Sunday, April 27, 2008


There is something attractive about the idea of socialism. Who could fail to be attracted by the ideal of giving to those who are needy and receiving from those with a surplus? Wouldn't you want a world of peace, where disputes were settled by reasoned argument rather than by power plays, where nationalism takes a back-seat to community and where all are considered equal before God and the law?

What a splendid idea that the sick should not want for medicine because the whole society picks up the bill, that the poor and handicapped have the rich and privileged as benefactors and even the criminal can be forgiven and redeemed.

Why is it, then, that socialist states bankrupt themselves, tend toward authoritarianism, imprison and execute those who disagree with their leaders and level down rather than raising up?

An old saw says anyone who is not a socialist before they are 25 hasn't got a heart; anyone who is still a socialist after they reach 25 hasn't got a head. It is certainly true that socialists tend to be younger than conservatives. The only time I rejoiced in a socialist victory in the polls was in 1966 when I was 23.

The answer to all these questions, is, of course, human nature. I am sure that in heaven we will hold all things in common, and there will be no police state, no greed, no backbiting, no internal strife. Everyone who goes to heaven has to be transformed by the Holy Spirit. Published today are the memoirs of Michael Levy, Tony Blair's fixer. Last year he was arrested, though not charged, concerning the 'cash for honors' scandal. What the memoirs reveal is how deep was the quarrel between Blair and Gordon Brown, the current Prime Minister. Blair, he says, thought that Brown could never defeat David Cameron in a general election. He thought that Brown was a liar who couldn't be trusted. In the end Levy came to realise that Tony Blair, his mentor and friend, was just a politician - in it for himself.

One reason that I would never put myself forward for office is that I know myself. I couldn't be trusted not to put my own interests first. Why is it that politicians generally are held in such low esteem? Because people recognize what human nature is like. The current battle between Obama and Clinton is revealing the dark side of both candidates.

For a socialist Tony Blair was a remarkably successful politician, but he achieved this by abandoning most socialist principles. His first act as leader was to get the Labor party to disavow its commitment to taking major industries into public ownership. He continued Mrs Thatcher's policy of espousing free market economics. He did not repeal the anti-Trades Union legislation that Thatcher had enacted. Nevertheless, he kept the welfare state, introduced a negative income tax for the poor and poured money into free education and the NHS.

In the end, he was brought down by hubris. Perhaps because of his supposed intimacy with God, he thought he could solve everybody's problems. He brought the Catholics and Protestants together in Northern Ireland. He intervened in Bosnia and Kosovo. He sorted out Sierra Leone. He became a firm ally to George Bush after 9/11 and sent the second largest contingent of troops to Afghanistan. Then came Iraq. I do not know Bush's motive in invading Iraq. I think I know Blair's. He wanted legality; he wanted an excuse that would justify invasion in the eyes of the world; but most of all he wanted an end of the foul regime of Saddam and the Baathists. He thought he was the man to do it.

Alas liberating Iraq was not like liberating Paris. It was more like taking the lid off a pressure cooker. I believe that Bush was naive about Iraq though Cheney was seeking the main chance and Rumsfeld was conducting an intellectual experiment with people's lives. In the end Iraq may yet end up a better place, at the expense of hundreds of thousands of lives, but it could have been done better. Worst of all it has deterred intervention in a dozen other places where cruelty and hardship are inflicted by criminal rulers. Darfur, Congo, Zimbabwe and Burma are just a few of the failed states beyond help.

The failure of socialism is that individuals do not suffer the consequences of their actions. Those who do not save for their old age are supported by the taxpayer; so why should anybody save?

Those who do not work are fed and housed by the taxpayer; so why should anybody work?

Those who do not obey the law are let off several times before they receive a prison sentence, and while in prison are provided with color TV, recreation, table tennis, snooker, a library and cheap drugs; so why should anyone obey the law?

You might reply that life is better if you do work, save and obey the law. Not if taxation burgeons.

Blair promised to be tough on crime; tough on the causes of crime. Sounds good, though he thought crime was caused by poverty, social deprivation, poor housing and the like. That's the wrong diagnosis. Crime is cause by the rebellious human heart. The guy who swindles millions on the stock exchange is neither poor, poorly housed nor socially deprived. He's wicked. Just like the thug who mugs old ladies, the black kid who stabs another for wandering on to his 'turf', the motorist who drunkenly ploughs through a bus queue or the philanderer who turns in his 50-something wife for a newer model.

Socialism doesn't work because of the human heart. It's nice to have ideals but I'd prefer politicians who are realists.

Thursday, April 24, 2008

Running with horses.

Do you get thoroughly disgusted with the shams and morons that are served up to us daily as celebrities? There is so little to admire in our culture. There are no heroes to imitate. Our celebrities are adulterers and fornicators, drug addicts and drunks, liars and exhibitionists. Infamous criminals act out the aggressions of timid conformists and petulant and spoiled athletes play games vicariously for lazy and couch-potato spectators. People, aimless and bored, amuse themselves with trivia and trash. Neither the adventure of goodness nor the pursuit of righteousness capture the headlines.

