Tuesday, November 28, 2006

Vladimir Polon

A few days ago I posted on the folly of buying the new Eurofighter to defend ourselves against attack by the Russians. Has all this changed with the apparent murder of Alexander Litvinenko in London?

After faffing around with stories about Thallium, it has become clear that he was killed by ingesting the radioactive substance Putinium 210. Media speculation has it that his assasination was ordered by Russian President Vladimir Polon. Is this likely to be true?

The Russians have a history of murdering dissidents in London. Georgi Markov, the Bulgarian, was killed during the Cold War by a ricin injection from an umbrella tip.

Funny how these conspiracy theories have a hematological flavor. Ricin, the poison derived from the Caster oil plant, is employed as an anti-cancer agent. Ricin is one of the ribosome inactivating proteins which inhibit protein synthesis by enymatically interfering with the binding of the 60s microsomal subunit to elongation factor 2 (which I wrote about in Lancet 1983 i:512). Despite the many attempts to use ricin as a warhead for immune guided missiles, killing Russian dissidents seems to be the only practical use. Now we have the Russain dissident apparently killed by radioactivity which among other things wipes out the bone marrow.

Like most commentators in the MSM I have obtained most of the following information from Wikpedia.

Polonium was discovered by Marie Curie in 1897 while investigating the cause of pitchblende radioactivity. She named it after her homeland of Poland (Latin: Polonia,) then under foreign domination (by the Russians among others) in the hope of making a political point.

In 1934 an experiment showed that when natural 209Bi is bombarded with neutrons, 210Bi, the parent of polonium, is created. Polonium may now be made in milligram amounts in this procedure which uses high neutron fluxes found in nuclear reactors. Only about 100 grams (three and half ounces) is believed to be produced each year, making polonium exceedingly rare. Since it is also very heavy, three an half ounces is very small beer indeed.

210Po is the most available isotope. It is an alpha emitter with a half-life of just over 138 days. A milligram of 210Po emits as many alpha particles as 5 grams of radium. A great deal of energy is released by its decay with half a gram quickly reaching a temperature above 900 °F. Because it emits many alpha particles, which are stopped within a very short distance in dense media and release their energy, 210Po has been used as a lightweight heat source to power thermoelectric cells in artificial satellites.

Polonium dissolves readily in dilute acids, and it is easily vaporized. 50% of a sample is vaporized in air in 45 hours at 131°F. Hence the worry in London that others might have been exposed by inhaling the vapor.
Polonium is a highly radioactive and toxic element and is very difficult to handle. Even in microgram amounts, handling 210Po is extremely dangerous, requiring specialized equipment and strict handling procedures. Alpha particles emitted by polonium will damage organic tissue easily if polonium is ingested, inhaled, or absorbed (though they do not penetrate the skin and hence are not hazardous if the polonium is outside the body).

To produce a potentially lethal radiation dose of 10 sieverts, if ingested, requires just 0.12 micrograms (millionths of a gram) of 210Po (about 525 microcuries of radioactivity). A cube of pure 210Po about the size of a written period (full stop, if you are English) would still be 3400 times the lethal dose. The maximum allowable body burden for ingested polonium is only 1,100 becquerels (0.03 microcurie), which is equivalent to a particle weighing only 6.8 × 10 to the power of -12 gram. Weight for weight, polonium is approximately 2.5 × 10 to the power of 11 (250 billion) times as toxic as hydrogen cyanide. The maximum permissible concentration for airborne soluble polonium compounds is about 7,500 Bq/cu m (2 × 10 to the power of -11 µCi/ cc). The biological halflife of polonium in humans is 30 to 50 days.

What is it used for?

  1. When it is mixed or alloyed with beryllium, polonium can be a neutron source: beryllium releases a neutron upon absorption of an alpha particle that is supplied by 210Po. It has been used in this capacity as a neutron trigger for nuclear weapons. Other uses include:
  2. Devices that eliminate static charges in textile mills and other places. However, beta sources are more commonly used and are less dangerous.
  3. Brushes that remove accumulated dust from photographic films. The polonium used in these brushes is sealed and controlled thus minimizing radiation hazards.
  4. As 210Po, a lightweight heat source to power thermoelectric cells.

Alexander Litvinenko became a KGB agent in 1986 and in 1988 was drafted into military intelligence. From 1989 to 1991 he served in counter-intelligence. In 1991, he was promoted to the Central Staff of the MB-FSK-FSB, specialising in counter-terrorist activities and infiltration of organized crime. In 1997, he was again promoted to the Department for the Analysis of Criminal Organizations of the Russian FSB with the title of senior operational officer and deputy head of the Seventh Section.
In 1998, Litvinenko claimed his superiors had ordered the killing of Boris Berezovsky, a Russian businessman who then held the high government post of Secretary of the Security Council and was close to President Boris Yeltsin; Berezovsky later fled to the UK. Litvinenko claims that he was dismissed from the FSB, and then arrested twice on charges which were dropped after he had spent time in Moscow prisons.

In 1999 he was arrested on counts of abusing duties during the anti-terrorist campaign in Kostroma. He was released a month later upon signing a written undertaking not to leave the country. Using his acquired freedom, Litvinenko fled before he could face the trial. He made his way without a passport to Turkey, where he joined his wife Marina and their son Anatoly, who had entered Turkey on tourist visas. On 1 November 2000, they immigrated to the United Kingdom, claiming political asylum, and in October 2006 he became a British citizen. In London he was employed by Berezovsky, and judging from his movements (which can be traced by a trail of radioactivity) he lived high on the hog. He has extensively criticized President Vladimir Putin, particularly his position on Chechnya.

He alleged that agents from the FSB co-ordinated the 1999 apartment block bombings in Russia that killed more than 300 people. Russian officials blamed the explosions on Chechen separatists. In December 2003 Litvinenko alleged that Vladimir Putin during his time at FSB was personally involved in organized crime.

Earlier that year he alleged that two of the Chechen terrorists involved in the 2002 Moscow theater siege were working for the FSB, and that the agency manipulated rebels into staging the attack. He claimed that the FSB got its agents out before the final attack.

In April 2006, a British MEP for London, Gerard Batten (UKIP), cited allegations by Litvinenko that Romano Prodi, the Italian Centre-Left leader (now Prime Minister) and former President of the European Commission, had been the KGB's "man in Italy". He told the European Parliament that Litvinenko had been informed by FSB deputy chief, General Anatoly Trofimov (who was shot dead in Moscow in 2005) that "Romano Prodi is our man (in Italy)". Among Litvinenko's most serious claims is that Prodi assisted in the protection of KGB operatives allegedly involved in the assassination attempt on Pope John Paul II in 1981.

In July 2006, an article written by Litvinenko alleged that Putin was a paedophile.

The papers are hinting that Putin is to blame, but as a reader of detective stories I am sensitized to the most obvious suspect being the killer. There have certainly been a series of suspicious deaths among Russian dissidents, of whom Anna Politkovskaya was the most recent until Litvinenko. We are hearing today on the News that a former Russian prime minister is ill in Moscow and that poisoning is suspected.

We have to ask the question, "What would Putin gain by having a critic killed in such a public way?" If he just wanted him disposed of, why not make it look like an accident or suicide? Was he just flexing his muscles knowing that with Europe dependent on Russian oil, he is untouchable?

