapsed or resistant chronic lymphocytic leukaemia.[130] The findings of this trial were remarkable because the complete remission rate was 50%, with a third of these patients having no detectable disease with a very sensitive method.

References

121 BD Cheson, JM Bennett and M Grever et al., National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment, Blood 87 (1996), pp. 4990–4997.

122 MJ Keating, S O'Brien and S Lerner et al., Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy, Blood 92 (1998), pp. 1165–1171.

123 H Myint, JA Copplestone and J Orchard et al., Fludarabine-related autoimmune haemolytic anaemia in patients with chronic lymphocytic leukaemia, Br J Haematol 91 (1995), pp. 341–344.

124 M Steurer, G Pall and S Richards et al., Single-agent purine analogues for the treatment of chronic lymphocytic leukaemia: a systematic review and meta-analysis, Cancer Treat Rev 32 (2006), pp. 377–389.

125 M Cavo and M Baccarani, The changing landscape of myeloma therapy, N Engl J Med 354 (2006), pp. 1076–1078.

126 D Catovsky, S Richards and E Matutes et al., Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial, Lancet 370 (2007), pp. 230–239.

127 KR Rai, BL Peterson and FR Appelbaum et al., Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia, N Engl J Med 343 (2000), pp. 1750–1757.

128 BF Eichhorst, R Busch and G Hopfinger et al., Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia, Blood 107 (2006), pp. 885–891.

129 T Robak, JZ Blonski and J Gora-Tybor et al., Cladribine alone and in combination with cyclophosphamide or cyclophosphamide plus mitoxantrone in the treatment of progressive chronic lymphocytic leukemia: report of a prospective, multicenter, randomized trial of the Polish Adult Leukemia Group (PALG CLL2), Blood 108 (2006), pp. 473–479.

130 F Bosch, A Ferrer and A Lopez-Guillermo et al., Fludarabine, cyclophosphamide and mitoxantrone in the treatment of resistant or relapsed chronic lymphocytic leukaemia, Br J Haematol 119 (2002), pp. 976–984.

CLL: when to start treatment

Most patients with chronic lymphocytic leukaemia present without symptoms or signs; they are identified simply because a blood test has been requested for an unrelated reason. Many of these people never progress or need treatment; however, those who do need treatment usually present in the same way.

Findings of a meta-analysis of seven trials including 2048 early-stage patients randomly allocated either immediate or deferred treatment with chlorambucil (with or without prednisolone) showed no benefit for either treatment group.[120] In a French study,[96] 51% of Binet stage A patients allocated to the deferred group eventually needed treatment and 27% of this group died of a cause related to chronic lymphocytic leukaemia.

Standard management of chronic lymphocytic leukaemia, therefore, includes a period of watchful waiting until features of progression are noted. These signs—of bulk disease, lymphoma-related symptoms, and marrow failure—have been codified by a working group sponsored by the American National Cancer Institute.[121] The document is currently under revision and is unlikely to include recommendations for changes in treatment based on new prognostic markers, but it is likely to recommend new randomised clinical trials with stratification based on such markers. Readers can view the new guidelines here.

With more effective treatments than chlorambucil and better ways of establishing which patients are unlikely to progress, the strategy of watchful waiting should be revisited. Randomised trials of early versus delayed treatment for early-stage patients with poor-risk prognostic markers are planned or underway in Germany, France, the USA, and the UK. In a meta-analysis of ten trials including 2035 advanced-stage patients,[120] addition of anthracycline or a vinca alkyloid to the alkylating agent was not shown to affect outcome.

References

96 G Dighiero, K Maloum and B Desablens et al., Chlorambucil in indolent chronic lymphocytic leukemia, N Engl J Med 338 (1998), pp. 1506–1514.

120 CLL Trialists' Collaborative Group, Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials, J Natl Cancer Inst 91 (1999), pp. 861–868.

121 BD Cheson, JM Bennett and M Grever et al., National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment, Blood 87 (1996), pp. 4990–4997.