I am quoting (loosely) from Eugene Peterson's (author of The Message) 1983 book, Run with Horses. If anything has changed in the 25 years that have passed since he wrote that it is that the situation is worse. Nowadays people become celebrities, not for being able to run fast, or throw a ball better, or having a pretty nose, but because they have appeared on reality television. They are famous for being famous. Their behaviour is ever more outrageous and the TV camera laps it up.

These extraordinarily exotic performers are featured because they seem so different from our own humdrum lives. We feel ourselves to be plain and ordinary, a mass of nondescript conformists who just follow the rules. So bo-o-o-ring.

When Peter Jackson was filming Lord of The Rings, the story for thousand of actors, more than there were people in New Zealand. He solved his problem by duplicating his few actors over and over again with CGI. God is not like that. He never, through fatigue or worn out by the rigors of creativity, resorts to mass-produced copies. God's creative genius is endless. Each life is a fresh canvas on which he uses lines and colors, shades and lights, textures and proportions he has never used before.

Yesterday I listened to a discussion on the radio between the poet Bernard O'Donahue, author Salman Rushdie, film maker Mike Leigh and critic Margaret Reynolds in which they agreed that it was difficult to portray goodness in fictional characters. Actors often prefer to play villains because it is easier to make a scoundrel interesting. Good men suffer from blandness.

We should all try to live good lives, but how do we encourage that without inciting pride and arrogance? Many voices to encourage us towards excellence, but they tell us to achieve excellence by gratifying our desires. You need to fulfill yourself, we are told, let go your inhibitions. The opposite is true. We need to lose our self to find our selves. Yet in denying ourselves we need to avoid becoming a doormat.

In contemplating how to achieve greatness through righteousness Peterson recommends a study of the life of Jeremiah, not his prophesies, but the biographical parts of his book.

Once in Jeremiah's life, when worn down by opposition and absorbed in self-pity, he was about to give in, to capitulate to those who urged him to follow the crowd and become just another Jerusalem statistic. At this moment he hers God's reprimand: If you have raced with men on foot and they have worn you out, how can you compete with horses? If you stumble in safe country, how will you manage in the thickets by the Jordan? (Jer 12:5)

Life is difficult. Are you going to quit at the first wave of opposition? Are you going to be content with three meals a day and a dry place to sleep at night? Will you leave the battle because the majority are more interested in keeping their feet warm than in living at risk for the glory of God? Is caution or courage your watchword?

It is easier to be neurotic. It is easier to be parasitic. It is easier to be average. Easier but not better. Easier but not more significant. Easier but not more fulfilling. We are called to a life of purpose and promised the strength to carry it through. If we are worn out by this run-of-the-mill lot of mediocrities, what will we do when the real race starts? Are we going to shuffle along with the crowd or run with the horses?

Do we difine ourselves minimally as featherless bipeds or maximally as "a little lower than God"? Jeremiah's choice was to run with the horses and dare the jungle of the Jordan.

Tuesday, April 22, 2008

More about Ronnie and June

And so I did. By the time I had finished, Corky had stopped his cussing and struggling and was sleeping peacefully.

Relieved that he had finally succumbed to the booze, I started to examine him properly. I asked Jeremy Stevens “Should he have different sized pupils?”

Stevens had never moved so fast. He zoomed him up to neurosurgery where they relieved the pressure by undoing my stitches and Corky woke up. The Casualty officer had to take the flak for that, but since no harm was done (apart from what the Indians had inflicted on Corky who survived for several more years before the cirrhosis got him),

I told the story to June with flamboyant humour. She was not impressed and called me callous and unfeeling. I lost my temper and stormed out. A week later I came back with flowers and we were ‘on’ again. That’s how it went; one month we were together, the next we were apart. We both had strong opinions and didn’t hold back for the sake of not giving offence.

We talked about getting married but in the end the strong emotions made harmony impossible. I was surprised that she was so upset when I told her that we had no future as a couple. Within a week she had resigned her job and flown to Hong Kong.

I was already a consultant when I saw her again. Time had passed. I was married with children and consumed with the busy-ness of life. My secretary buzzed and told me that a Mrs Thompson wanted to speak to me. None of my patients were called Thompson, so I had no special expectations.

“John? It’s June.”

June Thompson was not a name I knew. There was something strange about her accent. “I’m sorry, are you Scottish?”

“John? It’s June Peters.”

This was the last thing I was expecting. Frankly, I had never expected to hear from her again.

“I am in England. Can we meet?”

Of course, I should have said there was no point. But I was so full of myself. I was walking on water in my job. My practice was booming, my reputation burgeoning and my income swelling. I had bought a large house and I drove a smart car. I had even appeared on television. Fame was beckoning. I believed that nothing could go wrong and that I could get away with anything.