Granted, Polonium210 is very difficult to get hold of and to handle, suggesting that a Government was involved. But perhaps Litvinenko was just a rather sophisticated suicide bomber (even perhaps an involuntary one); the point is not the death but the propaganda. Comrade Berezovsky might well be resourceful enough, brazen enough and callous enough to try something like that.

Sunday, November 26, 2006

News from Pakistan

A report from Pakistan in today's Sunday Times caught my eye

One woman is raped every two hours and one gang-raped every eight hours, according to the country’s independent Human Rights Commission. But under the ordinance introduced in 1979 by the dictator General Zia ul-Haq as part of an Islamization campaign, rape cases have to be dealt with in sharia courts. Victims need four male witnesses to the crime — or face prosecution for adultery.

More than 2,000 women are in jail for intercourse — either victims of rape or those who have eloped to marry for love and have then been reported, usually by one of their parents.

But after 27 years of protests by activists such as Bokhari, Pakistan’s Senate finally voted last week to pass an amendment to the ordinance drawn up by President Pervez Musharraf, despite resignation threats from MPs from religious parties.

Described by Musharraf as “a victory of justice, truth and the progressive forces”, the Women’s Protection Bill will allow civil courts to try rape cases and admit DNA evidence. It also drops the penalty of stoning to death for sex outside marriage, although activists acknowledge that such sentences are not carried out.

Throughout Europe and now in America there is a war-weariness that wants to bring the troops home from Iraq and Afghanistan. All would be well if we were to leave the Middle East to the Islamists. They would not trouble us. we could live our lives and they could live theirs. This is totally to misunderstand the nature of the war we are fighting. 9/11 was not an isolated incident. There had been Islamist attacks on the West before and there have been since.

Also in the Sunday Times from Pakistan comes this.

THE British will never win in Afghanistan by military means and should open negotiations with the Taliban, according to the former leader of Pakistan’s forces in the border areas.

On the eve of a NATO summit in Riga at which member nations will be urged to send more troops, Lieutenant-General Ali Mohammad Jan Aurakzai, who led Pakistan’s hunt for Al-Qaeda until 2004 and is now governor of North West Frontier province, said: “Bring 50,000 more troops and fight for 10 to 15 years more and you won’t resolve it. The British with their history in Afghanistan should have known that better than anyone else.”

Aurakzai said that NATO had failed to achieve any of its objectives. “Why did the coalition come to Afghanistan? To find Al-Qaeda, Osama Bin Laden, Mullah Omar and the Taliban; for democracy, reconstruction and development, and [to] leave a stable Afghanistan which wouldn’t be vulnerable to terrorists.

“All very noble, but tell me which one of those objectives have been achieved? I went to Kabul in September and they are all living in a big bunker with no control over Afghanistan. There’s no law and order. The insurgency has become far worse . . . is that a success?”

Remember the Taliban? Remember how they dealt with women?

Many years ago it was common in India for widows to throw themselves on their late husband's funeral pyre. The British, as colonial power, outlawed the practice. Many years ago it was common for black men to be transported from Africa to the New World to work as slave labor for white men on cotton or sugar plantations. The British as colonial power outlawed this and fought battles to enforce their view. Eventually Americans fought an engagement in which more Americans were killed than any other to outlaw slavery.

What has happened to Principles? Millions of people worldwide are enslaved by evil men whose philosophy has not moved on from a 7th Century religious text written by an uneducated nomad. I'm not condemning Islam as a whole; no doubt many wise men have derived from that text principles suitable for living in the 21st Century, but the Islam of the Taliban is like the Christianity of mountain men who pick up snakes and drink poison because of the spurious ending Mark chapter 16. To abandon millions of people to Taliban rule would be cowardice and selfishness, and in the long term a spectacular own-goal.

This is not to say that you can gain victory with tanks and guns, but you can certainly achieve defeat without them. There are other weapons in this war that we are engaged in. Education, construction, fresh water and proper sewage systems, electricity, good roads, and above all religious instruction are all potent armaments, but without the defense forces to protect them from mortar attacks and machine guns, they cannot be deployed.

Christians, in particular, should listen to their own Bible. "Nothing can hinder the LORD from saving, whether by many or by few." The words were spoken by Jonathan, the son of King Saul, at a time when the Hebrews were oppressed by the Philistines. Blacksmiths had been banished from the land and the Hebrews had to take their ploughshares and pruning hooks to the Philistines for sharpening at exorbitant cost. Only Jonathan and his father owned a sword. Yet armed with sticks and stones alone the Hebrews were led by God to drive the Philistines from the land.

Time has come for Christians to put away the image of God as a wimp in a white nightdress. In the Old Testament God is established as an awesome figure. To have dealings with Him is a fearsome business. In the New Testament, Jesus shows us that God has that power under control; that He can act with gentleness and kindness; that His grace is as great as His power. But is folly to disregard His power or to think that He winks at sin. The book of Revelation is explicit about the judgment to come. Jesus explicitly tells us to fear Him.

Saturday, November 25, 2006

Cross and crosser

The worm is turning. Christians are tired of being doormats. For years it has been forbidden (and downright dangerous) to mock a Moslem, bruise a Buddhist, jostle a Jew, harass a Hindu or slander a Sikh, but Christians have been fair game for any fundamentalist secularist to be rude about. Thus we have had the absurd Winterval as a replacement for Christmas, the Red Cross barring Christmas trees from its charity shops, the ridiculous "Happy Holidays" replacing "Merry Christmas", the dreadful "Jerry Springer - the opera", and religious symbols made from frozen urine and elephant dung.

Perhaps it is the injunction to 'turn the other cheek' and 'go the extra mile' that has restrained Christians, and given the impression that Christians find some sort of perverse pleasure in being insulted. Church authorities have urged restraint and tolerance. Goodness knows we don't want to go back to the Spanish Inquisition.

Now two issues have roused the troops. The first is the small cross that a member of the check-in staff at British Airways wishes to wear, that technically breaks the Uniform code. Nadia Eweida could very well wear her cross beneath her uniform, but she chooses not to; she wants to display a visible evidence of her faith. Christians differ on such emblems, much as Moslems do with the wearing of the Hijab. It is not compulsory, but a matter of personal choice. Many years ago I wore a small fish as a lapel badge, not because of any superstition but because it identified me as a Christian to other Christians, and it could also be a conversation starter. After they became very common in the 1970s I stopped, largely because they were no longer started conversations.

People who don't live in Britain will not appreciate that the part of London around Heathrow has a large population from the Indian subcontinent. Large numbers of airport workers come from what are still termed the 'ethnic minorities' Many of these are allowed to wear symbols of their faith - turbans, bangles, red spots on their foreheads and headscarves - because they can't be worn invisibly beneath their uniforms. So it appears to be discriminatory against Christians.

The suspension of Miss Eweida has caused a furore. Bishops and archbishops have written a letter to the Times, 100 MPs have vowed to boycott BA, and a website has been started called BA Boycott. From this I have selected on comment which puts the thing in a nutshell:

To BA: So, tell us. When are you morons going to paint over the British flags on all of your aircraft? I’m an American, but even I know that your flag consists of three ***gasp*** crosses. The Cross of St. George, the Cross of St. Andrew, and the Cross of St. Patrick. Just imagine how “offensive” THAT is. Remove those, as surely you must to remain consistent in your foolishness, and all you’ll have left is a WHITE FLAG. How appropriate.