Fundamentalist or Evangelical

We have a problem with names. The term 'fundamentalist' means someone who religion is based on the fundamentals (the basics) of the faith. But words change their meaning. Nowadays the term is most commonly applied to Muslims who like blowing up themselves and everyone around them. When applied to Christians it refers to the Religious Right, but it can be applied to anyone whose attitudes are inflexible and hostile. Richard Dawkins has been called a fundamentalist atheist.

'Evangelical' is similarly traduced. Originally, it referred to the good news, and applied to Wycliffe, Whitefield and Wesley and later to the social reformers, Wilberforce and the Clapham sect, a recent survey of British parliamentarians though it referred to those opposed to condoms (I though that was Catholics). Indeed Hansard also reveals a whole set of negative meanings; those who are opposed to contraception of any sort, who campaign against homosexuals, are opposed to women priests and bishops, open private 'creationist' schools, and preach witchcraft!

No word of the fact that Evangelicals led the campaign against slavery, the abuse of women and children in coalmines and factories, founded charities like Oxfam, Action Aid, Barnardos, the Salvation Army, Help the Aged, Tear Fund and many others. We are called anti-intellectual when we can boast Michael Faraday among our numbers.

Nevertheless, words change their meanings and we can't stick to the old terms if they now mean something else. It has been suggested that we call ourselves Biblical Christians, or Classic, Orthodox, Creedal, Historic or perhaps Committed Christians.

CLL; Assessment of prognosis

In chronic lymphocytic leukaemia, a third of patients never need treatment and have long survival; in another third, an initial indolent phase is followed by disease progression; the remaining third exhibit aggressive disease at onset and need immediate treatment.[95] The Rai and Binet staging systems have enabled individuals with chronic lymphocytic leukaemia to be divided into three prognostic groups (good, intermediate, and poor) and have provided a foundation for clinicians to design therapeutic strategies for the disease. However, with neither the Rai nor the Binet staging system can we predict who in the good prognosis group will develop progressive disease.[96] Several attempts have been made to address this deficiency. Lymphocyte doubling time, the pattern of bone-marrow involvement, and concentrations in serum of β2 microglobulin, thymidine kinase, and soluble CD23 all have some value but also important drawbacks.[97] Lymphocyte counts can double in response to infection, vaccination, and steroid treatment; patterns of marrow involvement need invasive investigation; measurement of thymidine kinase in serum needs a radioassay; and amounts of CD23 and β2 microglobulin indicate both bulk of disease and rates of progression.

As reported above in the section on Genetic abnormalities, chronic lymphocytic leukaemias with mutated immunoglobulin genes have good prognosis and those with unmutated genes show poor prognosis.[67], [68] and [98] The mutational profile of immunoglobulin genes delineates prognostic groups within all Binet's stages.[67] and [99] The IGHV mutational profile has the advantage that it remains constant during clonal evolution, which contrasts with genomic aberrations and serum markers. Since sequencing IGHV genes is seen as costly and time consuming (though this is probably not true), and it is unavailable at most medical facilities, detection of appropriate, reliable surrogate markers for IGHV mutational status has attracted worldwide attention.

An early candidate surrogate marker was expression of CD38. However, although CD38 expression is associated with poor prognosis, its relation to immunoglobulin mutational status remains controversial.[68] and [100] Furthermore, expression of CD38 can change during disease evolution and concerns exist with respect to interlaboratory variations and the definition of the best cutoff value.[97] and [101]

Crespo and colleagues [102] developed a multivariable flow-cytometric test for ZAP70 that showed 95% correlation with IGHV gene mutational status; this finding was confirmed by a similar assay that used a slightly different way of expressing the results.[103] However, these tests used indirect immunofluorescence, and a more convenient assay using direct immunofluorescence gave only 77% concordance with mutational status of IGHV genes.[104] With the direct assay, ZAP70 seemed to be superior to IGHV genes in prediction of time-to-first treatment, whereas in ZAP70-negative patients, IGHV mutational status delineated good from intermediate prognosis.104 So far, this assay has not exported well to other laboratories and considerable dispute remains about how ZAP70 amounts should be estimated.[105]