We agreed to meet at Winchester Cathedral. It was halfway between her and me, and I could manufacture an excuse to go to Winchester.

A few days later I parked my car in the nearby multi-story and walked to the Cathedral Close. She was late or I was early, and I panicked and thought myself a fool for agreeing to this when I couldn’t find her. I thought I must have missed her. Then I saw her. She hadn’t changed. She still had the rather short fair hair, the same tip-turned nose, the same earnest look. As we approached I wondered whether we would shake hands or just speak, but she threw her arms around my neck and kissed me. We held hands as we walked to the nearby pub where she drank lemonade; I drank shandy. We talked of what might have been, all the time our eyes locked as if they were beads strung on the same necklace.

She had married an Thai man and had two children. She was teaching eleven-year olds in Singapore. She was visiting her parents for the first time in seven years. She talked, I talked. We had adultery in our hearts and on our minds. We agreed to go to a hotel. “You drive,” she said.

We walked together back to the multi-story car park. As we reached the correct floor, I was perplexed to see my car hood open. There was a pool of water on the floor beneath it. I looked beneath the hood. The radiator was missing. A black, greasy handprint was on the wing.

This was in the days before cell phones and it took us some while to find a pay-phone. I called the police. “My car radiator has been stolen.”

“Your car radio?”

“No, not radio. Radiator.”

Silence. “Exactly where are you, sir?”

It took ages to get things sorted out with the police and the car towed away to the garage. The moment had passed. There was no more magic. I never saw her again until now.

Monday, April 21, 2008

1 Timothy 6:17-19

Command those who are rich in this present world not to be arrogant nor to put their hope in wealth, which is so uncertain, but to put their hope in God, who richly provides us with everything for our enjoyment. Command them to do good, to be rich in good deeds, and to be generous and willing to share. In this way they will lay up treasure for themselves as a firm foundation for the coming age, so that they may take hold of the life that is truly life.

'From each according to his abilities; to each according to his needs' is a Marxist principle that Karl Marx derived form the early church (his parents were Christians). In Acts 2:44-45 we read that the church sold, pooled and shared their resources. Alas, Romans 15:25-27 tells us that, like the Eastern European states that adopted this policy, the Jerusalem church became penniless and dependent on aid. It was probably their belief in the imminent return of the Lord that prompted them to act so recklessly, but later, when Paul was writing to his young colleague, Timothy, he still stresses the need for the wealthy to be generous.

A pastor friend of mine, early in his ministry was caught up in a previous housing price collapse. His house became worth less than his mortgage. If he sold it he would be left with an unsecured debt, so the bank called him in to examine his finances. They were astonished to find that 10% of his salary was remitted back to the church that employed him. Now that we have minimum wage laws they might have told him that this was an illegal practice, an employer cannot use this technique to get around minimum wage provisions. But there was no compulsion about it, He tithed voluntarily out of gratitude to God. The church as a whole had no knowledge of what he gave. Many people give through an anonymous Trust to keep it secret between themselves and God. Otherwise it might become a matter of boastfulness. I heard of churches in South Korea, where part of the service comprises the reading out of who gave what at the previous week's services. What can be the point of that except to gain the praise of men.

Someone recently left this comment on an earlier article on the blog: "According to the Bureau of Labor Statistics, Department of Labor, United States Government, the average salary of a general practitioner with more than one year's experience is $156,010 per annum. An anesthesiologist with more than one year's experience averages $321,686 per year. No matter who you ask, those salaries are way above average; some may call them extraordinary".

I agree. Doctors earn far more than they need to live on. But then, compared with similar over-achievers who go into finance, the law, or big business, the financial rewards are less than average. Perhaps unfortunately, if you are fishing for big fish you have to cast your nets into a deep pool. But having accumulated all this wealth, what's a rich man to do with it? It is certainly true that he can't take it with him when he dies, and if he dies a rich man, then he has worked hard for the reward of some writing on a piece of paper.

He might decide to leave it to his children. It is a true saying that where there's a will there's an argument. A sure way to spoil your children is to give them something that they haven't worked for. Of course, it is useful to help them onto the housing ladder and give them a good education, and you must cater for any special health needs or handicap, but why would they want to be afflicted with your money in their fifties or sixties?

Therefore, Paul's advice is sound. Do good, be rich in good deeds, and be generous and willing to share. The reason to do this is not to gain merit for yourself. It is not to buy your salvation. It certainly not to obtain the praise of men. I urge you do your good deeds secretly. It is to 'take hold of the life that is truly life'.

Sunday, April 20, 2008

More aphorisms

The peculiar arrangement of the human ocular apparatus precludes one's viewing that which is immediately anterior to one's olfactory organ.

Flowers are the sexual organs of plants; they are far more attractive than those of animals.

We all have freedom of choice, but we are not free to choose the consequences of our choices.

“Imagination is more important than knowledge” Albert Einstein.