The second issue is the banning of Christian Unions by several British Universities. Their offence? They refuse to allow non-Christians on their Executive Boards. Now can you imagine the Moslem Society being run by Hindus? Or the Labor party being run by Conservatives? Or the Jewish Society being run by Moslems? Again the Bishops and Archbishops of the Church of England have been moved to protest. Indeed the Christian Law Society is going to the Courts about it.

What about turning the other cheek? Sometimes we long for the days when God used to unleash thunderbolts on the slightest offender. But these are days of restraint. God is not willing that any should perish but that all would turn from their wicked ways and live. However, St Paul in prison stood up for his rights as a Roman citizen and Christians should remember that the Jesus they follow is not a long-haired wimp in a white nightdress, but the coming King. Show Him some respect, for God's sake.

Thursday, November 23, 2006

Chemotherapy combinations

Whenever an oncologist finds two drugs that are both effective in a particular cancer, his natural inclination is to combine them. It makes little sense to combine similar drugs, which work in the same way and have similar side effects. There would be little point in combining chlorambucil with cyclophosphamide or cisplatin with carboplatin or vinblastine with vincristine, but where you can mix drugs that have very different modes of action and different side effects then it often makes sense. One of the most successful combinations has been cyclophosphamide, vincristine, adriamycin and prednisolone (CHOP). Recently it has been shown that adding rituximab to this combination - R-CHOP - is even better in diffuse large cell lymphoma. However, it cannot be assumed that combination chemotherapy will necessarily be better than single agents with every tumor types. A good example of this is the comparison of CHOP and chlorambucil in CLL. Trials have shown that neither is superior, though chlorambucil is less toxic.

The CALGB trial that compared fludarabine with a fairly low dose of chlorambucil also originally had a third arm, fludarabine plus chlorambucil. The dose of fludarabine was reduced in this arm from 125 to 100 mg/sq m/month and the dose of chlorambucil was reduced from 40 to 20 mg/sq m/month. However, recruitment to this third arm was abandoned mid-trial because the toxicity was too great. Infections were more than three times as common as in the chlorambucil arm.

Cyclophosphamide is reputed to be less marrow toxic than chlorambucil, though perhaps more immunosuppressive. It didn't take a rocket scientist to think that the benefits of combination might be allied to less toxicity by combining fludarabine and cyclophosphamide (FC). The MDACC group performed a phase II trial with this combination (published in J Clin Oncol in 2001) with encouraging results. Consequently, both the Germans and the British have performed randomized phase III trials comparing fludarabine with FC. The trials differed slightly. The German trial was restricted to patients under 65, while the British trial also included an arm in which chlorambucil was given at a higher dose. The Germans used a slightly higher dose of fludarabine 150 versus 125 mg/sq m/month in the single agent arm and 90 versus 75 mg/sq m/month in the FC arm. For the latter two thirds of their trial the British used the drugs orally in equivalent doses. The CALGB trial had use 100 mg/sq m/month of fludarabine in the fludarabine plus chlorambucil combination.

Both the British and the German trials showed a higher response rate, higher complete response rate, and longer progression-free survival for the FC arm, but no difference in overall survival. In both trials FC gave significantly more bone marrow toxicity and in the British trial but not the German one, this translated into significantly more hospital admissions. In both trials the incidence of hemolytic anemia was much less in the FC arm.

In the follow up of the CALGB trial a paper published in J Clin Oncol in 2002 reported an excess of patients with myelodysplastic syndrome or acute myeloid leukemia occurring in patients who were entered into the abortive fludarabine plus chlorambucil arm There were 3.5% in this arm compared with 0.5% in the fludarabine arm and 0% in the chlorambucil arm. Indeed Guillaume Dighero, who ran the French CLL trials for many years, told me that he had never seen or heard of a case of MDS or AML occurring after chlorambucil treatment in any of the French trials. The possibility of late side effects after the combination of fludarabine plus an alkylating agent is something that needs to be worried about, and in that respect it is interesting that so far there has been only one patient developing MDS so far in the CLL4 trial. As might be expected this patient received FC, but it is far too early to draw any conclusions.

To sum up: FC might be better than chlorambucil for CLL, but it performs better only in respect of surrogate markers. It does not make you live longer than good old chlorambucil.

Interestingly, NICE looked at the the FC combination and were on the verge of recommending it on health economic grounds - a QALY would cost less than £3000. However, there is no marketing authority for the use of fludarabine in combination in the UK, and because of this NICE declined to make a recommendation. This seems to me to be crazy. There used to be a TV program in Britain called That's Life. Every week they would make a Jobsworth award for the silliest use of petty rules to avoid doing something sensible (Jobsworth comes from the expression "It's more than my jobs worth to allow you to do that"). It was suggested that a Jobsworth award should go to the British Airways official who prevented a check-in worker from wearing a small cross around her neck. With 100 British MPs vowing to boycott Brotish Airways flights, this is a supreme case of shooting yourself in the foot.

I suggest the Jobsworth award to NICE for their refusal to pronounce on the FC combination.

Wednesday, November 22, 2006

Faith Schools

Dr Patrick Sookhdeo is a priest in the Church of England. He is of Pakistani origin and is a convert from Islam. He is an academic with several links to various research institutions. This article appeared in the London Evening Standard last September.

Once there were tens. Then there were hundreds. Now Peter Clarke, head of Scotland Yard’s Anti-Terrorist Branch, speaks of thousands of militant British Muslims, indoctrinated and radicalised in British mosques and madrassas.

This is not, primarily, because of the influence of a handful of “preachers of hate”. Islamic extremism has spread in Britain thanks to a particular brand of multiculturalism encouraged by this Government. And until ministers tackle it - especially the influence of Muslim faith schools - all their new efforts to build cohesion will come to very little.

The context goes far beyond Britain. Contemporary Islam has burst out of its colonial restraints. Once colonialism removed power, jihad and territorial control from Islam, it was left a benign force focusing on prayer and good deeds. But contemporary Islam has reverted back to early Islam, with all its theological rage against the non-Muslim world. Issues like Iraq and Afghanistan have become valves for expressing this anger and hatred against Britain and the West.

Increasingly, it is the values and culture of Islam which define the identity of British Muslims. A senior British Muslim leader has defined Muslim identity as: creed, sharia and umma.

The Islamic creed is non-negotiable. Those who do not share this creed are despised as kafir (infidels). Hatred of non-Muslims is preached in many British mosques.

Meanwhile Islamic law, sharia, is deemed by the majority of Muslims unalterable. Its medieval formulations cannot be updated. Yet it is this discriminatory law which many British Muslims wish to see enforced.

Finally the umma, the worldwide community of Muslims, is the primary focus of loyalty. It represents the political as well as the religious. Muslims have a duty to defend each other. This defensive jihad is what leads Muslims to go and fight in places such as Iraq.

It might seem paradoxical that the UK, which has granted Muslims greater freedoms than any other Western country, should be the greatest Western incubator of Islamist violence. The explanation lies not only in the radicalisation of Islam but also in the Government’s policy on multiculturalism.