LPL is consistently overexpressed in patients with unmutated chronic lymphocytic leukaemia and has also been proposed as a surrogate marker.[106] By contrast with ZAP70, which sometimes fails to identify advanced forms of disease, this marker seems to be an independent prognostic factor for individuals with Binet stage B and C disease.[106] and [107] Assay by real-time quantitative PCR is less widely applicable than flow cytometry, but data suggest that this method is as good as IGHV mutational analysis and more reliable than ZAP70 as a prognostic factor.[108]

For laboratories with facilities to measure concentrations in serum of thymidine kinase, high amounts at diagnosis identified patients categorised into good prognosis groups by other biomarkers (IGHV, ZAP70, CD38, del13q14) who subsequently progressed to advanced disease.[109] Measurement of telomere length also refined the prognostic analysis of IGHV unmutated cases. Patients with short telomeres had significantly shorter progression-free and overall survival than did those with long telomeres.[110] Low amounts of the chemokine receptor CXCR3 predict reduced survival independent of IGHV mutations and CD38 levels.[111] The degree of upregulation of CLLU1 is an independent prognostic marker in patients younger than age 70 years.[112]

Although all these markers provide useful prognostic information, the mutational status of IGHV genes and del 17p and del 11q are the most robust prognostic indicators, having been validated in prospective phase III clinical trials. Findings of a US Intergroup study comparing fludarabine with fludarabine plus cyclophosphamide[113] showed that median progression-free survival was significantly lower for patients with del 17p13 or del 11q23 than for those with other cytogenetic findings. Although progression-free survival was longer for individuals with mutated IGHV genes than for those with unmutated genes, the study was insufficiently powered for this finding to reach significance.[113] In the UK Leukaemia Research Fund CLL4 trial comparing fludarabine, fludarabine plus cyclophosphamide, and chlorambucil, the effect of prognostic markers on outcome was assessed prospectively.[114] Importantly, prognostic factors had a greater effect on overall survival than did choice of treatment. Patients with del 17p in more than 20% of cells had a significantly poorer response rate and median overall survival than did all other individuals, whereas those with unmutated IGHV genes or del 11q23 had significantly shorter progression-free and overall survival than did those with mutated IGHV genes, no matter which treatment they were given. Findings of a CALGB 9712 phase II comparison of different schedules of rituximab given with fludarabine [115] showed that median progression-free and overall survival were significantly greater in patients with mutated IGHV genes than in those with unmutated genes. Survival was also significantly increased with the Döhner hierarchical classification of FISH results moving from del 17p13 to del 13q14.

Combinations of prognostic factors might be more useful than individual factors. CD38 and IGHV mutations100 or CD38 and ZAP70[116] and [117] both perform better than any one factor. A scoring system based on six surface molecules (CD62L [SELL], CD54 [ICAM1], CD49c [ITGA3], CD49d [ITGA4], CD38, and CD79B) detectable by flow cytometry has been proposed.118 Another using the easily available factors of age, sex, Rai stage, number of lymph nodes involved, absolute lymphocyte count, and β2 microglobulin has been assessed in many patients.[119]

By multivariate analysis, both Binet staging and IGHV genes retain their independent prognostic significance in chronic lymphocytic leukaemia and are complementary.[67] and [99] As table 2 shows, addition of Binet staging to the mutational profile of immunoglobulin genes and 17p13 deletion, which is the strongest independent prognostic marker, allows segregation of patients into five prognostic subgroups. We do not claim this prognostic system to be definitive; undoubtedly incorporation of other factors will give greater refinement, but it makes use of the best established and validated factors.

In conclusion, recognition of novel biological variables has had a major effect on our understanding of chronic lymphocytic leukaemia. Some variables seem to be of considerable prognostic importance but, as yet, no evidence is available to suggest that changing therapeutic approaches on the basis of these results will lead to improvement in outcome. Prospective clinical trials are needed to address the stratification of patients according to these factors.