"If I could remember the names of all those particles I could have been a botanist" Enrico Fermi.

Fame is a food that dead men eat,-
I have no stomach for such meat.

What is fame? An empty bubble;
Gold? A transient, shining trouble.

Love of fame is the last thing that even learned men can
Bear to be parted from – Tacitus

It’s not the violence of the few but the silence of the many that scares me.

People will not care how much you know until they know how much you care.

God isn’t interested in your ability; just your availability.

Psalm 123.

Psalm 123 is a very short one, only four verses, but it addresses a problem for the modern Christian. That problem is the ridicule and contempt of the world. It is not a new problem. Think of the Apostle Paul preaching on Mars Hill. His sermon is an example of his vow to know nothing but Jesus Christ and him crucified, but although some of his audience wanted to hear more, others sneered at the mention of the resurrection from the dead.

Or think of Jesus on the cross. As he was dying, the people watching mocked, "He saved others, but he can't save himself. He trusts God. Let God rescue him." The soldiers also mocked him as they pretended to worship him. The robbers crucified with him heaped insults upon him.

Remember who we are. If they abused Him, they will surely abuse us. The public have flocked to read books by Richard Dawkins and Christopher Hitchens and Sam Harris, that insult Christians and lie about the Church. They show films and television programs that mock our God and offend Christians. No-one cares that film scripts are littered with the name of Jesus Christ used as an expletive.

All through history true Christians have been the butt of abuse. Think of the Lollards, the evangelistic preachers of the fourteenth century sent out by John Wycliffe. The very name 'lollard' was a term of abuse. The Hebrew word translated 'ridicule' in the Psalm meant babble in baby talk - very like the Greek term 'barbarian'. Someone whose words went "Ba, ba, ba or lo,lo,lo" like a baby. It meant that people aped them with baby talk, implying that they were talking nonsense. The Puritans, Pietists and Methodists all received their names as terms of abuse. The Salvation Army in the nineteenth century were mocked by the established church. The other word used in this Psalm is 'contempt'. The Hebrew word refers to that which is trodden underfoot as we might stamp on a bug. In 1914 the British Expeditionary Force was holding up the Kaiser's march on Paris.The Kaiser referred to them a "Sir John French's contemptible little army". Thereafter, the British Army, which performed heroically in the First World War, referred to itself as the 'Old Contemptibles'. The term was to rebound on the Kaiser.

How should we respond to this mocking and ridicule?

First, verse 1: Remember who God is. God is not mocked. He is the Master of the Universe who sits on the throne of heaven. The earth is his footstool.He holds kings in the palm of his hand. He made us and He will judge us.

Second, verse 2: Let's keep ourselves in respective. We are servants. We look to God as a slave does to his master or a maid to her mistress. We are being mocked because of the God we serve and He can take care of himself.

In verses 3 and 4 we are shown our proper response.

We should pray. We might want revenge and punch the mocker on the nose. But we should pray. We might want to sue him for justice in the courts. But we should pray. We should pray for mercy. The word for mercy here is not the word for grace. It is not the word for salvation. We have our salvation; by grace we have our saviour. No, it is the word for help and succor. We pray for relief from our suffering.

Vengeance belongs to the Lord. Justice will come in the last days. But today is a time of mercy.

As we pray, the Lord might wreak vengeance, but we should not pray for it. I remember an old lady lividly angry at one of the decisions of the church. When visited by an elder she exclaimed in high dudgeon, "May God strike me down if this ever happens in this church!" As the elder turned his back she slipped and fractured her hip.

On one occasion in my professional life I was being attacked by a colleague in an unfair and underhand way. He was telling lies about me. Alone in a hotel bed in London, I could not sleep. I prayed to God, "Please release me from these attacks". The next day my attacker slipped on some leaves and was put out of action for several months. Be careful what you pray for.

Sometimes God will say, "My grace is sufficient for you," and we must endure, but we have the example of Christ.

This is a day of mercy. There is still time, even for the mocker. Jesus tells us to pray for our enemies. Remember that Paul held the coats of those who stoned Stephen. Suppose Richard Dawkins put his talents at the disposal of Christ. Suppose Christopher Hitchens were converted and put his energy into telling others of the gospel.

Anthony Flew was one of the world's most famous atheists. When about to debate with a Christian over the existence of God he suddenly had a change of heart. The evidence convinced him. There must be a God. There is no other explanation.

Pray for enemies. Miracles really do happen. Would you rejoice to see Dawkins destroyed and Hitchens in hell? The Word tells us that God is not willing that anyone should perish and that the angels rejoice over a single sinner saved. Don't damn Dawkins; pray for him.

Saturday, April 19, 2008

Big Pharma: hero or villain?

The relationship between pharmaceutical companies, patients and doctors is a complex one. It derives from a mish-mash of motives.

