Early stage treatment

What follows is an early draft of a paper I am writing that makes the case for new trials of whether early treatment might benefit some patients with CLL. I would welcome comments.

Introduction

For most patients with neoplastic disease it is almost axiomatic that early diagnosis leads to earlier treatment and better outcomes. For chronic lymphocytic leukemia (CLL) there is no evidence to support this. Indeed a meta-analysis of six trials involving more than 2000 patients that compared early treatment with treatment deferred until the disease became progressive or symptomatic showed no significant difference in overall survival [1]. However, in these trials nearly half the patients in both arms were still alive after 10 years follow-up and therefore the trials must have included patients who would never under require treatment current guidelines [2]. Moreover, the patients were treated with chlorambucil, with or without prednisolone. Many authorities believe that there are now more effective treatments than that. Although there as yet no randomized clinical trials that show longer overall survivals for any first-line treatment than chlorambucil [3], the use of purine analogues alone or in combination with cyclophosphamide with or without rituximab and with or without mitoxantrone all give a higher rate of complete remission and complete remissions without minimal residual disease, as well as longer progression-free survivals [4-8].

In recent years several prognostic markers have been described that are able to predict which patients will eventually require treatment. In particular, unmutated IGVH genes [9, 10], the use of the IGVH3.21 gene [11], increased CD38 expression [9, 12], increased ZAP-70 expression [13-15] and the detection of deletions of portions of the long arm of chromosome 11 (del 11q23) or the short arm of chromosome 17 (del 17p13) by fluorescent in-situ hybridization (FISH) [16] all usefully predict poor outcome in early stage disease. Patients with del 17p13 are a group with very poor survival with disease that is resistant to most active agents [17] and because of this we have excluded them from this analysis.

In this study we have looked at the feasibility of re-examining the question of early versus deferred treatment in a new randomized controlled trial.
Methods

Patients
In this retrospective study we have examined 297 patients with Binet stage A CLL who presented at the Royal Bournemouth Hospital and have had prognostic markers performed. The following prognostic markers were studied: IGVH mutational status, use of IGVH 3.21 heavy chain gene, CD38 expression, ZAP-70 expression and the presence of deletions at 11q23 or 17p13. Those with del 17p13 were excluded from the analysis. Patients were treated according to NCI guidelines [2]. Times from presentation to first treatment were calculated and treatment-free survival times calculated for patients with nought, one, or two or more adverse factors. Overall survival curves were also calculated for the same three groups.

IGVH gene analysis
Prior to October 2004 IGVH genes were sequenced as previously described [10]. The preferred source material was RNA. cDNA was synthesized and amplified by polymerase chain reaction (PCR) using a mixture of oligonucleotide 5’ primers specific for each leader sequence of the VH1 to VH6 families or a consensus 5’ FW1 region primer, together with either a consensus 3’ primer complementary to the germ line JH regions or a 3’ primer complimentary to the constant region. From 2004 onwards gDNA was extracted from whole blood using the QIAmp®DNA mini kits (Qiagen, Crawley, West Sussex, UK) according to the manufacturers instructions. gDNA was amplified in a single multiplexed PCR reaction consisting of 6VH framework 1 primers combined with one JH consensus primer (standardises BIOMED-2 primers). Clonal sequences were determined by sequencing amplicons from at least 2 independent PCR reactions. The majority of samples were sequenced directly using an automated DNA sequencer. Nucleotide sequences were aligned to EMBL/GenBank and current databases (V-BASE sequence directory IMGT/V-QUEST, using MacVector 4.0 sequence analysis software; International Biotecnologies, New Haven, CT, and Lasegene; DNASTAR, Madison, WI.). Percentage homology was calculated by counting the number of mutations between the 5’ end of FR1 and the 3’ end of FR3. Homology with the germline sequence of 98% or more was regarded as unmutated.
CD38
CD38 expression on fresh or cryopreserved cells was determined by flow cytometry as previously described [12] using FITC labeled anti-CD5 (clone DK23; DAKO, Glostrup, Denmark), PE labeled anti-CD38 (clone HB7; Becton Dickinson, San Jose, CA) and RPE-Cy5 labeled anti-CD19 (clone HD37, DAKO). We chose a cut-off point for CD38 that give the highest possible Youden index. Cut-off points of 20% and 30% gave the highest, but similar, Youden values—58% and 60%, respectively, and in this instance we chose 20%.
ZAP-70
ZAP-70 expression on fresh or cryopreserved cells was measured by flow cytometry as previously described [14], using an indirect assay that makes use of an unlabelled anti-ZAP-70 (clone 2F3•2, Upstate Biotechnology, Milton Keynes, UK) followed by secondary antibody (Sheep-anti-mouse FITC-conjugate, Novocastra, Newcastle Upon Tyne, UK). An isotype control (mouse IgG2a, DAKO) was used to define negative staining and T and NK cells were identified using and anti-CD2-PE conjugate (DAKO). A cut-off level of 10% positivity was chosen as previously described.
FISH
Separate hybridizations were carried out for loci on chromosomes 11 and 17 as previously described [18]. LSIp53, together with CEP17 alpha satellite DNA probe labeled with Spectrum Orange and Spectrum Green (Vysis UK, London, United Kingdom), respectively, were used to evaluate chromosome deletion at 17p13.1. For chromosome 11, CEPH yacs 755b11 and 801b11 were labeled by nick translation with Spectrum Orange dUTP and Spectrum Green dUTP (Vysis), respectively, according to the manufacturer’s protocol. Hybridization was to peripheral blood lymphocytes or to cells from our archive of fixed TPA stimulated lymphocyte cultures.
Statistical methods
Data were analyzed using GraphPad Prism 4. Survival functions comparing patients have been estimated using the product limit method of Kaplan Meier.

Results

Of the 297 stage A patients there were 148 patients who had none of these adverse factors, 78 who had one of them and 71 (23.9%) who had two. Actuarial treatment-free survival curves were constructed for these three groups and are shown in the figure. Median treatment-free survival for those with no adverse prognostic factors has not been reached; for those with one adverse prognostic factor the median treatment-free survival was 123 months and for those with two it was 37 months (p<0.0001).

The median overall survival for patients with at least two adverse prognostic factors was 102 months.

Discussion

Nearly a quarter of all stage A patients presenting to a district general hospital had at least two adverse prognostic markers. Half of these required treatment according to NCI guidelines within three years of diagnosis. Given the number of patients presenting annually in the United Kingdom there should be no difficulty in accruing sufficient patients for a randomized clinical trial of early treatment versus ‘watch and wait’.

On the other hand the use of only a single adverse prognostic factor (such as unmutated IgVH genes) would mean that it would take more than ten years for half the patients to require treatment and some patients would normally remain treatment-free for more than 20 years. In view of the unproven nature of early treatment, such a trial would be ethically suspect.

Of greater difficulty is deciding which treatment should be offered. Although drug combinations that include purine analogues yield the highest complete response rates, the possibility of selecting for p53 mutant subclones has been raised [19] and risk that early intervention might generate drug-resistant disease is apparent. Furthermore, the prolonged depletion of CD4 positive T cells might be responsible for the reported higher incidence of Richter’s syndrome after fludarabine therapy [20]. To avoid the potential dangers of early chemotherapy, treatment with monoclonal antibodies might be assessed. Although single agent rituximab does produce objective responses in 51% of patients when used first line in CLL [21], complete responses are very rare.

On the other hand alemtuzumab is capable of producing complete remissions in 72% of patients without lymphadenopathy and complete remissions with the absence of minimal residual disease in 39% [22]. Although its toxicity is seen as an important drawback in multiply treated patients, when used as a first line agent its only serious toxicity is CMV viremia and this is regarded as manageable [23]. Although profound depletion of CD4 positive T cells occurs following alemtuzumab treatment, recovery is probably quicker than after treatment with fludarabine [24].

The most meaningful end-point for a trial of early treatment versus deferred treatment is overall survival. Trialists have been reluctant to use this as an endpoint for clinical trials in CLL, preferring progression-free survival as a surrogate, since patients may be expected to be long-lived and receive several rounds of subsequent therapy. However, this particular group has a median overall survival of only eight and a half years so that any difference in overall survival is likely to be apparent well before the ten year follow up of the meta-analysis quoted above.