References

95 G Dighiero, Unsolved issues in CLL biology and management, Leukemia 17 (2003), pp. 2385–2391.

96 G Dighiero, K Maloum and B Desablens et al., Chlorambucil in indolent chronic lymphocytic leukemia, N Engl J Med 338 (1998), pp. 1506–1514.

97 E Montserrat, Classical and new prognostic factors in chronic lymphocytic leukemia: where to now?, Hematol J 3 (2002), pp. 7–9.

98 K Maloum, F Davi and H Merle-Beral et al., Expression of unmutated VH genes is a detrimental prognostic factor in chronic lymphocytic leukemia, Blood 96 (2000), pp. 377–379.

99 Y Vasconcelos, F Davi and V Levy et al., Binet's staging system and VH genes are independent but complementary prognostic indicators in chronic lymphocytic leukemia, J Clin Oncol 21 (2003), pp. 3928–3932.

100 TJ Hamblin, JA Orchard and RE Ibbotson et al., CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease, Blood 99 (2002), pp. 1023–1029.

101 P Ghia, G Guida and S Stella et al., The pattern of CD38 expression defines a distinct subset of chronic lymphocytic leukemia (CLL) patients at risk of disease progression, Blood 101 (2002), pp. 1262–1269.

102 M Crespo, F Bosch and N Villamor et al., ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia, N Engl J Med 348 (2003), pp. 1764–1775.

103 JA Orchard, RE Ibbotson and Z Davis et al., ZAP-70 expression and prognosis in chronic lymphocytic leukaemia, Lancet 363 (2004), pp. 105–111.

104 LZ Rassenti, L Huynh and TL Toy et al., ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia, N Engl J Med 351 (2004), pp. 893–901.

105 G Marti, A Orfao and C Goolsby, ZAP-70 in CLL: towards standardization of a biomarker for patient management: history of clinical cytometry special issue, Cytometry B Clin Cytom 70 (2006), pp. 197–200.

106 P Oppezzo, Y Vasconcelos and C Settegrana et al., The LPL/ADAM29 expression ratio is a novel prognosis indicator in chronic lymphocytic leukemia, Blood 106 (2005), pp. 650–657.

107 D Heintel, D Kienle and M Shehata et al., High expression of lipoprotein lipase in poor risk B-cell chronic lymphocytic leukemia, Leukemia 19 (2005), pp. 1216–1223.

108 MB van't Veer, AM Brooijmans and AW Langerak et al., The predictive value of lipoprotein lipase for survival in chronic lymphocytic leukemia, Haematologica 91 (2006), pp. 56–63.

109 C Matthews, MA Catherwood and TC Morris et al., Serum TK levels in CLL identify Binet stage A patients within biologically defined prognostic groups most likely to undergo disease progression, Eur J Haematol 77 (2006), pp. 309–317.

110 I Ricca, A Rocca and D Drandi et al., Telomere length identifies two different prognostic subgroups among VH-unmutated B-cell chronic lymphocytic leukemia patients, Leukemia 21 (2007), pp. 697–705.

111 E Ocana, L Delgado-Perez and A Campos-Caro et al., The prognostic role of CXC3R expression by chronic lymphocytic leukemia B cells, Haematologica 92 (2007), pp. 349–356.

112 P Josefsson, CH Geisler and H Leffers et al., CLLU1 expression analysis adds prognostic information to risk prediction in chronic lymphocytic leukemia, Blood 109 (2007), pp. 4973–4979.

113 MR Grever, DM Lucas and GW Dewald et al., Comprehensive assessment of genetic and molecular features predicting outcome in patients with chronic lymphocytic leukemia: results from the US intergroup phase III trial E2997, J Clin Oncol 25 (2007), pp. 799–804.