There is a positive aspect to a multiculturalism where people share and enjoy each other’s cultures. But the UK’s well-meaning policy of validating every faith and ethnic community culturally, in a depoliticised way, is naïve when it comes to Islam. For Islam does not separate the sacred from the secular: it seeks earthly power over earthly territory. The result is that already the UK has reached the stage of parallel societies, where purely Muslim areas function in isolation.

Worse, this is about to be made semi-official. In West Ham a gigantic mosque is planned by the radical Tablighi Jamaat group. The London Thames Gateway Development Corporation says that the new mosque will make West Ham a “cultural and religious destination”. This will be nothing less than an Islamic quarter of our capital city. But has anyone asked the people of West Ham? The non-Muslims? The moderate Muslims such as Barelwis and Sufis? The Muslim women? And shouldn’t the Government be looking into why a movement claimed as inspiration by a number of convicted terrorists should be allowed to control a whole community?

One must feel grateful for the police’s interception of terrorist plots. Yet we must tackle the root causes, rather than dealing with this threat simply by vigilance and appeasement. Giving in to the demands of Muslim extremists will not turn them into liberals loyal to the UK. They will simply want further concessions.

This is now the Government’s dilemma. With the launch of the Commission on Integration and Cohesion last month, it recognised that it must address the development of separate societies. Privately, ministers are deeply worried.

Yet at the same time the Government seems fixated on empowering an ultra-conservative Muslim leadership embodied by the Muslim Council of Britain and Muslim Association of Britain. It says sharia will never be permitted in Britain, yet it has allowed sharia-compliant mortgages, and admits that many British cities have sharia councils.

Just as important, communities minister Ruth Kelly has already excluded faith schools from the remit of her examination of integration and cohesion. Yet many Islamic schools are known to nurture values that are radically different from those of the prevailing society.

Faith schools have a long and noble tradition within the British Isles. Christian denominational schools as well as Jewish schools continue to play an important role in community cohesion. Whether Islamic schools can fill such a role is highly questionable.

Has the time come to say no to Islamic schools, whilst allowing the others to exist, even though this may seem unjust? Or should we consider a new kind of school where all children can study core subjects together in the same environment, with religious teachers - be they mullahs, rabbis or priests - instructing the children in their own faiths?

I believe Islam needs different treatment from other faiths because Islam is different from other faiths. It is the only one which teaches its followers to gain political power and then impose a law which governs every aspect of life, discriminating against women and non-believers alike. And this is ultimately why a naive multiculturalism leads not to a mosaic of cultures living in harmony, but to one threatened by Islamic extremism.

Most British Muslims are not supporters of terrorism. Some have embraced Western liberal values and society. Others are peaceful but simply prefer to live in their own separate community. Mainstream figures such as Shahid Malik MP have courageously called for British Muslims to fight against extremism.

But unless all of us, Muslim and non-Muslim alike, join forces against the kind of multiculturalism which has nurtured extremism, we may eventually find that whole swathes of London and other cities have become “cultural and religious destinations” dominated by Islamic extremists - men who would remove the very freedoms so many moderate British Muslims now appreciate.

Tuesday, November 21, 2006


Dr Patrick Sookhdeo, International Director of Barnabas Fund, sends this message from Uzbekistan

During August 2006 there was evidnece of increasing persecution of Protestant church leaders and their families, many of whom have now gone into hiding. This follows a surge of anti-Christian activity in Uzbekistan over several months. It is believed that this is linked with the 15th anniversary of Uzbekistan’s independence, today, 1st September.

A well-known church leader and evangelist, Sergey Hripunov, was given a week to leave the country with his wife and children. This is the second incident of deportation of a church leader from Uzbekistan in a month. The leader of a church started by Sergey Hripunov was given only 24 hours to leave the country with his wife and two children, the youngest of whom was only two weeks old. They were given no reason for the order, nor was there a court order accompanying it.

Around 24th August a group of Christians were arrested in the town of Termez by the Security Services. Some of the Christians, including women and children, were beaten. The following day some of the group were released, but six men were kept under arrest. Officials have as yet given no information as to why the Christians were arrested. One of the men detained was a Ukraine national, called Yuri Stefanko, visiting some friends in Uzbekistan.

In another incident in August a group of Uzbek Christians, mostly young men but also including a pregnant woman, were arrested in Surhandarya. The men were beaten and detained in jail.

Earlier in August the government introduced an increase to fines for unregistered religious activity. Anyone caught sharing their faith will now face fines between 200 and 600 times the minimum monthly salary. This is an increase on the current fines which stand at 50 to 70 times the minimum monthly salary. According to some reports their church minister will also face a fine. If a person continues to share their faith and is caught a second time they, and their church minister also, will face a prison sentence of three to eight years.

Surrogate markers

A recent Cochrane review of trials comparing fludarabine and alkylating agents (such as chlorambucil) as first line treatment for CLL found no difference in overall survival. In a meta-analysis of five trials randomizing 1838 patients there was no significant difference. What is more, it is highly likely that however many trials are done and however long we wait, we will never find a difference.

In my opinion there will be no more trials comparing fludarabine with alkylating agents. For one thing these trials take so long to do. The successor to CLL4 was projected to last 11 years. Even the MRC, which is committed to staying the course, jibbed at that. Pharmaceutical companies, who must see a return on their investment before the patent runs out, are not going to consider such trials. Another reason is the fact that you don’t just get treated once for CLL. When you relapse there is something else to try, and with the number of new agents in the pipeline there will be things to try even if you were to relapse 10 years down the line.

I want to draw your attention to an abstract at the forthcoming ASH meeting in Orlando.

This is abstract # 304 from Daniel Catovsky, Monica Else, Sue Richards, Peter Hillmen: The Lack of Survival Differences in Randomized Trials in CLL May Be Related to the Effect of Second Line Therapies. A Report from the LRF CLL4 Trial.

“We conclude from this analysis that the likely reason for the lack of (overall) survival differences in CLL4 and in other CLL trials relates directly to the better responses and improved survival rates after second line treatment in those receiving the less effective therapy first, i.e. chlorambucil (or fludarabine) in CLL4.”

What they are saying is that CLL differs from acute leukemia where the response to the first course of treatment determines the outcome. It has even been suggested that you can tell from a bone marrow biopsy 6 days after chemotherapy for acute leukemia whether the patient is going to be a long term survivor. If there is any leukemia left the patients will do badly. However, it seems to be the case that it doesn’t matter whether you give fludarabine or chlorambucil first, because you will able to get a good response second time around.

They go on to say:

“Our findings support the view that PFS (progression-free survival) and quality of life should be used when assessing new treatment modalities in CLL, while continuing to evaluate survival differences to ensure that there is no adverse effect.”

Those who design clinical trials in CLL have accepted that overall survival cannot be used as an end-point except in patients who have had several rounds of treatment and have a short life expectancy. These other end-points, PFS and QOL (quality of life), are known as surrogate end points.

I won’t say much about quality of life in this essay. For one thing it is very difficult to measure – one man’s meat is another man’s poison, but also CLL4 has so far shown no difference in QOL. It seems to be the case that patients in remission have a better QOL than patients in relapse, but whether that still holds good when you push chemotherapy to get a deeper remission has yet to be evaluated.