References.
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2. Cheson BD, Bennett JM, Grever M, Kay N, Keating MJ, O'Brien S et al. National Cancer Institute-Sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 1996;87:4990-7.
3. Steurer M, Pall G, Richards S, Schwarzer G, Bohlius J, Greil R; Cochrane Haematologic Malignancies Group. Single-agent purine analogues for the treatment of chronic lymphocytic leukaemia: a systematic review and meta-analysis. Cancer Treat Rev. 2006;32:377-89.
4. Rai KR, Peterson BL, Appelbaum FR, Kolitz J, Elias L, Shepherd L et al. Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 2000;343:1750-1757.
5. O'Brien SM, Kantarjian HM, Cortes J, Beran M, Koller CA, Giles FJ et al. Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia. J Clin Oncol. 2001;19:1414-20.
6. Bosch F, Ferrer A, López-Guillermo A, Giné E, Bellosillo B, Villamor N, et al. Fludarabine, cyclophosphamide and mitoxantrone in the treatment of resistant or relapsed chronic lymphocytic leukaemia. Br J Haematol. 2002;119:976-84.
7. Keating MJ, O’Brien S, Albitar M, Lerner S, Plunkett W, Giles F et al. Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia J Clin Oncol 2005;23:4079-88.
8. Wierda W, O’Brien S, Faderl S, Ferrajoli A, Wang X, Do K-A et al. A Retrospective comparison of three sequential groups of patients with recurrent/refractory chronic lymphocytic leukemia treated with fludarabine-based regimens. Cancer 2006;106:337–45.
9. Damle RN, Wasil T, Fais F Ghiotto F, Valetto A, Allen SL et al. Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 1999; 94: 1840-7.
10. Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 1999; 94: 1848-54.
11. Tobin G, Thunberg U, Johnson A, Thorn I, Soderberg O, Hultdin M. Somatically mutated Ig VH3-21 genes characterize a new subset of chronic lymphocytic leukemia Blood. 2002;99:2262-4.
12. Hamblin TJ, Orchard JA, Ibbotson RE, Davis Z, Thomas PW, Stevenson FK et al. CD38 expression and immunoglobulin variable region mutations are independent prognostic variables in chronic lymphocytic leukemia, but CD38 expression may vary during the course of the disease. Blood 2002, 99: 1023-1029.
13. Crespo M, Bosch F, Villamor N Bellosillo B, Colomer D, Rozman M et al. ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med. 2003;348:1764-1775
14. Orchard JA, Ibbotson RE, Davis Z Wiestner A, Rosenwald A, Thomas PW et al. ZAP-70 expression by flow cytometry is a good prognostic marker in CLL and a potential surrogate for immunoglobulin VH gene mutations. Lancet 2004 363:105-111.
15. Rassenti LZ, Huynh L, Toy TL Chen L, Keating MJ, Gribben JG et al. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. N Engl J Med. 2004 351:893-901.
16. Dohner H, Stilgenbauer S, Benner A, Leupolt E, Krober A, Bullinger L et al Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. 2000;343:1910-6.
17. Catovsky D, Richards S, Matutes E, Oscier D, Dyer MJS, Bezares RF et al. Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet 2007; 370:230–9
18. Oscier DG, Gardiner AC, Mould SJ, Glide S, Davis ZA, Ibbotson RE et al. Multivariate analysis of prognostic factors in CLL: clinical stage, IGVH gene mutational status, and loss or mutation of the p53 gene are independent prognostic factors Blood.2002;100:1177-84
19. Rosenwald A, Chuang EY, Davis RE, Wiestner A, Alizadeh AA, Arthur DC et al. Fludarabine treatment of patients with chronic lymphocytic leukemia induces a p53-dependent gene expression response. Blood. 2004;104:1428-34.
20. Thornton PD, Bellas C, Santon A, Shah G, Pocock C, Wotherspoon AC et al. Richter's transformation of chronic lymphocytic leukemia. The possible role of fludarabine and the Epstein-Barr virus in its pathogenesis.
Leuk Res. 2005;29:389-95.
21. Hainsworth JD, Litchy S, Barton JH, Houston GA, Hermann RC, Bradof JE et al. Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: A phase II trial of the Minnie Pearl Cancer Research Network . J Clin Oncol 21:1746-51.
22. Keating MJ, Flinn I, Jain V, Binet JL, Hillmen P, Byrd J et al. Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood. 2002;99:3554-61.
23. Hillmen P, Skotnicki A, Robak T, Jaksic B, Sirard C, Mayer J. Alemtuzumab (CAMPATH ®, MABCAMPATH®) has superior progression free survival (PFS) vs chlorambucil as front line therapy for patients with progressive B-cell chronic lymphocytic leukemia. Blood 2006;108:93a (abstract 301)
24. Lundin J, Porwit-MacDonald A, Rossmann ED, Karlsson C, Edman P, Rezvany MR et al. Cellular immune reconstitution after subcutaneous alemtuzumab (anti-CD52 monoclonal antibody, CAMPATH-1H) treatment as first-line therapy for B-cell chronic lymphocytic leukaemia. Leukemia 2004;18: 484–90.

Marriage a la mode.

I don't normally pick these things up, but there is a piece in the Independent that caught my eye. When Elizabeth Hurley got married recently at her local parish church, the vicar waived the usual £1000 fee in the expectation that a larger donation would be forthcoming. None was.

Maybe we were naive and should have stuck with our normal charges," the church treasurer added ruefully. "We'll know next time she gets married."

Quite apart from the fact £1000 seems a bit extortionate the whole point of a church marriage seems to be lost. No wonder young people choose to live together instead.

Leukemic Stem Cells

The question is often asked as to whether there are leukemic stem cells for CLL. The theory goes like this. Most of the cells in a cancer are committed cells without self-renewal capacity. In any tumor there are small numbers of stem cells carrying the basic neoplastic defect that are capable of self-renewal and differentiation. The great bulk of the cells are differentiated cells that have committed themselves to maturation and eventual death. If you transplanted only those, they would eventually die out because they do not have the capacity for self-renewal. It is suggested that such cells are the ones that are killed by conventional therapy, while the true stem cells are resistant to treatment. This explains the phenomenon of remission and relapse. The great bulk of cells of the tumor are not stem cells so that when they respond to treatment the patient appears to be in complete remission. However, lurking somewhere in the body are the stem cells that are resistant to the treatment, and when the coast is clear they will start dividing and replenish all the cells that have been killed so that the disease relapses.

This scenario certainly appears to be the case for many solid tumors like colon cancer and pancreatic cancer, and is also the case for myeloid leukemias, both acute and chronic. Is it also the case for lymphoid tumors, and especially for CLL?

I submit that it cannot be so. The stem cells of lymphocytes are pluripotent blasts found in the bone marrow, that can commit to either myeloid or lymphoid tumors. That is why in chronic myeloid leukemia, transformation can be to either acute myeloid leukemia or acute lymphoid leukemia. However, lymphoid tumors mostly arise from lymphocytes that have already committed themselves by rearranging their immunoglobulin genes (in the case of B cells tumors) or their T cell receptor genes (in the case of T cell tumors). This is a step that can't be gone back on. You can certainly conceive of a stem cell origin for a lymphoid tumor, but there is no reason that all the cells in such a tumor would have the same Ig rearrangement in every cell as happens in CLL, myeloma and mantle cell lymphoma, and while where there is some variation in follicular lymphoma, it is usually possible to construct a 'family tree' of the variations demonstrating an origin in a single cell.

If relapse in CLL was fed by a self-renewing stem cell from a lineage arising before Ig rearrangement the relapsing tumor would have a different rearrangement.

In fact lymphocytes have a circular lifestyle. The apparently small mature lymphocytes of CLL can turn back into blasts capable of division before resuming their 'mature' appearance again. there is no need for a stem cell to answer the relapse/remission conundrum. There may certainly be cells that lack Cd20 and are thus immune to rituximab, but they are not stem cells in the conventional way.

Making Money

The new Terry Pratchett has arrived. The star of the book is again Moist von Lipwig whom we last saw in Going Postal. In this one Vetinari, the despot who runs Ankh-Morpork, decides to put Moist in charge of the central bank. The Bank has run on the gold standard for years and Moist decides that the whole thing would run better on paper money. After all gold is a pretty useless commodity that you can't do anything with; it's not worth as much as potatoes. If you were shipwrecked on a desert island, which would you rather have, a bag of gold or a bag of potatoes? It would be far better to base the currency on the strength of the City, its entrepreneurship, energy and hard work.

Those who start here should know that Moist is in reality Albert Spangler, the notorious con-man whom Vetinari (clearly a pun upon Medici) smuggled out of the hangman's grasp to put his talents to work for the city. Von Lipwig is the man in the golden suit, the man who could sell sand to the Arabs and ice to the Eskimos. To sell the sausage, he says, you must be able to sell the sizzle. Moist can sell the sizzle without necessarily being able to produce the sausage.

The story is full of characters who are not quite what they seem. Another, rather dimmer, con-man appears to be as sort of priest of an obscure religion, a Chief Cashier at the bank is actually a clown, an Igor (a race of Frankenstein's monsters with a penchant for recycling bits or corpses) reveals that his lisp (or lithp) is not real but put on for show, a golem (large clay men with nothing in the trousers department)thinks it is a modest young lady and the chairman of the bank is a dog. But Cosmo Lavish, one of the Bank's shareholders, takes the cake. He imagines he is Vetinari, the ruling tyrant.

To know a man, walk a mile in his shoes. He takes things rather literally and gets his servant, Heretofore, to steal a pair of Vetinari's old boots (they are too small, but it's a good pain). He grows a goatee beard like Vetinari's, though it looks ridiculous on his heavy jowls. He has a ring made of stygium (a very strange metal - or alloy - that heats up when exposed to the light. It is engraved with a 'V' and it too is too small. His finger becomes a stranger and stranger color as the book progresses. Try as he might he cannot pull off his Vetinari impression (or the ring, for that matter). He is too slow, too fat, not fast enough on his feet, too maladroit. He ends up in a madhouse in a ward for megalomaniacs. Vetinari triumphs and Moist von Lipwig is clearly destined for bigger things. What task for the man that everybody loves to love? It looks like he is set to run the tax office. That will test his bonhomie.

Of course, Pratchett is funny because he comments on our existing society. Who is Moist von Lipwig? Why, who but Tony Blair? The man that everyone loves to love. The crook who could sell you your own hands and feet. We know he's a rogue but we enjoy being taken to the cleaners.

And who is Cosmo Lsvish? Who do we know who tries to be leader, but is too fat, too ponderous, can't think on his feet and used to run a financial institution?

David Cameron took him to pieces at the Dispatch Box this week at PMQs.

Pan's Labyrinth

Last night I watched the DVD of Pan's Labyrinth, which some have called the only great film of the 21st Century. This is Mexican director, Guillermo del Toro's masterpiece. Set in 1944 in Spain, it tells the story of a Falangist Captain Vidal whose mission is to wipe out the remaining Republican irregulars (he would call them terrorists) holed up in the mountains. He summons his very pregnant wife to the military camp together with his 10 year old step daughter, Ofelia.

The film explores the parallel worlds of Ofelia and Mercedes, the Captain's peasant housekeeper. Ofelia is drawn into a world of fantasy where she a lost princess is set three tasks that she must accomplish to return to her father and his kingdom. Mercedes is a spy in the camp, aiding the rebels with succor and information.

The Spanish Civil War was the war that the baddies won. Hitler's ally Franco defeated the Republicans who were a mixture of liberals, intellectuals and soviet-style communists. It was a very dirty war in which the fascists were not the only villains. Nevertheless in this story Vidal (played by comic actor Sergi Lopez)is a vicious tyrant, shooting prisoners and torturing the wounded. He sees himself as one of a ruling elite and the notion that all men are equal as laughable.

The underlying themes are those of obedience and choice. In her fantasy world Ofelia triumphs by choosing to shed her own blood rather than that of an innocent. In the real world Franco triumphed and the rebels were scattered. In the long run Spain has become a democracy and Franco is a hated figure. Perhaps in the long run Ofelia's fantasy (or something like it) is the real world.

Private Practice in the UK

The great debate on health service financing has produced an array of mutually exclusive solutions. The one that is most laughable is the suggestion that private health care as currently practised in the UK might expand to fill the gap. It is perfectly possible to argue that some form of compulsory insurance, perhaps related to employment, might generate money more acceptably than direct taxation, but to suggest that the shortfalls in care for the elderly, hip replacements, accident and emergency departments, kidney transplants and anti-cancer drugs can be made good by the stately pleasure domes of BUPA hospitals is to betray a crass misunderstanding of why such palaces make their money and what the health service really needs.