114 DG Oscier, R Wade and J Orchard et al., Prognostic factors in the UK LRF CLL4 trial, Blood 108 (2005), p. 299.

115 JC Byrd, JG Gribben and BL Peterson et al., Select high-risk genetic features predict earlier progression following chemoimmunotherapy with fludarabine and rituximab in chronic lymphocytic leukemia: justification for risk-adapted therapy, J Clin Oncol 24 (2006), pp. 437–443.

116 I Del Giudice, A Morilla and N Osuji et al., Zeta chain associated protein 70 and CD38 combined predict the time to first treatment in patients with chronic lymphocytic leukemia, Cancer 104 (2005), pp. 2124–2132.

117 R Schroers, F Griesinger and L Trumper et al., Combined analysis of ZAP-70 and CD38 expression as a predictor of disease progression in B-cell chronic lymphocytic leukemia, Leukemia 19 (2005), pp. 750–758.

118 A Zucchetto, R Bomben and M Dal Bo et al., A scoring system based on the expression of six surface molecules allows the identification of three prognostic risk groups in B-cell chronic lymphocytic leukemia, J Cell Physiol 207 (2006), pp. 354–363.

119 WG Wierda, S O'Brien and X Wang et al., Prognostic nomogram and index for overall survival in previously untreated patients with chronic lymphocytic leukemia, Blood 109 (2007), pp. 4679–4685.

FISH and mutations

I have recently been asked whether del 11q is also influenced by the mutational status of IgVH genes. As you can see by these two survival curves, the answer is yes. I had not asked our data the question before, but the answer is clearly that for untreated patients the IgVH mutations trumps FISH. It ought to be publicised amongst oncologists because not a lot of people know this.

Fish oil scam

In a recent Doctor Who story aliens took over a school and fed chips fried in a special alien brain-improving oil to the kids. Students who performed poorly were taken out of class and eaten. This was fiction but not a million miles away from what actually happened in schools in Durham in 2006-7. In September 2006 all year 11 pupils at the county’s 36 comprehensive schools were offered omega-3 fish oil supplements. Dave Ford, the county’s chief schools inspector, said: “We are able to track pupils’ progress and we can measure whether their attainments are better than their predicted scores.”

Although the GCSE results were published last summer, the county has still to say whether the omega-3 supplement had any effect.

County councillor Michelle Hodgson: “Our evaluation of levels of take-up and perceptions of staff, pupils and parents will be made public once all of the relevant information from participating schools has been properly collated and analysed.”

She added: “As we have said previously it was never intended, and the county council never suggested, that it would use this initiative to draw conclusions about the effectiveness or otherwise of using fish oil to boost exam results.”

Really?

Take a look at Ben Goldacre's blog.

Dr Madeleine Portwood, senior educational psychologist at Durham county council, who ran the “trial”, says: “Previous trials have shown remarkable results and I am confident that we will see marked benefits in this one as well.”

In the Daily Mail article from September 5 2006 headlined “Fish oil study launched to improve GCSE grades“, Dave Ford, the council’s chief schools inspector, says: “We will be able to track pupils’ progress and measure whether their attainments are better than their predicted scores.”

Durham county council’s own press release from the beginning of the “trial” reads: “Education chiefs in County Durham are to mount a unique back-to-school initiative today which they believe could result in record GCSE pass levels next summer.”

It says that children are being given pills “to see whether the proven benefits it has already brought children and young people in earlier trials can boost exam performances too”. The council’s chief schools inspector is “convinced” that these pills “could have a direct impact on their GCSE results … the county-wide trial will continue until the pupils complete their GCSE examinations next June, and the first test of the supplement’s effectiveness will be when they sit their ‘mock’ exams this December.”

Unfortunately the GCSE results for Durham were rather disappointing this year. This fact was not press-released by the county council.