Let's start with the patient. He or she wants to be cured; if not cured, to have a longer life and a better one. Sometimes it's a choice between a longer uncomfortable life and a shorter more comfortable one. Most times neither the doctor nor the patient really knows what the outcome of treatment will be and decisions are made of a basis of statistics, false impressions and wishful thinking. Probably for most things the doctor knows best, but for other things the patient knows better. There is asymmetrical knowledge between doctor and patient. This is common in most professional relationships, but it does not make for a fair market.

When you are perplexed about whether you should buy a Ford or a Toyota there are magazines you can read to give you some insight into the choice. Should you get a Sony or a Samsung, an Epson or a Canon? Buy a "What Car" or a "What TV" or a "Which Printer" and become an instant expert. But it's not like that in medicine. A smooth talking physician may know nothing about your condition; a rude and brusque surgeon may know exactly what's right for you. How can you possibly tell? Trial and error may leave you dead or disabled. Market forces may have calamitous results.

The doctor has many motives. You might think his prime purpose is to cure as many people as possible, but if that were his motive pure and simple, he would be working in Africa and not many are. Why am I not working in Africa? Many reasons. I don't like the heat. I would miss all the mod cons. I don't speak the languages. I would miss all the diseases that are interesting to me and without the facilities I have in Britain I would be pretty useless. I need the money to support my family. And why lay it on a doctor's conscience? Africa needs engineers, accountants, businessmen, teachers and factory owners too.

So although a doctor wants to cure the sick, he wants lots of other things too. He certainly wants paying well. Not many doctors take poorly paid positions. He also wants the good wishes of the community; he likes to be well thought of. He may also want fame. Perhaps he would like the rewards that go with a successful academic career such as foreign travel, smart hotels, and lavish entertainment. Perhaps his real interest is in the science; ferreting out the mechanisms of disease.

Now let's consider the pharmaceutical company. Like any other company its main purpose is to make money. How do they make money? By providing the best product to their customers at the best price. Competition ensures that those who don't perform fail. That's how the market works.

That's how it ought to work, except that the market is deficient. For one thing, it is hard to know whether a particular treatment works or not. Patients often get better from some diseases without treatment. The mere presence of a sympathetic doctor and a pink pill will cure some things. In order to sort this out, we have regulators who apply an expert eye to this thorny question. They regard the randomized controlled trial as the only legitimate way of knowing whether a drug works.

However, even randomized controlled trials (RCT) can be manipulated. For marketing is not just about ensuring that the customer knows that your product is best, but about giving the impression that your product is best. If your marketing is good people can be induced to buy an inferior product.

In an RCT, the new treatment should be compared with whatever has been the best hitherto, not with something that used to be the best. Of course, a drug might have a niche market. There may be some patients for whom what is generally the best is not the best for them. An example of what I mean is this: probably the most effective treatment for CLL is FCR, but not for patients with del 17q, for whom it works very poorly. If a new treatment is worse that FCR for most patients, but better for these patients, then it should be licensed for this exception, but not for the whole gamut of CLL.

Lately, new drugs have been compared with chlorambucil. Now I think chlorambucil is a fine drug, but I do not claim it is the most effective drug in CLL. Until fludarabine came along, chlorambucil was regarded as the standard treatment, but the Rai et al trial in the NEJM in 2000 demonstrated that fludarabine was superior in terms of response rate, complete response rate and length of remission, though not in terms of overall survival. What nobody noticed at the time was that the dose of chlorambucil chosen as a comparator was on the low side - much lower than is usually used in the UK by CLL specialists, though comparable to the dose used by US oncologists who do not specialize in CLL (in other words the dose was a very safe one).

The CLL4 trial published in the Lancet last year demonstrated that fludarabine was no better than chlorambucil when chlorambucil is used in its usual UK dose, and fludarabine is more toxic than chlorambucil used at that dose. That's why fludarabine is not licensed in the UK for first line use in CLL. However, the same trial showed that the combination of fludarabine and cyclophosphamide is superior to both chlorambucil and fludarabine given separately. And the German CLL8 trial, although it has not reported formally, is believed to show that FCR is superior to FC.

Now there may be niches where chlorambucil should be preferred - older patients, frailer patients - and there is still no evidence that any other first line treatment improves overall survival, compared to chlorambucil, but the proper comparator should be FCR now, not chlorambucil, unless one is aiming for a niche market and trying to sell the new drug as an alternative to chlorambucil on the basis that it is less toxic (either short term or long term) or cheaper.

The difficulty anyone has in using FCR as a comparator is that the average length of remission with FCR is very long - perhaps greater than 6 years - and the patent would run out on a new drug before the trial was done. So the pharmaceutical companies try to hoodwink us, by choosing a feeble comparator; not just chlorambucil but chlorambucil in a half-hearted dose.

There is another way that the market is rigged. People don't pay for their own drugs. The cost is borne by the community; either directly by the state or through an insurer who passes the cost on to employers or individuals who don't have the disease. These third party payers have little inkling of whether they are getting value for money. The UK has set up NICE to answer that, but like all bureaucracies it is slow, ponderous and lacking in insight.