In Britain, the private sector thrives on exclusivity. This is the Virgin Upper Class of health care. You have a room to yourself, a telephone, china cups and Sky TV. You don't have to strap hang with hoi polloi. Who would want to go private if everybody did it?

Private practice is a form of alternative medicine and is successful for the same reason. Make the patient feel special. Your disease is not something that any doctor can deal with. It requires my personal attention.

Guidelines for Clinical Trials

The CLL Guidelines also lay out special recommendations for clinical trials.

1 For patients who enter clinical trials it is recommended that a full range of prognostic marker tests is performed. This includes FISH for del 13q14, del 11q23. del 6q, del 17p13 and trisomy 12; IgVH mutations; CD38 and ZAP-70 by an agreed and valdated method, and serum tests for beta-2 microglobulin, CD23 and thymidine kinase. There are other prognostic markers under study, and these could with profit be evaluated at teh same time.

2 CT scanning of chest, abdomen and pelvis is encouraged especialy in trials where complete response is the aim. (Note however that these will not change the Rai of Binet stage).

3 Definitions of different types of response have been clarified. Complete remission (CR) requires all of the following for at least three months: absence of clonal lymphocytes in the blood; absence of lymph nodes > 1.5 cm in diameter by both physical examination and CT scan; no splenomegaly or hepatomegaly by both clinical examination and CT scan; absence of constitutional symptoms; neutrophils >1.5/microliter, platelets >100,000/microliter, Hb >11.0 g/dL (untransfused).

4 Bone marrow aspirate and trephine performed at least three months after last treatment should be free of clonal CLL B cells (by conventional imunophenotyping). In some bone marrow trephines lymphoid nodules could be detected; the term nodular PR was used. This term is now discarded; immunohistochemistry should be used to distinguish whether these are T cells, normal B cells or tumor B cells. If teh marrow is hypocellular it should be repeated after 4-6 weeks. The timing of a marrow might have to be delayed until the other criteria of a CR are fulfilled, but it should not be delayed after 6 months.

5. For patients who fulfill all teh other features of a CR, but fail to recover their blood counts, the term CR with incomplete bone marrow recovery (CRi) shopuld be used.

6 Partial remission requires the following: a decrease of blood lymphocytes by at least 50%; reduction of lymph node size (by CT scan) of at least 50% in the sum of the products of up to 6 lymph nodes or in the diameter of one lymph node if only one lymph node was present before treatment AND no new abnormal nodes and no increase in size of any nodes; a decrease in the size of liver and/or spleen by 50% or more; and at least one of teh following:- neutrophils at 1,500/microliter of a 50% improvement over baseline without G-CSF support, playelets at 100,000 or a 50% improvement over baseline, or Hb >11.0 g/dL or a 50% improvement without transfusion or Epo support.

7. Progressive disease (PD) is defined by the appearance of any new lesion such as a lymph node >1.5 cm in diameter, clinical splenomegaly, hepatomegaly or infiltration of any other organ; by the increase of >50% in the greatest diameter of any previously documented disease; an increase in spleen or liver size by 50%; an increase of lymphocyte count by at least 50%; transformation to Richter's syndrome (confirmed by lymph node biopsy); occurrence of any cytopenia attributed to CLL (as opposed to the treatment).

8. Stable disease refers to those who do not achieve CR or PR yet do not have PD.

9 Duration of response is measured from the date of the end of last treatment until evidence of PD. Progression-free survival is defined as the interval between the first day of treatment and the first sign of disease progression. event-free survival is defined as the time from the first day of treatment to the first sign of progression or treatment for relapse, or death. Overall survival is the interval from the first day of treatment until death.

10. Relapse is defined as evidence of disease progression after a period of 6 or more months after a CR or PR. Refractory is defined as failure to achieve a CR or PR within 6 months of the last anti-leukemic therapy.

11. The elimination of Minimal Residual Disease (MRD) may be a desirable treatment endpoint, though prospective clinical trials are needed to demonstrate that this has clinical benefit. he techniques for assessing MRD have been standardized. Either four-color flow cytometry or allele specific oligonucleotide PCR are reliably sensitive down to a level of one cell in 10,000 leukocytes. It is satisfactory to use blood for this estimate except within three months of treatment with monoclonal antibodies, in which case marrow must be used.

Jab and Dab

Readers will know all about the problem of infection in CLL. Although there are many treatments that make the lymph nodes go away and the white count come down, although both hemoglobin and platelet counts can be restored to normal, although the marrow can be cleared of CLL cells, nothing makes the immune system normal.

Everybody agrees that it is worth being vaccinated against common infections including influenza, but tests show that responses to vaccines are poor. For this reason and inspired by an idea of Chaya's we are recruiting to a trial which attempts to enhance the response to flu vaccine.

The Jab and Dab trial is being sponsored by CLL Topics and details are laid out on Chaya's website. Briefly it involves the use of imiquimod, a cream used to treat rather indolent skin cancers, to be rubbed on the skin after the flue jab. Imiquimod activates one of the Toll-like receptors, TR7, which stimulates the immune response. The trial will be run by Dr Helen McCarthy in Bournemouth. The trial protocol and patient information sheet are available on line.

Dr McCarthy is one of the hematologists who replaced me when I retired from Bournemouth. She has a long standing interest in CLL and spent a year working with Dr Keating and Dr Wierda at MD Anderson. While there she discovered that high levels of AID could be detected in patients with unmutated IgVH genes.

Del 11q23

I am responding to one of my correspondents up front because not everybody reads the 'comments' on this blog. 'Anonymous' has misinterpreted the situation with del 11q23, which means I have made myself insufficiently clear, and I apologise.

Up to 20% of patients with CLL have del 11q23 at diagnosis, and more acquire it as the disease progresses. On the piece of chromosome that is deleted is the gene that codes for the the protein that is missing in a strange congenital disease called ataxia telangectasia. The gene is known as ATM (which stands for 'mutated in Ataxia Telangectasia). We know the gene is involved in the same apoptosis-inducing pathway as p53, but it seems that whereas a defect in only one of the two p53 genes is necessary to cripple this pathway, both ATM genes have to be damaged or missing to achieve the same effect. You can read in more detail about it here.

The importance of this pathway is that most of the drugs that kill CLL cells do so by making use of it. This is true for fludarabine, chlorambucil and rituximab. The only exceptions we are sure of are Campath (alemtuzumab) and high dose steroids. Flavopiridol also by-passes this pathway, but a safe and effective way of giving it is still being developed. Revlimid (lenalidamide) might also be useful in this situation, but comprehensive results are not in. HuMax is another antibody not fully tested in this situation.

Clinical trials have shown that most patients that are primarily resistant to fludarabine combinations have a defect of p53. On the other hand patients with del 11q tend to respond well, but they also tend to relapse earlier than other patients. This may be because there is an increased tendency for these patients to acquire an ATM defect on the other chromosome 11. The problem then becomes how should such patients be retreated. Another round of FCR or perhaps PCR will put most patients back in remission, but being exposed to these drugs a second time raises risk of immunodeficiency and marrow failure. Perhaps these patients should be the ones in whom clinical trials of newer agents should take place. Drugs like HuMax, Revlimid and flavopiridol might be tried. Newer drugs that inhibit the enzyme PARP1 look promising in the laboratory, and I hope they will shortly make an appearance in the clinic.

Some would argue that such patients should be treated with Campath and high dose steroids. This regimen would likely work as well as it does for p53 deleted patients, though it cannot at the moment be justified for use as first line treatment in those who have never been treated. The problem with Campath and steroids is that responses are likely to last less than 18 months, and this regimen is best used in preparation for a later low intensity allograft.

I have been criticised as being unduly pessimistic about stem cell transplants. I might respond that that is because transplanters are unduly optimistic. To a man with a hammer, everything looks like a nail. But I want to reflect the truth, not opinion. It is true that a stem cell allograft is probably the only treatment that offers a cure in CLL, even in those with bad-risk cytogenetics. There is a sufficient graft-versus-leukemia effect to be confident that when it works patients can enjoy a long and healthy life. However, it is risky. Transplant-related-deaths used to account for 40% of patients when full intensity conditioning was used. It was higher in CLL then in other conditions because the patients tended to be older, they were already immunodeficient and it was usually done as a last resort when all sorts of other body poisons had been administered. It had been hoped that the introduction of reduced intensity conditioning would reduce the treatment-related mortality.

What has happened is that the age at which transplants are attempted has increased. It is quite commonplace for patients up to the age of 70 to be offered a transplant, whereas 50 used to be the absolute upper age limit and most were unhappy about anyone over 40. The reason for increasing the age is that patients would no longer have to withstand total body irradiation or high dose cyclophosphamide and busulphan. Instead they might simply receive immunosuppressive treatment such as fludarabine and Campath. That being said there is not just one type of reduced intensity conditioning, and no-one has worked out what is best for CLL. At Seattle the use low-dose total body irradiation; at Kings College, London they use fludarabine, busulphan and Campath. At University College, London they have been doing a trial to see how little Campath they can manage with. Others use anti-lymphocyte globulin. There are many possibilities. So when you sign up for a reduced intensity allograft - also known as a mini-allograft - you are taking part in experimental therapy.

The problem that transplanters are grappling with is graft-versus-host disease. This first shows itself as a rash, typically involving the palms of the hands and soles of the feet, and if that is all it is it can usually be managed - indeed those who have grade I GVH have the best outcome. But it also involves the gut (causing diarrhea), the liver and other organs. Acute GVH can be avoided by removing the T cells (Campath does a very good job), but abolishing GVH gets rid of the graft versus leukemia effect and without that, relapse is inevitable. So you need some T cells, and indeed, if the disease shows signs of relapsing the transplanters add some back as a donor lymphocyte infusion. Keeping the balance between too many and too few T cells is the transplanters' art. Too many and the graft versus host disease becomes uncontrollable, too few and not only is relapse likely, but viral infection - especially from CMV becomes a danger. Even if acute GVH is avoided, chronic GVH can be very difficult to live with.