CLL: apoptosis and proliferation

Accumulation of mature B cells that have escaped programmed cell death and undergone cell-cycle arrest in the G0/G1 phase is the hallmark of chronic lymphocytic leukaemia.[83] These cells have a low proliferative activity, and data lend support to the hypothesis that in-vivo defective apoptosis accounts for accumulation of B cells. In chronic lymphocytic leukaemia cells, translocations of the BCL2 gene are rare (fewer than 1% of cases)[84] despite high amounts of the BCL2 protein. The role of BCL2 in apoptosis inhibition is not clear, since no correlation exists between in-vitro apoptosis and the amount of BCL2 expression.[85] However, other members of the BCL2 family, such as anti-apoptotic proteins BCL-XL (alternative splice variant of BCL2L1), BAG1, and MCL1, are overexpressed whereas proapoptotic proteins, such as BAX and BCL-XS (alternative splice variant of BCL2L1), are underexpressed.[83]

Deregulation of cell-cycle regulatory genes might also contribute to accumulation of malignant cells in early phases (G0/G1) of the cell cycle. In chronic lymphocytic leukaemia cells, raised amounts of the cyclin negative regulator CDKN1B protein are recorded in most patients.[85] In view of the key role of this protein in cell-cycle progression, its overexpression in chronic lymphocytic leukaemia cells could account for the accumulation of B cells in early phases of the cell cycle. These data suggest that chronic lymphocytic leukaemia is a disease resulting from accumulation rather than proliferation.

By contrast with in-vivo results, apoptosis happens after in-vitro culture, indicating a role of the microenvironment in chronic lymphocytic leukaemia cell survival.[86] and [87] Findings showing that apoptosis in vitro is prevented by exposure to interleukin 4 and by stimulation via surface CD40 also favour this view. In vivo, such inhibition can happen in pseudo-follicles seen in the lymph nodes and in cell clusters described in bone marrow.[88] These pseudo-follicles include, in close contact with proliferating B cells, increased numbers of CD4 T cells expressing CD40 ligand. These activated CD4 T cells could be recruited by tumour B cells, since they constitutively express the T-cell-attracting chemokines CCL17 and CCL22.[88] and [89] This idea could be in agreement with a model of selective survival of certain clonal submembers, which would receive survival signals in these particular sites.

With a non-radioactive, stable isotopic labelling method to measure chronic lymphocytic leukaemia kinetics, Messmer and colleagues [90] showed that B-cell chronic lymphocytic leukaemia is not a static disease, resulting simply from accumulation of long-lived lymphocytes, but is a disease with a dynamic process in which cells proliferate and die, sometimes at appreciable levels. This finding is in conflict with the view that chronic lymphocytic leukaemia is characterised almost exclusively by cell accumulation due to a defect in apoptosis. This mechanism might compensate for the clonal decrease that could take place in the periphery by apoptosis and, depending on its importance, could have a major role in regulation of tumour burden.

A picture is emerging that emphasises the importance of proliferation centres in lymph nodes spleen and bone marrow. Here, stimulation by CD31 on endothelial cells and CD154 on T-cells activates chronic lymphocytic leukaemia cells, upregulating CD38 and perhaps ZAP-70, provoking cell division and reinforcing resistance to apoptosis. From the proliferation centre the cell emerges into the circulation, where levels of activation markers begin to decline at a rate determined by intrinsic qualities of the cell. Cells that are better at retaining activation markers are drawn back into the tissues by chemokines and once there repeat the whole cycle. CD38 can be seen as an index of how recently the CLL cell has visited a proliferation center. [91], [92], [93] and [94]

References

83 F Caligaris-Cappio and TJ Hamblin, B-cell chronic lymphocytic leukemia: a bird of a different feather, J Clin Oncol 17 (1999), pp. 399–408.

84 MJS Dyer, VJ Zani and WZ Lu et al., BCL2 translocations in leukemias of mature B cells, Blood 83 (1994), pp. 3682–3688.

85 R Vrhovac, A Delmer, R Tang, JP Marie, R Zittoun and F Ajchenbaum-Cymbalista, Prognostic significance of the cell cycle inhibitor p27Kip1 in chronic B-cell lymphocytic leukemia, Blood 91 (1998), pp. 4694–4700.