So what's the answer? It's not to nationalize the pharmaceutical companies. Leukaemia drugs do occasionally come out of communist countries. Bendamustine came from East Germany, and both ATRA and Arsenic came out of China, but most drugs have come from the big pharmaceutical companies of America, Britain, Germany, France and Switzerland. Paradoxically, my solution would be to extend patent protection for drugs. Currently it is 17 years. I would make it 35 years. This would give the companies long enough to do proper trials, and long enough to recoup their costs without inflicting unnecessarily high costs on third party payers.

Can Islam be reformed?

Can Islam be reformed? Many commentators have suggested that what Islam needs is a Reformation akin to the protestant reformation of the fifteenth and sixteenth centuries. Others have suggested that it really needs a large dose of Enlightenment. How might it be reformed? Can you do a scissors and paste job on the Koran? Is it possible to reinterpret the verses of the Koran metaphorically or to 'spiritualize' them? Or is the Koran unreformable? Is the violence and mayhem integral to its message? For a fascinating debate on the subject go to Front Page.

Friday, April 18, 2008

Next page

“It would seem that the running here was involuntary. Just exactly how did a body disappear from the morgue? One heard such terrible stories about Northern Ireland, of course, but I was under the impression that things were better now. Yeats turned against them in the end, you know.”

Fiona looked puzzled, “Yates?”

“W.B. Yeats, the poet chappie. Couldn’t stand Devalera. Thought the whole thing was priest-ridden.”

Prof was on one of his famous digressions. Fiona knew better than to follow that hare. “The body was taken to the morgue on the Friday night and an autopsy scheduled for first thing Monday morning. When the pathologist came to do it, there was no body there.”

“Hm. Priest-ridden or not, we must presume that someone stole the body rather than it got up and walked away. Is there anything else that connects the two cases?”

“Yes, It appears that Kevin Murphy, the name the patient gave, was not his real name and all his other details were false too, including his next of kin. Grandmother Murphy was sorry to hear that Kevin was dead, especially since he was sitting there having tea with her when the hospital called.”

The professor sipped his tea. “I am afraid, my dear, that this has gone cold. Let’s retire to the kitchen and make another pot.”

As she waited for the kettle to boil, he sat at the table with his head in his hands. “Let us summarise. You have brought me two cases of a very rare type of leukaemia. They were both men of a similar age, both gave false details and both have disappeared, one alive and one dead.”

He thought some more. “I presume you have done a literature search?”

She brought the newly emptied teapot to the kettle and poured a small amount of boiling water into it. She swirled the water round and then emptied it down the sink. “Yes. The phenomenon of pseudo-Chediak-Higashi granules in acute leukaemia was first reported in the American Journal of Clinical Pathology in November 1974. Since then there have been around thirty similar reports from all round the world: Canada, India, Saudi Arabia, China, Sweden, Spain, most recently from the Sultanate of Oman.”

“No, not that one.” She was about to spoon tea from a packet labelled ‘Sainsbury’s Darjeeling’. He jumped up and bounded across the kitchen to the overhead cupboard from which he took a brown paper bag. “This is a special Darjeeling that Dr Chopra sends me. You remember Chopra? Or was he before your time?”

She spooned some of the dark tea leaves into the warmed pot. “Yes I remember Prakesh.” She poured the boiling water on the leaves and then closed the pot and surrounded it with the knitted tea cosy. “You know, of course, that the genetics of Chidiak-Higashi has been sorted out? It is due to a mutation in the lysosomal trafficking regulator gene known as LYST. Since the same gene is required for moving the pigment, melanin, around the kids are often albinos. They all have very poor immune systems and die young from infections, unless they have a bone marrow transplant.”

“LYST? I seem to have come across that before.” He opened a drawer of the dresser and began sorting through neatly stacked exercise books. He opened the one labeled with a large ‘L’ and flicked through the pages. “LYST”, he read,”thought to be affected in some cases of white tiger and white killer whale.”

“I see you still write things down.”

“I am afraid I am afflicted with this atrocious memory. I remember bits of things, but never the whole story. Unless I write things down, it all come out in a jumble. Dorothy is very good at filing things for me. I imagine that the same gene is not involved in the ‘pseudo’ cases?”

She winced at his memory lapse. During her own bereavement she had found herself talking of Graham as if he were still alive. “No, the gene is not involved. In fact, a whole host of different genetic abnormalities have been associated with the leukaemias. I am afraid that we are being distracted by the science. The most important fact is that we have two missing persons and we don’t know why.”

Wednesday, April 16, 2008

Aldershot Phoenix

After sixteen years Aldershot are back in the football league.