In my reading about stem cell transplants, I have found it difficult to find much comment about chronic GVH. One text book (Handin, Lux and Stossel) says "It is the most insidious of transplantation complications and, in some respects, the most difficult to handle." Characteristically it involves the skin which develops a condition akin to scleroderma, with thinning, scarring, and ulcer formation. Hair loss is a feature as well as photosensitivity and depigmentation. There is an absence of saliva and tears. Muscle and joint pains, inflamed tendons, joint contractures, strictures of the gullet, sore mouth, liver damage and cirrhosis, and failure of the immune system are all problems that occur. Of course, it is not severe in everyone, but it is quite common. In a study from Nashville two thirds of patients had some degree of chronic GVH and in a third of these it was classified as severe.

This is what Peter Dreger, the leader of the German stem cell transplant program, said at the IWCLL meeting in London, "Allo-SCT from matched-related or matched unrelated donors can be highly effective in patients with otherwise resistant CLL. With modern strategies, non-relapse mortality can be kept to ~20% or lower, but the morbidity asociated with graft-versus-host disease remains a significant problem. Due to the absence of controlled trials in defined disease settings, however, it is unclear what the real impact of allo-SCT in the treatment of CLL might be, and whether it can change the natural history of poor-risk CLL. A randomized phase III trial addressing these issues, as well as the optimum time of transplantation is currently being prepared by the German CLL study Group."

The difficulties of reduced intensity stem cell allografts in CLL are reflected in the outcome data. No-one has huge experience, but there are a number of reports of 30-70 patients treated at single centers or groups of centers. Treatment-related-mortality varies from 18% to 39% and two year survival from 51% to 80%. There is no way of selecting out who does it best, because none of the studies is really a clinical trial, there are no standard entry criteria and some of the studies (including one of the largest with the best results) used several kinds of conditioning regimes over the period of the study.

So I am not against stem cell transplants any more than I am against marriage. And you know what the Book of Common Prayer says about marriage, "...it is not by any to be enterprised, nor taken in hand, unadvisedly, lightly or wantonly ... but discreetly, advisedly, soberly and in the fear of God."

A Day at Exbury

Fawley must be one of the ugliest places on earth.


The Exxon refinery is the largest in the UK. With its intricate pipework knitting, ugly containers and distressed buildings it might have been the model for the sets in Blade Runner. It is plastered onto the end of Southampton Water, opposite the Isle of Wight and my vision of Hell on Earth.

Yet only a couple of miles away is the Heaven on Earth of Exbury Gardens.


On Friday the weather forecast said it would be a cloudless day and we took the opportunity to take the day off and go out for the day. We hadn't visited Exbury for about 15 years, and when we last went Diane developed such severe hay fever that we had to curtail our visit. That was in May, so October should have been alright. Late April to May is the optimal time to visit Exbury, because the attraction is the world famous collection of Azaleas and Rhododendrons. The gardens are those of a stately home owned by the de Rothschild family. They comprise 280 acres with 26 miles of pathways. October sees the rhododendrons and azaleas in leaf but not in flower, but the attraction is the other trees turning red, yellow and gold. We had thoughts of New England in the Fall, but here, not thirty miles from our front door was its rival.

We arrived at 11 am and just sauntered through the gardens. We were there for almost 5 hours, just meandering along pathways. There were perhaps a hundred other people there, so plenty of solitude. At the furthest edge of the estate were delightful views over the Beauleu River and the Solent, on Friday, electric blue in color. In the sundial garden, walled in by Yew hedges, sun-trapped Cannas bloomed and strange sub-tropical plants flowered in bright blues and oranges with alien-shaped blooms.

Each member of the family seemed to have a hobby, for one it was rhodedendrons, for another it was steam trains. In the past five years they have laid a narrow gauge (12.5 inches) track and two steam trains pull passengers through part of the gardens only accessible that way. I have had fun helping to build my grandson's model railway, but this is the way that a really rich man does it.

Another family member has a passion for Nerines. These are sometimes known as the Spider Lily, Jersey Lily or Guernsey lily. originally native to South Africa, they can thrive only in the balmiest parts of England such as this. The temperature on Friday was in the low seventies. The collection on view was bred by a retired civil servant, now at 93, living in Switzerland, and his collection housed with the de Rothschilds for safe keeping.

Conradin Kreutzer

An almost forgotten German composer, Kreutzer was born in 1780 and like Beethoven, studied under Albrechtsberger in Vienna. He is believed to have been the last pupil of Joseph Haydn. He died in Riga in 1848.

I have been listening to two of his pieces all week. Opus 62 is a septet and opus 43 a piano trio. The CD I have features the Mithras Octet (of the Broadcasting Corporation of Saarland) with Paul Rivinius on piano.

The music is delightful. If you can get hold of the disc I recommend it.

CLL Guidelines

Guidelines for the management of CLL were issued in 1988 and 1996 and these are about to be replaced by a new set of guidelines produced by a group from the IWCLL led by Michael Hallek. There are several changes. Here are the most important.

1 The new WHO classification makes it clear that we no longer have to talk about B-CLL. What used to be called T-CLL is now recognized as T-PLL, so all true CLL is B-CLL and just needs to be called CLL. CLL is only distinguishable from SLL by appearing in the blood. Thus SLL with a lymphocyte count of at least 5000 per microliter is called CLL. CLL with less than 5000 lymphocytes per microliter is called SLL if there enlargement of lymph nodes, spleen or liver (either by physical examination or an imaging technique or if there is a cytopenia caused by marrow infiltration; if there is not it is called monoclonal B-lymphocytosis (MBL), which may or may not progress to CLL.

2. The diagnosis of CLL, as well as having a lymphocytosis of at least 5000 per microliter, must have lymphocytes that are small and mature with a narrow border of cytoplasm and a dense nucleus lacking discernable nucleoli and having partially aggregated chromatin. There may be an admixture of atypical cells, cleaved cells or prolymphocytes. The matter may under extremes circumstances comprise up to 55% of cells. If there are more then the condition is B-PLL. Smudge cells (also known as Gumprecht shadows) are often a feature of CLL.

3. For diagnosis of CLL it is essential to do an immunophenotype. CLL cells co-express CD5, CD19, CD20 and CD23. The levels of surface immunoglobulin, CD20 and CD79b are characteristically lower than what is seen on normal B cells. There is restricted expression of either kappa or lambda chains of immunoglobulin. There is no such thing as 'polyclonal' CLL, but there is a 'polyclonal lymphocytosis' characterized by binucleate lymphocytes, which characteristically occurs in female smokers. It is a benign condition, but sometimes confused with CLL.

4. No other tests are necessary for diagnosis and only one other test currently influences treatment decisions. A FISH test showing deletion of the short arm of chromosome 17 (del 17p13) signifies that the disease is unlikely to respond to conventional agents and that alemtuzumab (Campath), either alone or in combination, will be required.

5. Five other markers: Unmutated IgVH genes, use of VH3.21, increased expression of CD38 or ZAP-70, and del 11q23 are all associated with poor outcome. It is uncertain from clinical trials whether any of these, alone or together, influence response to treatment or overall survival once treatment is required. Trials are ongoing to establish this point. On the other hand the mutational status of IgVH genes in particular, and probably the other tests are useful for predicting the clinical course in individual cases, and may be recommended for patients who want a better prediction of the rate at which their disease might progress.

6 Several studies have found that the serum markers CD23, thymidine kinase and beta-2-microglobulin may predict survival or progression-free survival. Standardized assays for these and those in section 5 should be incorporated into all future clinical trials, but are not essential in general practice.

7. Bone marrow aspirate and biopsy are not required for the diagnosis of CLL. They may be useful to evaluate the factors that might contribute to cytopenias, and therefore they are recommended immediately prior to starting treatment.

8. Clinical staging is unchanged. It is emphasized that both Rai and Binet staging rely on physical examination and imaging techniques should not be used.

9. Evaluation before treatment is different for patients treated in general practice and those entered into clinical trials. The following are regarded as essential for all patients: CBC (including retics), immunophenotyping (if not already performed), history, physical examination, performance status, serum chemistry (creatinine, bilirubin, LDH, transaminases, alkaline phosphatase), serum immunoglobulins, Coombs test (DAT), chest X-ray, infectious disease status (HIV, Hep B and C, CMV). A marrow aspirate and biopsy is desirable. FISH for del 17p should always be performed. In general practice imaging tests are unnecessary unless the aim of treatment is CR, in which case the investigation of choice in CT scan, and not MRI or PET scan. US scan for abdominal nodes is used in some countries, but suffers from observer variability.

10. PET scans are only indicated where there is suspicion of Richter's disease and they are not 100% reliable for this.

11. Lymph node biopsy is not required except for the diagnosis of SLL or if Richter's transformation is suspected.

12. The indications for treatment are unchanged, but some of the details have been clarified. Lymphocyte doubling time can be determined by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of two weeks over an observation period of 2-3 months; patients with lymphocyte counts of less than 30,000 per microliter may require longer periods of observation. Other factors contributing to lymphocytosis such as infection or steroid ingestion must be excluded. Fatigue must be ECOG performance score 2 or worse (unable to work or carry out normal activities).

13. Neither a high white count nor low serum immunoglobulins are indications in themselves for starting treatment.

The rest of the new guidelines relate to clinical trials and I shall summarize these in a separate posting.

What is man? Psalm 8

What is Man? I remember fifty years ago as a young man being asked to lead a Bible Study on Psalm 8 and regaling my audience with a description of evolution cribbed from my Grove and Newell Biology textbook. In those days I saw mankind involved in a sort of brilliant progress from ape-man to superman. Everyday, in every way, things are getting better and better. It was a terrific time to be alive. On every front there was progress. Average life expectancy was increasing as the great infectious scourges of the past were defeated. Penicillin had only lately become available and the difference it had made was miraculous. Even more important, TB, ‘the captain of the men of death’, was being driven back by streptomycin. Infantile paralysis was being abolished by the Salk vaccine. Nuclear power, had not only ended a long and bitter war, but would now keep the peace and what’s more provide a cheap, safe and endless supply of electricity. Francis Crick and James Watson had unlocked the secret of DNA, and this would be the clue we needed to destroy the terror of cancer. Jet airplanes had made their appearance. The Comet made successful flights across the Atlantic and to Australia, holding out the promise of cheap travel. Science was the solution to all our fears and woes. There would be a better tomorrow. Poverty would be wiped out. Hunger would be no more. Insecticides like DDT were killing the mosquitoes that transmitted malaria, so that even in Africa people would be able to live healthy productive lives.