As far as PFS is concerned a salutary lesson was learned from a study in myeloma published earlier this year in the New England Journal of Medicine. The study from Little Rock examined the effect of thalidomide on patients having so called ‘total therapy’ ‘Total therapy’ means two autologous stem cell transplants. It had already been established that giving thalidomide after the second transplant prolonged life, so the obvious question was whether giving thalidomide from the beginning of treatment was even better. Sure enough, there was a higher response rate and a longer progression-free survival in those who had the long-term thalidomide. But overall survival was the same.

Now taking thalidomide is no picnic. It causes constipation, sleepiness and peripheral neuropathy. So the conclusion of the trial was that more thalidomide meant more side-effects but no more life.

Surrogate markers are useful if they really do translate into extra life or at least a better quality of life, but otherwise they give a false sense of security.

All we know from all these trials is that fludarabine is an active agent in CLL, with about as much activity as alkylating agents. When oncologists find two agents that are both active in a disease, which neither cures, the next thing we do is combine them. Next time I will write about combinations.

Orissa, India

It isn't only Muslims that object to conversion to Christianity as this message form India demonstrates:

Orissa: Six women converts to Christianity were beaten and then tonsured when they refused to return to Hinduism.

On 6 February a large gang of Hindu extremists forcibly entered the homes of six women, in Kilipala village, Jagatsinghpur district, and dragged them into the street. The women were singled out as they were converts to Christianity and refused to return to Hinduism. They were then subjected to beatings and the humiliation of having their heads tonsured. Those who resisted were further degraded by being stripped.

Sanjukta Kandi, one of the six victims, declared “The villagers tortured and humiliated me before forcibly tonsuring my head. They didn’t even spare my daughter.” Two of those attacked were only 15 years old. All of them have since fled the village, along with around 15 other Christians, for fear of future attacks.

Thirty-five people have been accused of the attack, including Hindu relatives of the six women. The district administration has promised to bring the perpetrators to justice, but the state of Orissa has a bad record for turning a blind eye to the persecution of Christians.

Monday, November 20, 2006

More on chlorambucil

Although in the latest British CLL4 trials fludarabine and the higher dose of chlorambucil were indistinguishable in efficacy, fludarabine was slightly more toxic. Neutrophil counts of less than 1000/cu mm occurred in 41% compared to 28%, hospitalization for more than a day occurred in 36% compared to 22% and diarrhea in 24% compared to 13%. Interestingly, haemolytic anemia was equally common in these two groups at 11% and 12%, but it tended to be more severe after fludarabine and there were some deaths among this group. Small wonder then, that NICE found that chlorambucil was actually superior to fludarabine as a single agent as first line treatment of CLL.

Why, you may ask, has the rest of the world preferred fludarabine? It was clearly on the basis of chlorambucil being given at a reduced dose in the CALGB trial. Remember that trial used chlorambucil at 57% of the dose used in the CLL4 trial, and even at the larger dose, chlorambucil was less toxic than fludarabine.

What is the proper dose of chlorambucil? For many years I have used the dose of 10mg daily for 14 days followed by 14 days rest. Few patients have not tolerated this dose. Expressed as mg/sq m/month and assuming an average surface are of 1.72 sq m, that works out as 81 mg/sq m. Clearly the LRF trial was not overdosing the chlorambucil at 70 mg/sq m.

Far be it for me to suggest that there was any irregularity in the choice of dose of chlorambucil in the CALGB trial, but the effect of this choice has been to maximize sales of fludarabine.

Another area of comparison between the two drugs has been in suppression of T cells. The results for CD4+ T cells after fludarabine are given in a paper by Keating et al in Blood 1998; 92:1165-71. They studied 127 patients whose median pre-treatment CD4+ count was 1562 per microliter. After 3 courses of fludarabine the median level was 172 and after 6 courses 163. It is difficult to discover what happens on follow up as no numbers are given, but there is a figure with a logarithmic scale. My reading of this figure is that the median CD4+ T cell count does not return to above 200 by 24 months follow-up. I should remind you that a CD4+ count of less than 200 in patients with HIV is what defines AIDS.

There are no precisely similar results for treatment with chlorambucil, but a paper appeared in Annals of Hematology last month (Lazlo et al, Ann Hematol 2006; 85:813-4). They studied the effect of chlorambucil 42 mg/sq m/week for 6 weeks and rituximab 350mg/sq m for 4 weeks followed by 4 additional cycles of chlorambucil 84mg/sq m/month on 27 patients with low grade lymphomas (some of which had CLL). Median counts at baseline were just over 500 and after the first 6 weeks they had fallen to a median of 246. After the 4 further months of chlorambucil they had fallen further to a median of 216. At nine months follow up the median count was back in the normal range.

While these studies are not completely comparable, they tend to confirm what has long been believed that fludarabine is particularly immunosuppressive compared with chlorambucil. Fludarabine is regularly used as an immunosuppressive in mini-stem cell transplants – nobody would use chlorambucil for that purpose.

Does this matter? The risks of T-cell depletion are mainly those of infection. The MDACC paper reported a risk of shingles in 13.8% of patients at risk and reactivation of herpes simplex in 3.8%. More important 8.8% developed Richter’s syndrome, which as we now know is frequently cause by failure of control of existing EBV infection. This is reminiscent of the experience of the Royal Marsden Hospital in London where they observed a 12% incidence of Richter’s transformation among CLL patients treated with fludarabine. (Thornton et al Leuk Res. 2005 ;29:389-95).

In the unpublished MRC CLL3NR trial patients failing to respond to chlorambucil or relapsing after chlorambucil were offered treatment with fludarabine second-line. The response rate was 80%. In LRF CLL4 the response rate to fludarabine given first line was 80%. In the UK fludarabine is licensed and recommended for use second-line in CLL.

As far as it goes the NICE decision not to recommend fludarabine as a single agent for first line use in CLL seems to me to be perfectly correct.

Sunday, November 19, 2006

Martyrs still

Somali Christian sources report that Ali Mustaf Maka‘il, who converted from Islam to Christianity eleven months ago, was shot and killed in the Manabolyo quarter of Mogadishu on 7 September 2006. Ali (22) was a cloth merchant and college student.

According to the source, the gunman was loyal to the Union of Islamic Courts (ICU), the Islamist organisation that took power in Mogadishu in early June 2006 and now controls much of southern Somalia. The gunman shot Ali in the back after he refused to join a crowd chanting verses from the Koran in honor of the lunar eclipse. (Solar and lunar eclipses are significant in Islam and are accompanied by special congregational prayers.) The ICU confiscated his body for 24 hours before delivering it to the grieving family.

It seems that under the new Islamist rulers, who include hard-line jihadi elements, the tragic history of persecution and martyrdom for Somalia’s tiny Christian community is set to continue and most likely to worsen.

In July 2006 there were unconfirmed reports that three Christians had been shot and killed by Islamists as they returned home from a prayer meeting. In October 2005 an evangelist and house church leader, Osman Sheik Ahmed, was shot dead by Islamist radicals. Children of Christian Somali refugees in Kenya have been kidnapped by Muslim relatives and taken to Islamic institutions in Somalia for “rehabilitation”.

The leader of the ICU, Hassan Dahir Aweys, promised to implement sharia in all areas he controls. According to his interpretation of sharia, apostates (those who leave Islam for another religion), must be killed. ICU leaders have even threatened to kill as apostates Muslims who are lax in their prayers, claiming this is commanded by sharia. Several Muslims have been publicly flogged for drug related offences since the ICU took control.