86 L Lagneaux, A Delforge, C Dorval, D Bron and P Stryckmans, Excessive production of transforming growth factor-beta by bone marrow stromal cells in B-cell chronic lymphocytic leukemia inhibits growth of hematopoietic precursors and interleukin-6 production, Blood 82 (1993), pp. 2379–2385.

87 F Caligaris-Cappio, Role of the microenvironment in chronic lymphocytic leukaemia, Br J Haematol 123 (2003), pp. 380–388.

88 L Granziero, P Ghia and P Circosta et al., Survivin is expressed on CD40 stimulation and interfaces proliferation and apoptosis in B-cell chronic lymphocytic leukemia, Blood 97 (2001), pp. 2777–2783.

89 FK Stevenson and F Caligaris-Cappio, Chronic lymphocytic leukemia: revelations from the B-cell receptor, Blood 103 (2004), pp. 4389–4395.

90 BT Messmer, D Messmer and SL Allen et al., In vivo measurements document the dynamic cellular kinetics of chronic lymphocytic leukemia B cells, J Clin Invest 115 (2005), pp. 755–764.

91 C Pepper, R Ward and TT Lin et al., Highly purified CD38+ and CD38− sub-clones derived from the same chronic lymphocytic leukemia patient have distinct gene expression signatures despite their monoclonal origin, Leukemia 21 (2007), pp. 687–696.

92 S Deaglio, T Vaisitti and S Aydin et al., CD38 and ZAP-70 are functionally linked and mark CLL cells with high migratory potential, Blood 110 (2007), pp. 4012–4021. Full

93 RN Damle, S Temburni and C Calissano et al., CD38 expression labels an activated subset within chronic lymphocytic leukemia clones enriched in proliferating B cells, Blood 110 (2007), pp. 3352–3359.

94 S Willimott, M Baou, S Huf, S Deaglio and SD Wagner, Regulation of CD38 in proliferating chronic lymphocytic leukemia cells stimulated with CD154 and interleukin-4, Haematologica 92 (2007), pp. 1359–1366.

Mad monks and a flat earth

'Can you imagine Julie Andrews in The Sound of Music staying with the Captain if the romance went out of their marriage? Would she not divorce him and grab his children to be her toys? All the elements of pornography are there...'

'The Sound of Music is an immoral film because it puts friendliness and fun in the place of authority'.

I report these sayings of Bishop Richard Williamson because he has recently hit the news by claiming that the Protocols of the Elders of Zion, a notorious anti-Semitic forgery that enjoys widespread currency in neo-Nazi circles, is authentic.

The dateline in The Catholic Herald is April 1st, so make of it what you will, but according to reports Richard Williamson who was an Anglican who defected to Archbishop Lefevre's Society of St Pius X where he was ordained a bishop in defiance of the Pope is currently ministering in Argentina to extreme right wing groups. He is widely regarded as the "Borat" of the Catholic Church.

I came across the Protocols of the Elders of Zion again yesterday while I was reading Serendipidies by Umberto Eco. Eco's books are erudite but hard to read. His most famous book is The Name of the Rose, a tribute to Sherlock Holmes set in the Middle Ages, but the other volumes of his that I have on my shelves have remained half read.

Serendipities is a series of essays, the first of which discusses among other things the idea that the Christian Church once believed that the earth was flat. It was a charge leveled at the church in the Darwin versus religion debate of the nineteenth century. It is claimed that Columbus was opposed by the clergy because they thought he would sail over the edge of the world as in Terry Pratchett's Discworld. Just like the Protocols of the Elders of Zion, the flat earth theory is a nonsense. That the world was spherical was known to the Ancient Greeks like Pythagoras and Euclid and certainly to the Church Fathers like Origen and Augustine,. Thomas Aquinas is very clear about it. There was a monk in the 4th century who believed the world was shaped like the Tabernacle of the Pentateuch, but no-one took any notice of him until he was translated into English by the Darwinists for a debating point.

As Richard Williamson demonstrates, you can always find a mad clergyman.