This was the hubristic view that I had of the world and Man’s place in it. Nemesis was to follow.

Antibiotic resistant bacteria appeared so that infectious diseases like MRSA and clostridium difficile run rampant through our hospitals. AIDS has killed millions, especially in Africa where malaria is unabated. TB, far from being defeated has returned in a yet more virulent form. While smallpox (vaccine available since 1796) has been wiped from the planet, polio remains; vaccinators frustrated by imams in Nigeria who teach their followers that vaccines are the work of the Devil. Nuclear power is no longer the savior of mankind, but another spawn of Satan (Chernobyl means wormwood). The Comet crashed because of metal fatigue and though Jet planes do circle the world they are now damned as CO2 polluters. And nobody dares use DDT. As for cancer, it (and DNA) appear much more complex than we ever contemplated. Our biggest success has come from epidemiologists who proved James the first right in hating tobacco smoke.

To think of evolution as a progressive force would be to be laughed out of court, nowadays. There is no progress, just ecological niches filled by chance and the survival of the fittest.

In 1916 James Leuba asked the question of scientists, “Do you believe in a God who actively communicates with humanity, to whom one may pray and expect an answer?”
40% of scientists said they did, 20% said they weren’t sure and 40% said they did not (a mixture of deists and atheists). Leuba predicted that over time as education improved, the proportion of scientists not believing in God would increase significantly.

The survey was repeated in 1997. The results then were 40% believed, 15% were agnostic and 45% were atheists or deists.

In 2006 Richard Dawkins published The God Delusion a polemical attack on religion that is largely a reworking of 19th Century atheistic arguments culled from the internet which also betrays the author’s ignorance of the subject of his attack. In the same year Owen Gingerich, a noted Harvard astronomer, published God’s Universe, declaring that ‘the universe has been created with intention and purpose, and this belief does not interfere with the scientific enterprise’. Francis Collins, Director of the National Center for Human Genome Research, and one of those who helped to sequence the human genome, published The Language of God: A Scientist Presents Evidence for Belief. Collins, an atheist when young was converted to Christianity after observing the faith of his critically ill patients and reading Mere Christianity by C. S. Lewis. A few months later, Cosmologist and former atheist, Paul Davies published The Goldilocks Enigma in which he argues that the existence of ‘fine-tuning’ in the universe that militates against it being a chance event.

None of these three would necessarily describe themselves as the sort of Christian that I am, but it does tend to blow holes in the Dawkins theory that science is a superhighway to atheism.

Psalm 8 is not about the hubris of mankind, nor about Man’s progress towards Superman. Still less is about the futility of life – it does not inform us that we are creatures of chance and necessity. In Psalm 8 we are told that God made us a little lower than the angels and that he put the world under our feet. We are to be custodians of the Earth.

What went wrong? Rousseau said, “Man was born free but everywhere he is in chains.” It is difficult to argue with him. Marx blames capitalism. Humanists blame lack of education. Existentialists say that Man cannot come to terms with the fact that life is pointless. But the Bible has a different explanation. In the parable of the wheat and the tares (Matthew ch 13) Jesus says, “An enemy has done this.” In the beginning of Genesis we learn that Eve and Adam were tempted by Satan, and believed him rather than God. This rebellion against God had disastrous consequences. There is something corrupt in the heart of man – Jesus, in Mark ch 7, says “For from within, out of men’s hearts, come evil thoughts, sexual immorality, theft, murder, adultery, greed, malice, deceit, lewdness, envy, slander, arrogance and folly. All these evils come from inside and make a man ‘unclean’.

If that is the diagnosis is there any remedy? In Hebrews Ch 2 there are echoes of Psalm 8. We read of Jesus, “He was made a little lower than the angels,” in other words he was made man, subject to the same pain and temptations that we are, and like us, mortal, so that ‘by his death he might destroy him who holds the power of death – that is the devil – and free those who all their lives were held in slavery by the fear of death. For this reason … he might make atonement for the sins of the people.’ v 18.

What can we learn? First, you are not a fool for believing in God, despite what Richard Dawkins and other media darlings say. Very learned men, with exactly the same access to the evidence as Dawkins, conclude that there is a God, and moreover one who interacts with humanity and answers prayer. Second, my fifty-year old ideas of mankind on an upward path are clearly wrong; the facts fit better with the Bible’s idea that we have gone in the opposite direction – we were created perfect but have fallen into corruption. Third, God has not left us there. God so loved the world that he gave his one and only son, so that all who believe in him should not perish but have everlasting life.

Poetry

For many years now, the most popular poet in America has been a 13th-century mystical Muslim scholar.

Translations of Mawlana Jalaluddin Rumi's - better known as Rumi - verse are hugely popular and have been used by Western pop stars such as Madonna.

Well, that's news to me and I suspect to most Americans.

I would guess that the most popular poet in America (if he can be called such) is Bob Dylan, but as far as proper poets are concerned William Shakespeare is unlikely to have been knocked off his perch. If we are talking about poets who lived in America then Robert Frost would be my choice, though others would vote for Walt Whitman or Emily Dickinson but remember Longfellow and Poe and countless other famous names. Of American born poets, TS Eliot is something special. Trust Al-Beeb to chose some obscure Muslim.

Visit the Rumi entry on Wikipedia and you will find that all the poems and sayings that are critical of Islam have been labelled as 'not by Rumi' but by an imitator and falsley attributed to him!

Children of men - the movie

I watched Children of Men on DVD last night. I was luke warm about the book - the first part was moving and interesting, but the plot resolution in the second half was lame and unbelievable. The film is indescribably bad. The Mexican director, Alfonso Cuaron, has been lauded for his approach, but he has produced a routine thriller with poor continuity. The characters retain only their names. The poignancy of a world without children has been completely lost; the religious sensitivity of PD James has been trampled on; and teh director has highjacked the story to make a left-wing statement about illegal immigrants and Guantanamo Bay. If you want to watch this film, I would advise not switching on the sub-titles. That way about half the profanities will go unheard.

2007 and all that

I was reminded yesterday that I hadn't blogged for a week; was I still alive? Alive, certainly, but busy. I have been painting the back of the house. We have one of those black and white, mock-Tudor houses. It is around 100 years old with the original wooden window frames. When I addressed the problem it was clear that the paint was stronger than the wood. It was necessary to do some remedial work before I could get the paint-brush out. These old houses are very impressive but they do require maintenance.

At the weekend my son visited us. David is an engineer who works for AP Racing. The company made its name by designing and manufacturing the clutch for the Ford Cosworth engine, which for many years was the basis of most car racing. He is an expert on brakes, and designed the brakes on many of the fastest cars on the planet. His role this year is to be the AP representative at the races. He has just returned from Salt Lake City where he covered some sort of racing event, but he had a free weekend to come and visit his ageing parents.

We took a walk on the beach on Sunday morning. The weather was balmy with a south west breeze and very few people around. Seven miles of sand in a long curve with cliffs behind. This is the time to best appreciate Bournemouth. The visitors have gone home, but it is still warm enough to walk in your shirtsleeves. Now the residents can enjoy the scenery without the smell of suntan oil and hot dogs. The cliffs here are covered with vegetation. I picked out wild roses, Michaelmas daisies and evening primrose, but there were many other species that I didn't recognize.

We have been talking about moving from Bournemouth, though it would be hard to leave. This is one of the most pleasant sections of the English coastline. However, we haven't walked on the beach since February and we could achieve that frequency if we lived in Birmingham.

In Bournemouth this week are the Labor Party for their annual Conference. Gordon Brown gave his first Conference speech as Prime Minister. There is talk of an early election so that he can have his own mandate, instead of inheriting Tony Blair's In fact there is no need. He has two and a half years before he need to call an election. This is a parliamentary, rather than Presidential, form of government.

Last night I watched a television program about the making of the film, Billy Eliot. Most of my readers will know that this is the story set against the miner's strike of 1984 of a young working class, miner's son who wants to become a ballet dancer. In the film they used the local ex-miners as extras. They were happy to play the striking miners, but no-one wanted to play the policemen who broke the strike. Not living in such an area I find it hard to appreciate the vehemence with which these communities hates (and still hate) Mrs Thatcher.

My take on British history since the second world war is that 1945 saw an irrevocable change. Workers were no longer content to be led by the 'Officer class'. They had seen for themselves that it was the sergeants who were the real leaders. Sure there were real leaders like Churchill and Montgomery who knew how to fight, but the young men from public schools who were the subalterns and junior officers were in the main no more fit to lead, and often far less so, than the NCOs who were their erstwhile mates. The Attlee government nationalized everything. Post war Britain was all but bankrupt, its industry had been bombed and much of its housing stock destroyed. Although it still had its bright young men and its Nobel prizes (the structure of DNA was discovered in Cambridge in 1953), its industry was old fashioned, the class structure was still ossifying society, and capital was in short supply. The Attlee government was stuffed with effete intellectuals and tough Union leaders. They were not up to the task. On an island built of coal and surrounded by fish they had contrived by 1947 to produce a shortage of both - as Sir Anthony Eden adroitly remarked. Their vision outran their competence.

Churchill's government of the fifties had the advantage of time passing since the war. Economic recovery had begun. But Britain had to come to terms with its new place in the world. As America's largest ally in Korea, it felt itself still to be a great power, but when the conspiracy with France and Israel to attack Suez and retake the Canal failed because America opposed it, the new Prime Minister, Macmillan, had to readjust to the new world. Britain acted quickly to divest itself of its Empire. India had gone in 1947, the White Dominions could stand on their own feet, and the rest was a burden rather than a benefit. Empire became Commonwealth, but Africa had little share in the common wealth. Following the Indian example the African colonies each produced their own Nehru, and endowed with schools, a civil service and the Church of England stepped out towards disaster.

Profumo brought down the Conservatives. Despite relative success of Macmillan's government - they were building 300,000 houses a year, there were new roads and railways, new schools and hospitals were constructed and the exploitation of the African had ended - they were still members of a different class. Profumo emphasized that. While the rest of us were working out butts off for the country, here was a member of the government consorting with call-girls, living it up at a country house and probably spilling secrets as he shared a mistress with a Russian spy. It was too much for Macmillan who fell ill, and when the Tories replaced him with the 14th Earl of Home, our suspicions were confirmed. We wanted one of us to lead us, not one of them.