Over 99.5% of Somalis are Muslims and regard Christianity as a foreign religion of their historic enemies in Ethiopia and of their former colonial masters the Italians and the British. There is a long history of conflict between Muslim Somalis and Christian Ethiopians, so anti-Christian sentiment runs deep. Most Somalis take it for granted that a true Somali is a Muslim and converts to Christianity must be traitors. These prejudices, widely held by Muslim Somalis, seem to used to justify violence against Christians, both indigenous and expatriate. The US-led invasions of Afghanistan and Iraq and the recent Israeli campaign against Hizbullah in Lebanon have fuelled and inflamed the inherent hostility to the West and to Christians.

Friday, November 17, 2006

NICE work

It is a full ten years since the Lancet paper from Steve Johnson and many others (you will find my name in the small print at the end of the article) demonstrated that fludarabine produced a higher response rate and a longer progression-free survival than CAP, a combination of alkylating agent, anthracycline and prednisolone, when used as first-line treatment for CLL. This CAP combination had been shown previously to be equivalent to chlorambucil in effect. It is 6 years since Kanti Rai's CALGB trial reported that fludarabine was superior to chlorambucil in the New England Journal. In America hardly anyone still uses chlorambucil. John Gribben joshes me when I mention it. He thinks he came across a History of Medicine paper that mentioned it once. Why is it then that chlorambucil is still the only drug that is licensed for the first-line treatment of CLL in the UK?

I was privileged to be asked to take part in the NICE review of fludarabine which took place this autumn. The National Institute for Clinical Excellence goes by the acronym NICE and there have been continual cracks about it being more nasty than nice. The job it has is to look at new and existing treatments for various diseases and make a recommendation as to whether they should be available on the National Health Service.

There are three 'E's when it comes to providing health care.

Equality is what the Government is most concerned about. This is supposed to be a National Health Service. They can't abide what is known as post-code prescribing: the idea that you can get a drug in Dover but not in Darlington or that you have to wait 3 months for your hip replacement in Bournemouth but 24 months in Birmingham. They won't listen to the argument that if there was a true market everyone could get it next week; markets in health care are an anathema to the British public. Markets would, of course, mean that you could buy different standards of care for different prices, and even New Labor shrinks at the idea that rich people should get better care than poor people. So regulation is necessary to hold back the convoy to the speed of the slowest ship.

Effectiveness is what the patient is concerned about and also the concern of most doctors. We want the best result for the patient in front of us. If treatment A cures 70% of patients at a cost of £100,000 a cure while treatment B cures 50% of patients at a cost of £1000 a cure, we would still want treatment A for all our patients.

Efficiency is what the health economists want. In a way you can see what's behind their thinking. Supposing there is a limited health care budget, you would want to see it spent in the most effective way. You would want everybody to get the most effective treatment. You wouldn't want money wasted on treatments that didn't work. You wouldn't want speculative spending at the expense of proven treatments. If there was a doubt about whether a treatment worked, you would want the treatment tested so that you knew for sure whether it worked. When new, expensive drugs were introduced, you would want to know whether they produce value for money, especially in days when the market is being flooded with new products, all very expensive.

In order to compare different treatments, they have hit upon QALYs. This stands for Quality Added Life Years. It boils down to, "How much does it cost to add one extra year of high quality life?"

This approach has inherent dangers. The most cost effective treatments turn out to be ones that reduce infant mortality. Allowing a baby to live who would otherwise die adds 80 or so QALYs. Helping an 80 year old live an extra 6 months doesn't score very highly. The policy is therefore Ageist. It is also misleading to suggest that there is a limited health care budget. America is now spending approaching 20% of GDP on health. In France and Germany it is 12+%. In the UK it is 7% - still comparatively very low despite the government massively increasing what it was pre-1997. Taxpayers will only stand so much taxation. Gordon Brown has proved a master in introducing stealth taxes that people have not noticed, but if that button is pressed to often the electorate will vote for the other lot.

The rest of government spending is not subject to the same stringency. Take Transport. Installing crash barriers between opposing lanes on motorways saves lives. It may well have saved my daughter's life last week. But the cost of each life saved is £1 million. For the automatic train warning system, a system that stops railway trains passing red signals, the cost is £3 million for every life saved. On the other hand if a new drug costs more than £25,000 per QALY it will not be recommended.

The Royal Air Force has just taken delivery of the new Eurofighter. These are superb airplanes. Probably they outperform anything the Russians or Americans have produced. If either America or Russia invades us we will be able to defend ourselves. Meantime, we are still using 'snatch' Land Rovers in Iraq and Afghanistan where they are susceptible to roadside bombs and RPGs because we can't afford better.

I could give examples across government spending. Educational policies are introduced at the whim of an advisor without objective evidence of improved effectiveness. An Identity Card is about to be introduced without evidence that it will help anything. Huge amounts (equivalent to 1% of the world GDP) have been committed to fight global warming when a fraction of the amount would wipe out malaria from the planet and as a consequence raise world GDP by 3%. Prisons policy, road building, housing policy; whatever are you look at government spending is in a spiral of out of control increase. Yet because it can be measured the cost of new effective drugs is 'controlled'.

However, this is the system we've got and we have to live with it.

The NICE examination was mainly informed by the recent LRF CLL4 trial that compared chlorambucil with fludarabine with fludarabine plus cyclophosphamide as first line treatment for CLL. The important difference from other trials was that chlorambucil was given in a bigger dose than previously. The dose in the CALGB trial was 40 mg per sq meter per month; in CLL4 the dose was 70 mg sq meter per month. Even at this dose it was less toxic than was the fludarabine arm. CLL4 showed that although there was a slightly higher response rate with fludarabine, this was not statistically significant. This was a large trial with nearly 800 participants. It was powered to detect quite small differences between the treatments. There was no difference between these two drugs in terms of progression-free survival or overall survival. The combination of fludarabine and cyclophosphamide (FC), however, proved superior to both chlorambucil and fludarabine as single agents in terms of the response rate, the complete response rate and the length of remission. The differences were statistically significant. However, there was no difference in overall survival between any of the treatment groups. In fact at 5 years follow-up the chlorambucil group was doing slightly better, though the differences were not statistically significant. Patients who failed to respond to the FC had a very poor survival indeed with most failing to live 2 years. On the other hand non-responders to either chlorambucil or fludarabine could be rescued by salvage therapy.

It is likely that this is the last word in chlorambucil trials. A recent Cochrane review, which performed a meta-analysis of all the trials comparing fludarabine and chlorambucil has failed to find a difference in overall survival. The most likely reason for this is that patients who fail treatment can be salvaged by other treatments so that it does not matter much which treatment is given first.

Is that the end of the story? Are all those people in the world who have avoided chlorambucil and gone straight to fludarabine combinations wrong? Don’t miss the next exciting episode of this story.

Tuesday, November 14, 2006


How do you cope with adversity?