When I was a young boy I was Aldershot's mascot. My father was secretary of the supporter's club (probably because he was the only one who could read and write). I remember the old days of the third division south. Before I was ten I had travelled to away matches on the team coach to such far away exotic places as Northampton, Walsall, Leyton Orient, Exeter, Watford, Swindon, Brentford and Reading. I remember particularly one wonderful winter afternoon at Leyton. Before then, I had always thought football was played on grass; I hadn't realised that you could also play it on mud. In those days we had a centre forward called Charlie Mortimore. He also played for the England amateur team and he was very good (his brother John went on the play for and manage Chelsea). On that muddy pitch Charlie scored five as we beat them 7-2. The other two were score by Hassal, the left winger, but all the goals were made by the little right winger Ronnie Hobbs.

In those days Stanley Matthews was the idol of all English footballers. The Blackpool winger was known as the wizard of the dribble. I suppose he was like Cristiano Ronaldo without the height, the good looks, the speed or the showboating. The 1953 Blackpool v Bolton cup final was known as Matthews final. Blackpool won 4-3 and my father was there. I went to the 1954 final which should have been Finney's final, but Tom Finney's Preston North End were beaten by West Brom.

Anyway, I think Ronnie Hobbs modelled himself on Stanley Matthews and that Saturday at Leyton it certainly paid off.

The team I remember was Ron Reynolds in goal Alf Rogers and Tom Jefferson were the fullbacks. The half backs were were White, Billington and Cropley and the forwards were Hobbs and Hassal on the wings, Laird and Menzies as inside forwards and Charlie Mortimore as centre forward.

There were many other memories: a goal in 8 seconds against Hartlepool (winning that one 8-1) and a tremendous cup tie against Stoke that went to a replay. Over 15,000 were crammed into the Rec for that match. I climbed a tree to be able to see anything at all.

Sixteen years ago for the want of £100,000, the club went into liquidation and were expelled from the football league after 69 years. The club reformed, now Aldershot Town FC, and began life 5 divisions below the football league. They have had a successful non-league career, and yesterday evening by drawing with Exeter away they were crowned champions of the Conference and next season will be a League 2 club (the new name for the old Fourth Division).

Page 3

“No. He has a patient precisely similar.”

“Remarkable. Like London buses. You had better begin at the beginning and tell me the whole story.”

“My patient,” she began, “is a 35 year old man who presented to the emergency department with fever and tiredness. He had bruises on his arms and legs and scattered crepitations in both lungs. Otherwise there was nothing to find clinically. He had no living relatives and no family history of leukaemia. When asked about his occupation he said he did a little of this and a little of that. He had been completely well until three weeks before he came to the hospital.”

“Anything else about his skin?”

“No, I don’t think so.” She took a notebook from her handbag. “Oh, he had tattoos and a patch of psoriasis at both elbows.”

“Go on.”

“We admitted him to Kinross ward, did a bone marrow and, just like you, we made a diagnosis of M3, promyelocytic leukaemia. Then the chromosomes came back and he didn’t have the 15;17 translocation as he should have done. So no PML/retinoic acid receptor conjoined gene and I suppose we should not have been surprised that he didn’t respond to ATRA. We added in daunorubicin; still no response. We changed to arsenic and he goes straight into complete remission. The bleeding was a problem as you might expect, but we stuffed him full of platelets and fresh frozen plasma and we managed.”

“And how is he now?”

“Goodness knows. Last Thursday night he did a runner. Sometime between ten at night and six in the morning he left the hospital and hasn’t been seen since. I went round to his address and it turned out to be bogus. He gave the name of a doctor in South London who doesn’t exist. The NHS number he gave is also bogus.”

“He was a white, Anglo-Saxon, I suppose?”

“Certainly seemed like one. He had a London accent. The name he gave, Harry Fisher, certainly sounds English, though there is no Harry Fisher on the National Database, not with the date of birth that he gave. “

“What about the Chediak Higashi granules in the lymphocytes? Did they disappear when he went into remission?”

“Yes. What about your case, Prof? Was he similar?”

“Hardly! He was an 87-year old who had atypical TB .” The professor consulted his blue notebook again. “Yes, he was though to be too old to warrant chemotherapy and died after four days of a cerebral haemorrhage.” He read on. “There follows a little bit more on what we knew about Chediak Higashi in 1974. Did you know that it used to be called the Chediak-Steinbrinck-Higashi anomaly? Large peroxidase-positive granules in myeloid cells, normally seen as part of a congenital disease. Did you know that it also occurs in mice, Hereford cattle and Aleutian mink? In 1974 there had been only 59 human cases worldwide. Most died in infancy, with only a few surviving to early adult life. This was the first time it had been seen in an old man and the first time the granules had been seen in lymphocytes. Since it occurred in a patient with leukaemia I believed that this was part of the dysmyelopoietic process. We know that lymphocytes and myeloid cells drive from the same stem cell. It follows therefore that in my patient there had been a acquired genetic defect in the common stem cell that manifested both as the bizarre giant granules and the leukaemic process. I see that I have a note here that says ‘there will be others’.”