The sixties were all about young people. The Beatles, the Prague Spring, Paris 68, Jack Kennedy, Viet Nam: Harold Wilson exploited the situation well. He was an Oxford intellectual who pretended to be working class. He affected a broad Yorkshire accent, smoked a pipe and entertained visitors to 10 Downing Street with beer and sandwiches rather than fine wines and French haute cuisine. He declined to send troops to Viet Nam, pursued Keynesian economics, let inflation rip, allowed the Trades Unions to dominate politics, spent taxpayers money on propping up ailing industries and presided over decline. It was like that line of Wilfred Owen's: "A slow drawing down of blinds."

The Tories gave us a Wilson clone in Edward Heath. A one-nation Tory, he pursued much the same economic policies as Wilson. Heath was a bachelor who loved classical music and yachting. His great ambition was to enter the Common Market as it was then known. Everyone envied the German economic miracle and wanted the same for themselves. The French wanted to keep it for themselves. Heath bought his way in. I guess his ambition was colored by the War. He had been a major in the Tank Corps and had been decorated. He saw the European Economic Community as the sure way to end war in Europe.

My view on Europe is different. Cynically, I regard it as a plot by the French to enforce the same sort of reparations on Germany as they did after the first world war. In trying to avoid another Hitler arising they locked Germany into a social arrangement by which German profits would featherbed French farmers while keeping Germany as a good neighbor. Naturally De Gaulle didn't want the British to have a share of the cake. The terms that Heath agreed to were such that the British ended up paying the French too (for having the cheek to save French bacon). Of course America was the real funder through the Marshall plan.

But it wasn't Europe that brought him down, it was the economy. The British economy had been growing at a rather slower rate than the German one, but it had been growing. Despite large numbers of immigrants from Jamaica and the Indian sub-continent there was a shortage of labor and the Unions exploited this. The main industries - coal, steel, automobile, telecommunications, shipbuilding, the docks and the railways had all been nationalized so the Unions had the ability to hold the country to ransom. The Arabs had shown how to do it by raising the oil price. Without fuel the wheels don't turn.

The coal miners went on strike. To save fuel Heath introduced a three day week. Electricity was cut off at regular intervals to spread the pain around. We were lucky; we lived next door to a hospital which was spared. Heath called a snap election on the issue of who rules - the Unions or the Government? But people were sick of the privation and voted Labor.

Wilson was back and his Industry Minister Eric Varley settled with the miners by giving them a 30% pay rise, but Wilson immediately recognized that the Unions had to be tamed. He instructed Barbara Castle to introduce legislation to curb them. "In Place of Strife" was hated by the Unions who mobilized their MPs to fight it. Their chief supporter was Jim Callaghan, a man who has the signal honor of holding the four great offices of state - Prime Minister, Foreign Secretary, Chancellor of the Exchequer and Home Secretary, and failing in every one of them. In a Cabinet revolt he defeated Barbara Castle. The Unions were unfettered, and in a surprise decision, perhaps because he recognized the beginnings of dementia, Wilson resigned.

Callaghan succeeded him and led the country into chaos. By 1979 strikes ruled. The economy had collapsed. The dead remained unburied, garbage was uncollected in the streets and rats had started invading people's house. Callaghan clung on until the last moment.

Then came Mrs Thatcher. It was not easy. To control inflation Geoffrey Howe produced a severely deflationary budget. It was not popular. The mood of the country was against her. Then the Argentinians invaded the Falklands. It was a Godsend. She mounted a task force with an 8000 mile logistic tail that retook the islands. It was difficult; we lost a lot of men, but it proved that low as we had sunk, we were still superior to some jumped up banana republic run by a bunch of Nazis whose heroes cheat at football.

Thatcher was re-elected and made plans to tackle the miners. It was a re-run of 1973-4. Scargill wanted to emulate Gormley, but he was a much nastier piece of work. Thatcher had prepared well. Coal stocks were at an all-time high and many of the power stations were gas-fired. She weathered the storm. Despite violent demonstrations, bullying and bitter enmity between working men, the miners were defeated and the Unions were broken. The great state monopolies were broken up and privatized. Anti-Union legislation reduced their powers. A stronger Mrs Thatcher even renegotiated the terms of EU membership and won a rebate on the punitive cost we were paying the French. She won a third term.

She fell over two issues. She would not pay for recombinant factor VIII for hemophiliacs and she replaced domestic rates (which had become unworkable) by a flat rate tax. This was dubbed the Poll tax by Labor bringing back memories of Wat Tyler. The Tories felt she had outlived her usefulness and brought in John Major who was supposed to lose in 1992. He won. Tempted by Europe to start to merge currencies, his first move was met by a run on the pound. The speculators won and Major was diminished. Not only was he now a lame duck, but he faced Tony Blair, a different kind of Labor leader.

Blair adopted Thatcher's economic policies, resisted the Unions, and to a degree kept the Chancellor's hands off interest rates. The economy boomed. His foreign policy involved interfering in the internal runnings of rogue states. This was successful in Bosnia, Sierra Leone and Kosovo, but Iraq became a millstone around his neck. His successor, Gordon Brown, is benefiting from not being Tony Blair, and despite being equally to blame for Iraq carries none of the fall-out from it. He has the reputation of a successful finance minister, but so far even the first run on a British bank for 147 years has not harmed him. Can it last?

He appeared in Bournemouth this week in sober suit against a blue (Tory) background and mentioned 'Britain' or 'British' 71 times in his speech. As a Scottish MP he is vulnerable to Scottish nationalism. He is also facing difficulties over Europe. His manifesto promised a referendum on the new European constitution. That was kicked into the long grass by the French and the Dutch, but has been resurrected, only slightly altered as a Treaty. He no longer wants a referendum (which would be lost), but if he calls an election it will become a referendum on Europe. Whatever the polls say, he might lose.

Alan Greenspan speaks

Margaret Thatcher appeared frail last week when Gordon Brown welcomed her to 10 Downing Street as an honoured guest. he was only doing her the same courtesy as previous premiers had done. All invite their predecessors in for a look round to see how the place is changing. Nevertheless it caused him some aggro at the Trades Union Congress, where she remains a hated figure.

To my mind the Blessed Margaret did two things for Britain that have cemented her place in history. The first was to dare to mount a military operation 8000 miles away to retake the Falklands. People forget that Britain was in seriously decline before that. In 1979 a strike in the public sector had left the dead unburied and garbage uncollected so that there were rats running rife in the streets. The Argentinian Junta must have thought that Britain was so weak that it wouldn't bother over a couple of rocks in the South Atlantic close to Antarctica where a couple of thousand sheep farmers live. I'm still not sure what motivated Margaret; I was in America at the time and I seriously doubted that Britain had the military strength to mount an operation so far away. I suspect it was when she saw that the Falklands were being forced to drive on the right. Anyway, despite setbacks, the Falklands were retaken by acts if bravery or fortitude. A right wing dictatorship was overthrown.

The other great thing she did was to defeat the miners. A decade earlier a Conservative government had been overthrown by Joe Gormley, the miners' leader, but this time she was ready for them. When Arthur Scargill attempted the same trick and used even more violent tactics than Gormley, he was defeated and the grip of the Labor movement was broken. Britain would no longer be a communist fellow-traveler; the economy was turned around by flexible labor laws and the Labor party would not return to power until Tony Blair reformed it, changing it into a party of the right.

Alan Greenspan, quoted in the Telegraph this morning concurs:

"You [in the UK] haven't even had a taint of a recession for an extremely long period of time – and a goodly part of that is the flexibility that came out of the crush between Scargill and Thatcher," he says.

"That was the defining moment, and to their credit Blair and Brown did not endeavour to unwind it. They recognised that there was something fundamentally good for British labour in having a flexible economy."

Chromosomes at IWCLL

In my first report from the IWCLL I want to focus on chromosomes. FISH - fluorescent in-situ hybridization is the mainstay of chromosomal examination in CLL. With this technique florescent probes are used to detect certain DNA sequences in the CLL nucleus. It has the advantage that the cell does not have to divide in order to be examined. and because of this many cells can be examines (typically 200). The disadvantage is that you can only see what you look for - usually deletions at 13q14, 11q23 and 17p13 plus trisomy 12. Sometimes del 6q is also looked for. There were reports at this meeting of the use of other techniques including looking for copy number changes and loss of heterozygosity using high density SNP arrays, and new mitotic agents to induce cell division.

In the SNP array paper from Freiburg, Germany an area at 2p16 that contains came under REL and BCL11A came under suspicion. BCL11A was one of the genes that is differentially expressed in mutated and unmutated patients, identified by the original Rosenwald paper.

Most people cannot get CLL cells to divide properly. A good way of checking whether chromosome banding techniques are successful is to compare the percentage of del 13q14 patients that are detected by banding and FISH. Most people find many more by FISH and by this reckoning only the Haferlach group at Munich and the Oscier group in Bournemouth are any good at chromosome banding in CLL, and both reported their results here. The Munch group largely confirmed the results that had previously been found by FISH, but added the fact that chromosomal translocations occur in about 20% of patients. Most involve either 14q32 or 13q14, and they are usually not balanced - the involve a loss of chromosomal material - effectively they are deletions. They do not have common partners and they do not form fusion genes. They also reported that trisomies of 3, 18 and 19 are seen as well as trisomy 12. Finally, about 16% have complex karyotypes which are usually associated with bad prognosis markers.

The Oscier group reported on karyotyic evolution. this can be detected by demonstrating sub-populations of cells with none, one, two or three abnormalities apparently acquired in a sequential way (eg 10% of cells have normal karyotypes, 27% just del 13q14, 48% of cells del 13q14 plus del 11q23, and the rest del 13q14, del 11q23 and del 17p13). Or they cen be demonstrated by watching for changes on sequential samples taken at interval - this would include someone who had 14% del 13q14 at diagnosis, but 85% del 13q14 four years later. The Oscier group reported on 342 patients. In 103 there was evidence that karyotypic evolution had occurred prior to diagnosis. 314 had a second sample taken after an interval of at least a year. Patients had a median of 4 (range 2-13) samples taken. 189 patients eventually showed evidence of karyotypic evolution (ie 55%). There were specific patterns of evolution. Those with trisomy 12 (which was almost universally a primary event) either acquired a 14q32 translocation (t14;18 or t14;19) or developed further trisomies (of 19, 18 or less commonly 3). Further trisomies only occurred on a background of trisomy 12, and only occurred in those with mutated VH genes.