Del 17p

One of the most feared findings in CLL is a loss of the short arm of chromosome 17. It is usually found by FISH testing and the technical term is del 17p. This stands for a deletion of the 'p' arm (chromosomes have short arms 'p' and long arms 'q')of chromosome 17 (remember there are 46 chromosomes, arranged in 22 pairs -1 to 22 - and the sex chromosomes X and Y). The reason it is feared is because the gene for p53 lives on 17p.

p53 is known as the guardian of the genome. It has many functions, but one of them is to preserve the integrity of genes. In every cell division it is necessary to make a complete copy of the cell's DNA. Each daughter cell has to have a full complement of DNA and it gets it when the parent cell makes a complete copy and hands out one copy to each daughter. The trouble is that this copying process is not as good as Xeroxing; it is a bit error prone. This is where p53 comes in. It zips up the DNA looking for errors and when it finds one it stops the whole factory process and brings in the DNA repair team. These enzymes attempt to repair the error and if they can, all well and good and the process of copying continues. If they can't then p53 sends a signal for the cell to self-destruct. After all you wouldn't want a defective product on your shelves, would you?

Every once in a while the random copying errors affect the p53 gene, so there is nothing to detect and correct the error. These p53 deficient cells are a liability. First of all because they are damaged goods that can accumulate further errors that won't be detected, and some of these errors are liable to make the cell grow at a very fast rate, but second because most of the drugs used to treat CLL require an intact p53 pathway to be able to kill the cell. Only Campath and high dose steroids are able to kill CLL cells that lack p53, although we shall soon have a new drug, flavopiridol that can do this too. So if we lack p53 the cells are liable to divide aggressively and be unkillable.

In recent randomized trials in Germany and the UK about 5% of patients were resistant to treatment with the combination of fludarabine and cyclophosphamide - most died within 2 years of entering the trials. Almost all of these patients had del 17p by FISH.

However in our series of patients in Bournemouth we have three patients with del 17p who have indolent CLL that has never required treatment. How can we explain this?

All three have mutated VH genes. CLL cells with mutated VH genes are almost always only slowly dividing. A missing p53 gene comes about by a rare mistake in cell division. Rare it may be, but it will occur much more commonly in cells that divide rapidly than those that divide slowly. Nevertheless, it can occur in slowly dividing cells. Secondly a missing p53 gene causes havoc when cells divide; if cells divide only slowly there won't be so much havoc.

Therefore, in most patients with del 17p a different treatment strategy is required. Currently we believe such patients should be treated with Campath plus high dose steroids, and once in remission they should proceed to stem cell allograft if possible. However, in patients with indolent disease in whom del 17p is found, a watch and wait policy should be adopted.

Although the incidence of del 17p is less than 5% in untreated patients, it is much higher, perhaps up to 30% in relapsed patients. Why is this? It is because the CLL cells that recover after chemotherapy are the ones that were most resistant to treatment the first time around. The best known cause of drug resistance is p53 deficiency. For this reason many people think that it is important to avoid treatment in CLL until it is really necessary.

Saturday, November 11, 2006


Lord Wavell was a British General in World War Two ut he also published a collection of poems entatitled "Other Men's Flowers". It is one of my favorite collections. As a battle commander he knew how to endure hardship, and some of his choices are rarely anthologized.

here is Kipling on Boxing:

Read here the moral roundly writ
For him who into battle goes—
Each soul that hitting hard or hit,
Endureth gross or ghostly foes.
Prince, blown by many overthrows
Half blind with shame, half choked with dirt
Man cannot tell, but Allah knows
How much the other side was hurt!

From the same poem come his comments on cricket.

Thank God who made the British Isles
And taught me how to play,
I do not worship crocodiles,
Or bow the knee to clay!
Give me a willow wand and I
With hide and cork and twine
From century to century
Will gambol round my shrine!

Finally, for Remembrance Dayand for remembrance of 7/7, this poem by Greta Briggs, London under Bombardment.

I, who am known as London, have faced stern times before,
Having fought and ruled and traded for a thousand years and more;
I knew the Roman legions and the harsh-voiced Danish hordes;
I heard the Saxon revels, saw blood on the Norman swords.
But, though I am scarred by battle, my grim defenders vow
Never was I so stately nor so well-beloved as now.
The lights that burn and glitter in the exile's lonely dream,
The lights of Picadilly, and those that used to gleam
Down Regents Street and Kingsway may now no longer shine,
But other lights keep burning, and their splendour, too, is mine,
Seen in the work-worn faces and glimpsed in the steadfast eyes
When little homes lie broken and death descends from the skies.
The bombs have shattered my churches, have torn my streets apart,
But they have not bent my spirit and they shall not break my heart.
For my people's faith and courage are lights of London town
Which still would shine in legends though my broadest bridge were down.

More swords of truth

I am well into the Terry Goodkind series now. As I said these books are superficially part of the Sword & Sorcery genre typified by Lord of the Rings, but deep down they are about social philosophy. "Soul of Fire" in particular is a contrast of Socialism and Capitalism. Socialism is presented as a society in which the individual has no value, where people become idle, expecting the 'state' to provide, where there is no idividual enterprise, where the do-gooder wives of rich people squander their wealth on idlers and malingerers and then complain at their husbands for being so greedy as take more than their fair share of work, denying it to the needy, and for making more money than they could possibly need, where all work is controlled by guilds (read 'unions') who inflict a pettyfogging beaurocracy on everything, so that it takes months to get a permit to do anything. All the time the beurocrats grow rich while everyone else starves. In contract, capitalism allows private enterprise, generates wealth for all, fills every niche, gives everyone a job, rewards hard work and eliminates poverty.

Now I am a capitalist and a conservative, but I can see the flaws in this picture. Unbridled capitalism allows protection rackets to thrive, provide no safety net for the unlucky or health care for the really sick poor. Mafias thrive on Capitalism (eg Russia under Yeltsin) and bribery and corruption are unchecked. Al Capone was a capitalist. So were the people at Enron.

The truth is that without the drive of personal profit society stagnates, but unless that drive is controlled and regulated we have 'nature red in tooth and claw' and we become like beasts.

Another strand in Goodkind's philosphy is self-regard. Call it self-confidence or self-esteem, the danger is selfishness. The great enemy in these books is self-distaste. The "Woe is my, I am unclean" attitude is anathema. The hero is somebody who is concerned for others, but overweaning self-confidence can become arrogance hust as a decent humility can become a snivelling submission. The answer is, of course, balance.

Kipling's poem "If" still sets for me where that balance should be.

If you can keep your head when all about you
Are losing theirs and blaming it on you,
If you can trust yourself when all men doubt you
But make allowance for their doubting too,
If you can wait and not be tired by waiting,
Or being lied about, don't deal in lies,
Or being hated, don't give way to hating,
And yet don't look too good, nor talk too wise:

If you can meet with Triumph and Disaster
And treat those two impostors just the same;
If you can bear to hear the truth you've spoken
Twisted by knaves to make a trap for fools,
Or watch the things you gave your life to, broken,

If you can make one heap of all your winnings
And lose, and start again at your beginnings
And never breath a word about your loss;
If you can force your heart and nerve and sinew
To serve your turn long after they are gone,
And so hold on when there is nothing in you

If you can talk with crowds and keep your virtue,
Or walk with kings--nor lose the common touch,
If neither foes nor loving friends can hurt you;
If all men count with you, but none too much,
If you can fill the unforgiving minute
With sixty seconds' worth of distance run,
Yours is the Earth and everything that's in it,

I could disagree with a line or two; I'm not stoic enough to be invulnerable to the hurt of friends.