“And now you have seen another.”

“I have seen one other case. It was presented at a meeting of the British Society for Haematology. I rather think it was the year that it was held at Lancaster University. I think the doctor may have come from Hereford though that may be the association with Hereford cattle. Sometimes my mind begins to play tricks with me.”

“Let’s look it up. The proceedings of the meeting will be published in the British Journal.”

“Alas, would that we could, but Lancaster was the meeting when something went awry and no abstracts were delivered to the Journal. I was on the Editorial Board at the time. You might say that Lancaster bombed.”

“Prof, was that one of your awful jokes?”

“Forgive me, it slipped out. But now we have four cases with your friend’s in Northern Ireland. Tell me about that case.”

“The Irish case was very similar to ours. A man of 34, sudden onset, M3 with Chediak granules in the lymphocytes, no chromosomal abnormality and unresponsive to ATRA and chemotherapy.”

“And did their case do a runner too, as you so entertainingly put it.”

“No, their patient died. They didn’t have access to arsenic. But what is really strange is that the patient didn’t disappear, but his body did.”

“It would seem that the running here was involuntary.”

Monday, April 14, 2008

Second page

As they sat at the pine table sipping tea from bone china cups she asked about his children. “Robert is in India working with UNESCO. Jeremy works in the City at what they call a hedge fund, whatever that is. Apparently it has nothing to do with horticulture. Joanna is in San Diego at the Scripps and Elizabeth is raising five of our grandchildren in Surrey. And you? Have you remarried?”

“Prof, if I had you would have been invited to the wedding.” Her husband had died three years previously of a particularly vicious sarcoma. The whole process had taken four months from beginning to end. She had taken six months leave of absence from her job afterwards.

“Do you still talk to him?”

“Not so much now,” she replied, “do you still talk to Dorothy?” His wife had died a year ago after a long decline into Alzheimer’s.

“All the time. I became used to not getting a reply when she was alive.”

They sipped some more tea and then he said, “Right, that’s got that out of the way. What have you really come for?”

“I have a problem.”

“Yes, that much is obvious. What sort of problem? Is it a medical one? Or financial, administrative, social, or romantic? I must warn you I have no money, the national health service has been through three reorganisations since I retired, my views on society haven’t changed since the nineteen sixties and I know nothing about the modern sexual mores.”

“I want to show you a blood slide.”

“In that case you had better come into my study. Bring your tea.”

In the study he switched on his microscope, the one his colleagues had bought for him when he retired from the hospital. She took the slide from her handbag and handed it to him. He quickly adjusted the focus and moved the stage rapidly from left to right.”

“Yes. Typical M3. Do you still call it that? Promyelocytic leukaemia with faggot cells.”

“Prof!” she said, shocked, “You mustn’t call them that. Sultan bodies is the correct name.”

“After Claude? Why ever not? Collections of granules that look like meatballs, why can’t I call them faggots?”

“Because that’s a slang term for homosexuals.”

“Really? I had no idea. Still, what’s that got to do with the price of fish? Meatballs came first.”

She changed the subject, “Anyway it’s not a typical M3. It doesn’t have the chromosomal translocation and it did not respond to ATRA.”


She sighed. This was a mistake. He was even more out of touch than she thought. “All trans retinoic acid. A form of vitamin A. It was a Chinese discovery after you retired.”

“Well, did he respond to chemotherapy?”

“Not to conventional drugs, but we did get a remission with arsenic.”


“That was after your time too. Arsenic trioxide turns out to be a useful drug in leukaemia.”

“I am afraid, my dear, that I am not going to be much help to you. My knowledge was useful for a certain time, but I am like a horse breeder in the age of the automobile. Time passes and life moves on. You have convinced me, if indeed I needed convincing, that I should stick to my dahlias.”

She tried again, “Look at the lymphocytes.”

He returned to the microscope and a few seconds later he said, “Chediak-Higashi granules?”

“You agree. Have you ever seen it before?”

“Why, yes, I believe I have. Let me see.” He walked across the room and opened a glass fronted bookcase filled with navy-blue notebooks. He withdrew one from the top shelf, opened it then replaced it. He counted five along and removed another one. He began to turn pages over quickly. “Yes, I thought so. June the sixth, 1974. George Turner, aged 35. M3 with Chediak Higashi bodies in the lymphocytes. Goodness me, a second case after all this time. My dear, do you want to write a paper?”

“If we did, we would have to include Peter Swift as a co-author.”

“From Belfast? Did he refer your patient to you?”

“No. He has a patient precisely similar.”

“Remarkable. Like London buses.”

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.

Saturday, April 12, 2008

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.

Friday, April 11, 2008

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.

Thursday, April 10, 2008


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."


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.

Wednesday, April 09, 2008

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.


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.


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?

Tuesday, April 08, 2008

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]


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.

Monday, April 07, 2008

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

Sunday, April 06, 2008

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.


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.