In patients withdel 13q14 the commonest progression was for the other chromosome to become involved with a similar lesion. These has been some debate as to whether this carries a poor prognosis. Other groups (including the Munich group) have suggested that it might do so although the figures do not reach statistical significance, However, in this series those with the second chromosome involved actually did significantly better than those with only one - possibly because this is a relatively late phenomenon, and the patient has to survive a long time without acquiring a different chromosomal abnormality in order to just have a homozygous deletion at 13q.

The hunt for the gene responsible at 13q14 has been long and apparently fruitless. The missing chromosomal portion was first reported in 1987:

Chromosome abnormalities involving band 13q14 in hematologic malignancies
Margaret Fitchett, Michael J. Griffiths, David G. Oscier, Sharron Johnson and Marina Seabright Cancer Genetics and Cytogenetics Volume 24, Issue 1, January 1987, Pages 143-150.

There have been several attempts to identify the genes on the missing fragment, largely by Dr Oscier's group, but to no avail until the problem attracted the big boys, Carlo Croce and Ricardo Dalla-Favera. They both agreed that there was no gene coding for any tumor-suppressor protein at this site. Croce's wide reading led him to microRNA genes and the discovery that two such genes, miR-16-1/miR-15a were located within the deleted area. miR genes interfere with the expression of messenger RNA, and thus the expression of a target protein. At least one of the targets of these genes is BCL-2, so that if they are missing BCL-2 is over-expressed and, as everyone knows, BCL-2 is over-expressed in CLL. this is thought to at least partly explain the resistance to apoptosis.

The miR genes in CLL are very close to one of the introns for Leu-2, a gene that is not translated into protein. Dalla-Favera decided to investigate what Leu-2 does. He produced evidence that Leu-2 is a long controlling gene. Thus it is not clear whether the effect of the 13q deletion is mediated just through the miR genes or whether the whole Leu-2 gene acts epigenetically to control some important function in B cells and that loss of this function leads to leukemia.

IWCLL 2007

This week I have been at the IWCLL meeting in London. This meeting began many years ago in Paris and I have been to most of them. We were shown a photograph of the meeting in Barcelona in 1991 where there were 44 delegates. Most of the 44 were at the London meeting, along with over 700 others. It is no longer a workshop. Nevertheless I would suspect that no disease has shown such an increase in interest over the past 20 years as CLL.

I will be blogging about some of the new stuff to come out of the meeting at a later date, but the hot news is about the Binet-Rai Medal which is presented at the meeting. The medal was first given to Kanti Rai and Jaques-Louis Binet for their invention of the CLL scoring systems. The third medal was given to Michael Keating for his work with fludarabine. The fourth and fifth medals were given to Nick Chiorazzi and myself for the discovery of the importance of VH mutations. The sixth medal was given to Daniel Catovsky for his work on the morphology of CLL and the MRC trials. The seventh medal was awarded this year posthumously to David Galton who died earlier this year. David was one of the first physician scientists to work on CLL and established many of the features of the disease and described lymphocyte doubling time as a prognostic factor. His widow and children accepted it on his behalf. The eighth medal went to Carlo Croce for his discovery of the miR genes 15 and 16 at 13q14 in the minimally deleted region and his TCL-1 mouse model of the disease.

The discoverer of leukemia

Rudolf Virchow was one of the two men who first described leukemia in 1845 (the other was John Hughes Bennett, an Englishman who was Professor of Medicine in Scotland). Virchow, as well as being the greatest pathologist ever, was also a Public Health Specialist and social reformer, and something of a politician. In this respect he quarreled with Bismark, the German Chancellor. Bismark challenged him to a duel, and being the one who was challenged, Virchow had the choice of weapons. He chose sausages. I came across this fascinating fact and the mind's picture of two hirsute Germans bashing each other with German sausages was funny but undignified. This is how Virchow wanted to fight to the death with a sausage. He proposed that one of the sausages should be injected with a deadly bacterium. Then each would choose a sausage and eat it. One of them would die a horrible death in writhing agony. After all, skill with a pistol or sword should not be the determining factor in an argument. If they could not agree by discussion, why not let chance sort out their disagreement. Bismark withdrew his challenge.

Mark 13 finally

As we come to the end of Mark chapter 13, how clued up are we about the Second Coming? There seems no doubt that He is coming. Not only does this the earliest gospel teach it quite plainly in this chapter, but the saying 'Maranatha' (Oh Lord, come!) became a greeting in the early church.

We also know that Jesus himself did not know when he would return (v 23). He accepted the restrictions of the human form at His incarnation, one of which is not being able to know the future. There were some things that had to happen first, though. Wars and rumours of wars, earthquakes, false prophets and the total destruction of the Jerusalem Temple. These things would be fulfilled within one generation (v30). And so they were. By AD70 the time was ripe for the Lord's return; everything that was needful had been.

But that was nearly 2000 years ago; how can it be said to be near?

This is a concept that needs to be clearly understood. It doesn't mean the same as soon. It means imminent; it could happen at any time. The idea of soon is in opposition to the idea that no-one knows the time. It means that nothing is preventing it. There is nothing that has to happen first. Like a seabird skimming over the surface of the water, at any moment it could dip below the surface and take a fish. It is always close, but no-one knows when it will dive.

How do we know he hasn't already come?

Because it will make a real splash when He does come v24-26. As Paul says it will happen with "a loud command, with the voice of the Archangel and the trumpet call of God." (I Thess 4 16) It will not be a hole in the corner affair.

What is the take home message?

We ought to be ready now. Are you thinking that you would like to be a Christian but not yet; you are too busy enjoying yourself? Don't delay, there may not be a 'later'. Are you a Christian but living a worldly life? Why risk all for those things that will perish? Money will be no use to you in Heaven. There are no pockets in a shroud. Even if the Second Coming is after your death, you don't know how many days you have left. Forgive me if this offends you but this Tuesday is 9/11. I imagine that the thousands who died that day were not expecting it. Were they ready? Would you be?

Jesus tells several parables about the unprepared. "If he comes suddenly, do not him find you sleeping. What I say to you, I say to everyone: Watch!"

War films flagging

'Flags of our Fathers' is a remarkable film. Since the 1960s we have accepted the message that war is horrible and one wonders what more there is to say on that theme. Before then we had seen war movies as keeping your chin up as our economies recovered from WWII. "Cheer up," they seemed to say, "your sacrifice was worth it."

With films like 'The Damn Busters', 'In Which We Serve', 'Reach for the Sky', 'First of the Few', 'The Colditz Story', 'the Battle of Britain', 'Odette', 'Carve her Name with Pride', and 'The Way Ahead', Jack hawkins, John Mills and Dickie Attenborough represented the common man whose steadfastness and courage carried the day. 'The Great Escape' and 'Where Eagles 'Dare turned the war into a Boy's Own adventure. Viet Nam soured any attempt to make war worthwhile. Lately 'Schindler's List' re-exposed us to the harrowing horror of the Nazi's and 'Saving Private Ryan' to the futility of the trying to order events in wartime.

'Flags of our Fathers' exposes the cynicism of politicians and the exploitation of soldiers. It might have been culled from Rudyard Kipling:

We aren't no thin red 'eroes, nor we aren't no blackguards too,
But single men in barricks, most remarkable like you;
An' if sometimes our conduck isn't all your fancy paints,
Why single men in barricks don't grow into plaster saints;

For it's Tommy this, an' Tommy that, an' "Chuck 'im out, the brute!"
But it's "Saviour of 'is country" when the guns begin to shoot;

Obviously, the story of the photograph of the American Flag being raise on Mt Suribachi which inspired the Washington war Memorial will have more significance for Americans than for me, and the story of Ira Hayes (then played by Tony Curtis) has been told before, but as a foreigner I can still get the irony. This is not an anti-war film, but it disparages the notion of heroes. It was necessary to take Iwo Jima. It was necessary to exploit the victory in order to fund the continuation of the war. But men laying down their lives for the country is a fiction. They died unexpectedly, but when they thought about it they died for their buddies.

Hugh and C(a)ry

Notting Hill I enjoy watching, Four Weddings even more so; About a Boy was good and I really liked Love Actually, but I am afraid that Music and Lyrics with Drew Barrymore is another Mickey Blue Eyes where the Hugh Grant charm doesn't work.

Hugh is often compared to Cary. He is after all an Englishman who went to Hollywood er... called Grant. I am afraid that the comparison does not flatter Hugh. Sure Cary often played himself, but it is hard to believe that an older Hugh will be able to carry a film like North by North West or even Charade.

Amazing Grace

The actors in this film were unaware of the story of William Wilberforce and even of John Newton. One wonders what is taught in schools today. No wonder people like Dawkins gets away with his claim that religion brings only misery and strife.

The Clapham Sect were a group of remarkable evangelical Anglicans who effected more social change in Nineteenth Century England than any other group - and since at that time England was the only world superpower, the influence was worldwide. Apart from the abolition of the slave trade, whose 200th anniversary this film and this year celebrates, their work led eventually to the emancipation of slaves, a land back in Africa for slaves who wanted to return (Sierra Leone), prison reform, free education and the establishment pf nursing (Florence Nightingale was the granddaughter of one of their members). Their zeal, perseverance, energy and philanthropy changed the world.

What about the movie? The young principals performed well, but were acted off the park by the two seniors, Albert Finney and Michael Gambon. The film was cheaply produced, without special effects and rather 'stagey'. This was the time of the American and French revolutions; we were given no sense of how close England came to suffering the same. We saw the shackles but no slaves. The TV series 'Roots' from many years ago showed us what life was like on the triangular passage; it could only be parsimony that deprived us of a similar visual shock.

I was looking forward to this film but I was disappointed in the result. The British parliament was portrayed as a unicameral affair with Lords and Commons taking part in the same debate. With such an economy with veracity, I didn't know how much of the story I could believe.

Tenderness of Wolves

If you haven't read 'The Tenderness of Wolves', the remarkable first novel by Stef Penney, I strongly recommend that you do. Set as it is in Canada of 1867, it is not immediately the sort of book I go for, and you might find it a trifle slow as it establishes its characters and its place, but persevere and it will reward you perseverance.