Friday, November 10, 2006

Gathering of Clans

It was just a small funeral. If you want a large funeral, then die young. I remember a patient of mine who died aged 40 of stomach cancer. He had a large general practice and he was deacon at his church. Over 4000 attended his funeral.

My father-in-law was just two weeks short of his 94th birthday. I had known him for 46 years, less than half his life. Almost all his contempories had preceded him. I knew something about his later career: the salesman-of-the-year awards, the blemish-free driving license despite hundreds of thousands of miles driven, the efficency of the paperwork completed and posted on the same day, the way he kept a hat that he would don just before entering a premises for the sole purpose of being able to doff it in greeting, the packet of cigarettes open to offer even though he had himself given up years previously, the natural gentlemanliness that everyone remarked on. Of his early life I knew very little. He came from the East End of London, later moving into Essex. As a young man he had boxed. He had attended a large Baptist Church and then a smaller Free Evangelical one. He served his apprenticeship in the Cigar industry becoming an expert in the field. He had been seriously ill when in his twenties, but made a good recovery. My grandchildren called him Domino Grandad, because whenever they saw him he would challenge them to a game of dominos. Being very low-church he used to mock Catholic ritual. "Who will play me a game of Dominos?" he would chant in a mock-Gregorian manner.

Sometimes he would get his guitar out - acoustic with steel strings and two 'F's like a violin rather than an 'O' to let the sound out. He used to play in a banjo, ukelele and guitar band in London.

My son in America couldn't be with us at the funeral, but he sent a message:

I have rarely met someone as consistently kind, generous, charming and at ease with the world as Grandad. In the fullest sense of the word he was a gentleman. My memories of him are as a quiet but forceful presence in the kitchen at Shandon, considered and thoughtful in what he said – his own man, not repeating the words or thoughts of others.

His consideration for others was always evident; but he was nobody’s fool. He was always courteous but never a push-over. He was gentle but with a wry and sly sense of humour.

I shall remember from childhood Murray Mints and a bristling moustache, a guitarist who drove dark blue Mk2 Escort. I shall remember from adulthood a merry twinkle in the eye, a refusal to complain even when in pain, a jolly greeting to the meals on wheels lady. I shall remember the interest and enthusiasm for the world around him, the laser-sharp, insightful mind that remained right until the end.

Grandad was a model of a life well-lived, a model of what true masculinity is about and an example that authority speaks softly. It was a pleasure to have known such a man; a privilege to have been related to him.

Hail and farewell Grandad, you have made our lives brighter for having been in it. May you rest peacefully.

As I read it out to the family assembled, it brought tears to our eyes.

There were 23 of us there. The next time we all meet will I hope be our 40th wedding anniversary. I pray that there are no funerals before that.

Monday, November 06, 2006

What questions shall I ask the doctor?

One of the commonest questions that I am asked is "What questions should I ask when I see my doctor about CLL?"

This is quite a difficult one to answer, because it depends what you are trying to find out. Are you trying to find out whether you doctor is competent to advise you about CLL? Or are you trying to find out about your CLL?

The fact is that some primary care physicians know this about CLL: It is one of the four types of leukemia and it's the one that has the best prognosis. If you've got to have cancer, it's the sort of cancer you would want to have. You might then get referred to an oncologist.

Some oncologists know this about CLL: It is one of the four types of leukemia and it's the one that has the best prognosis. If you've got to have cancer, it's the sort of cancer you would want to have. If you’re lucky you might get referred to a leukemia specialist.

Some leukemia specialists know this about CLL: You're lucky you don't have AML. CLL is the one that has the best prognosis. If you've got to have cancer, it's the sort of cancer you would want to have. If you’re lucky you might get referred to a lymphoma specialist.

Some lymphoma specialists knows this about CLL: You'd better have a lymph node biopsy. If you are really lucky you might get referred to a CLL specialist.

Some CLL specialists know this about CLL: I can cure you with modern treatment. He will greet you in a friendly manner, ask about your family, explain how treatment has improved over the past few years, order a bone marrow biopsy, infuse the first course of FCR and then send you off to be treated by your local oncologist. Your insurance company will receive a barely believable bill.

Now I might be being overly cynical; there are clearly doctors in all these categories that are extremely good, know their stuff and will give you excellent advice. American medicine is among the best in the world: and among the worst. Health care should come with a health warning that says: Market Forces Apply. Caveat Emptor.

The thing about markets is that there are losers and winners, and the winners will win out in the long run. If all you have to lose if you pick a loser is your money, then that might be acceptable, but if you are gambling your life on picking a winner, then you had better pick your doctor very carefully.

So what do you really want to know?

First of all, have you really got CLL? There are two conditions that are easily mistaken for CLL - mantle cell lymphoma and splenic marginal zone lymphoma. The way to distinguish them is by immunophenotyping. So this is a test you need to have. Look for cells that are CD5/CD19/CD23 positive. If they are CD5 negative they are likely to be splenic marginal zone lymphoma, and if they are CD23 negative they are likely to be mantle cell lymphoma. These are not the only differences and it's not as simple as that, but your doctor should be aware of the differential diagnosis and know how to tell the difference. There are other conditions that get confused; you may sometimes be told you have T-cell CLL. There is no such thing. There are three conditions, T-PLL, cutaneous T-cell lymphoma and T-cell LGL leukemia that get called T-CLL. These are all important diagnoses in their own right, but I won't consider them here in this essay; I will write about them later. You may also be told you have B-PLL or sometimes CLL/PLL. again these are important conditions that I have written about earlier this year and I shan't cover here.

The next thing you need to know is what stage you are. Most people in the world use Rai staging, named after Kanti Rai from Long Island. Stage 0 means you just have a lymphocytosis. Stage 1 means that you also have lymph nodes that can be felt. Stage 2 means the doctor can feel your spleen. Stage 3 means you are anemic and stage 4 means your platelet count is reduced. Notice that I said 'feel' and 'felt'. You haven't had a CT scan yet. Rai staging and the conclusions derived from it are based on what the doctor can feel, not what the CT scan shows. Rai staging helps the doctor work out what the doctor should do with you. If you are stage 3 or 4, it is likely that he will recommend treatment, if you are 0, 1 or 2, it is more likely that he will recommend waiting a while.

In fact the National Cancer Institute (NCI) has issued guidelines of when to start treatment. So a good question to ask is, "Do I meet the NCI guidelines for treatment?" If you do not you should be assigned to a watch and wait program. Some people call this watch and worry, but there is a good way of taking the worying out of the waiting and that is to get your prognostic markers done.

If you are stage 0 and your lymphocyte count is less than 30,000 per microlitre the the marker I recommend is CD38. Our experience is that if your are CD38 negative with this condition you almost certainly won't need any treatment and you will never die from the condition. If you have almost any other type of CLL I strongly recommmend that you have your IgVH genes estimated. These will tell you whether you fall into a good or bad category of CLL and give you an estimate of what the future holds. The other prognostic test that I strongly recommend is FISH for deletions of 17p and 11q. I will be writing about these in a future blog, but briefly these chromosome abnormalities are present in patients who either don't respondto standard types of treatment, or if they do, will relapse withing a short period of time. Obviously, these tests will help you decide on what type of treatment you should have.

Finally before you start treatment I would recommend that you read my articles on What is the aim of treatment here and here and here.