In essence it is a detective story, but there is no detective or even a policeman in sight. Mysteries pile up: a murdered man, a lost boy, lost girls, a lost husband, a missing wife, lost firs, a cryptic message, a lost language. The Canadian wilderness is the setting. The settlers are largely Scotch with a smattering of Frenchies. The native Americans have been exploited and ... 'enslaved' is too strong a word, but subjugated certainly. Women are exalted, then owned, then beaten. Boys are groomed, then bullied, then expected to mature - and if they fail they are thrown to the wolves. But in this story wolves hardly feature despite the title. They act as a symbol of the wild, but as we are repeatedly told, they seldom attack humans.

Stef Penney grew up in Edinburgh and studied at Bristol University (my old alma mater) before studying film and TV at the excellent College of Art here in Bournemouth. She was picked up by Carlton Television's New Writers scheme and has written and directed two films. She has never been to Canada and, like Karl Marx before her, did all her research in the British Library. (Why should that surprise us? Had Isaac Asimov ever been to outer space?) She has at least one anachronism: the town of Kitchener was named after the General; in 1867 it was called Berlin.

Mostly things resolve themselves, but with so many plot lines and over 50 characters there are some loose ends. What did happen to Amy Seton? Why was Jammet killed? What was Mrs Ross's first name? (Look away now if you don't want to see the spoilers) The answer to the last is Lucy as can be worked out from pages 165 and 170 and indeed from the final page. Jammet was killed because to prevent him taking what others covered and Amy Seton is surely the subject of another book, just as Mrs Ross's prequel is already the subject of a screenplay.

Playing Solitaire and learning from games

I have several games of patience on my computer. They are addictive and when I have a spare minute I often play a game. I limit myself. It teaches me discipline. One game only, then I leave it.

One of them, 'Spider Solitaire', is very difficult at the highest level and I win only once in a hundred times. You are called upon to make decisions. Shall I put that '6' or the other '6' on the '7'? When you see the result of your decision, you often wish you had made a different choice. But there is no going back. There is no point in worrying about the 'what ifs?' and the 'might have beens'. That's like life. We can be disappointed in the decisions we have made but the decisions can't be undone. We have to learn to live with them. Sometimes there is no choice; there is only one '6' to put on one '7'. If life turns out badly as a consequence we have nothing to reproach ourselves with, and even if there were a choice and there were no indicators to guide a choice, then it wasn't our fault if we made the wrong one.

'Free Cell' is a different type of solitaire. Supposedly it will always come out if we make the right choices. Of course, we often make wrong ones, but the game has the facility to be replayed. Sometimes I have nine or ten attempts before I make the right choices. Life isn't like that. It's not like 'Groundhog Day' where we replay the same day thousands of times before we finally get the girl. We only have one try and have to live with the consequences. 'Free Cell' is a more interesting puzzle, but 'Spider' is truer to life.

Winning isn't everything. Cricket teaches that. At least it used to. When I played I remember being told off by the captain for kicking the ball away in frustration when I had made a silly mistake. "That's not how we play the game."

Perhaps golf is a better model or snooker; game where you call your own fouls. Too much today sport is too much about winning. Athletes who build up their bodies with drugs, cyclists who increase their hemoglobin with EPO, footballers who foul behind the referee's back, cricketers who 'sledge' their opponents; what is the point of cheating to win? Recently Diego Maradona, the extremely gifted Argentinian footballer, appeared on a chat show run by Hugo Chavez. Together they celebrated the famous 'hand-of-God' goal that enabled the Argentinians to defeat England in the World Cup. Cheating may have gained Maradona a World Cup winner's medal, but today he is a fat, cocaine addicted failure. A price not worth paying?

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

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

Call me old-fashioned, but I prefer:


There’s a breathless hush in the close tonight
Ten to make and the match to win
A bumping pitch and a blinding light
An hour to play and the last man in
And it’s not for the sake of a ribboned coat
Or the selfish hope of a season’s fame
But his Captain’s hand on his shoulder smote –
‘Play up! Play up! And play the game!’

Boys' Toys

Apparently, Top Gear, the Jeremy Clarkson program about fast cars and boys' toys, is sold to 200 different countries and is even more popular in America than it is here. I write about it because my son, the engineer, is taking part in the program they are currently making. They are entering a car that they have built for a 24-hour race at Silverstone and my son has done the brakes. He was there today at the track, but the car was in limp-home mode and wouldn't go above 3000 revs.

Jeremy Clarkson is very tall (6ft 4) and comes across as a chain-smoking, coca-cola swilling curmudgeon who is waited on hand and foot by young girl PAs. It is probably an act; I am sure in the privacy of his home he is meekness personified and kind to pigeons. Richard Hammond is only 5ft 4 and so when they change drivers the seat has to be mightily adjusted and a new seat-belt fitted. James May is reputedly a terrible driver who has to be coached by Jackie Stewart when they drive fact cars. The Stig is no longer Perry ****** (I dare not reveal his new identity for fear of assassination). the first Stig was sacked when he revealed his name to a Sunday paper. He now runs a racing driver school in America. The new Stig is awesomely fast.

Charlotte Gray

I have been reading 'Charlotte Gray' over the past week. Sebastian Faulkes is sometimes regarded as the greatest living English novelist, but that is over-egging the pudding. I had previously read 'Birdsong' which was a flawed masterpiece, but in this one he has worked hard on making the flaws more apparent. For a start the plot is preposterous. He concentrates so much on the countryside that you don't notice how silly the plot is at first, but on reflection the story was so full of unlikely co-incidences as to detract from giving it serious consideration.

His style is to report scenes in great detail, but this detracts from pace, and if a book about the French resistance needs anything it needs pace. about half way through I doubted whether I could find the energy to finish it. Several characters form his earlier books make cameo appearances in this one, but whether this adds to the book, I doubt. Perhaps I am so accustomed to the Holocaust that the details no longer shock, so that the sections that dealt with the arrest of Levade and the deportation of the two little boys never really held my attention. Wost of all was the character of Charlotte Gray. Perhaps Kate Blanchett could make something of her in the film, but I just though she was a silly and headstrong child who needed her bottom smacked. The Spitfire pilot was thinly drawn and the most interesting character, Charlotte's father made only a brief appearance. I am afraid that the real problem is that the characters don't emerge from the page.

Prayer

In the Garden of Gethsemane the closest disciples of Jesus fell asleep when they were supposed to be praying. "Watch and pray," commanded Jesus, but three times he came back and found them slumbering.

If Peter, James and John couldn't hack it, what hope is there for you and me?

Why don't we pray? I have to admit that my prayer life is perfunctory; that I frequently get distracted and often fall asleep. Why is that?

First, it is because we are not really convinced that it is necessary. We take the view that God will run His universe without my help; that any advice I could give Him would be bound to be flawed; that we are beyond the shopping-list type of prayer of our childhood. In what sort of way could we change God's mind? Is God likely to re-order the world at our insistence? Is He not sovereign?

In this we are profoundly mistaken. Remember Abraham above Sodom. In a comical story reminiscent of Del Boy and Rodney (Google Only Fools and Horses if you don't get the reference) he beats God down to only 10 righteous men necessary to spare the city. Of course, God still destroys Sodom, but it demonstrates that He doesn't have a closed mind. Remember also James, "The prayer of a righteous man is powerful and effective."

The fact is that we cannot use our small minds to second guess God's will. The apparent conflict between God's sovereignty and human responsibility cannot be sorted out by us; the fact is that both are taught in the Bible and both are true. God's will will be done, but we are also commanded to pray. It seems that in some way God's will will only be done in the context of prayer.

Second, we are in a spiritual battle. "The devil trembles when he sees the weakest saint upon his knees". Consequently, he puts every obstruction possible in our way.
It is our responsibility to play our part in this battle and not to be distracted. We are only strong in that we pray. We are puny foes for the devil when we stand unaided, but when we stand with God we are invincible. Remember the story of Elisha surrounded by the army of Aram and how he said to his servant, "Don't be afraid, those that are with us are more than those who are with them." And he asked the Lord to open his servant's eyes so that he could see the hills full of horses and chariots of fire.

Third, we make excuses. It is not my gift. I cannot pray in public. I am shy. I am afraid of making a fool of myself. I am sure to come out with some terrible heresy. Prayer is not a gift, it is a responsibility. Everyone can pray and it is not a competition.

Fourth, we are tired. Just as the disciples at Gethsemane were tired we often choose the most inopportune moments to pray. If I get into bed late at night and expect to be able to pray I am doomed to failure.

We miss out on so much when we do not pray, and we deny our friends and family God's blessing. If we do not pray for our family, who will? If we do not pray for our friends will anyone else? If we do not pray for our city, will it stand? If we do not pray for our country, no wonder our politicians get caught in sex scandals and financial scams; no wonder our television is so revolting; no wonder our kids go astray; no wonder our influence in the world is declining; no wonder abortions are burgeoning; no wonder so many families are falling apart; no wonder young men are killing each other on street corners; no wonder babies are born addicted to crack cocaine; no wonder our prisons are full.

Prayer is the lifeblood of the church. What is the church for? The church is there to pray. CH Spurgeon, the greatest preacher of the Nineteenth Century was asked the secret of his success. "My people pray for me," was his reply.

Pray for your leaders, pray for your church, pray for the sick, pray for those with responsibility for traffic, air traffic controllers, sewerage workers and garbage men, prison officers and policemen, those in the armed services, firemen, nurses, doctors, teachers, even lawyers. Pray for those in government, those in the House and Senate, those facing testing, those who are sinning; pray for thieves and murderers, adulterers and homosexuals; pray for the angry, the hurting, the betrayed and those who betray; pray for widows and orphans, pray for refugees, pray for the homeless; pray for those without work, those without funds, pray for the sick.

This is such important work, make it a priority. Make lists. And give thanks. Today I examined a flower in my garden. In several shades of pink my gladioli attract the bees, but there was no need for them to be beautiful too. God did it to please me. God made a wonderful world for me. He gave me all the food I need. He gave me an interesting life with much to fire my imagination. He gave me beauty to appreciate and wonderful music. But this was not enough. Knowing that I would rebel; knowing that I would disobey Him, He sent His son to die for me, to pay the price of my felonies so that I should not perish but have everlasting life. He sent His Spirit to awaken this dead soul and make me aware of Jesus and gave me all I need for salvation. Before you start praying, praise Him for His glorious majesty and thank Him for his magnificent grace.

In England Now

Little blogging this week, mainly because I have been doing my accounts for the tax man. This is the task that I hate the most. I suppose I should do them as I go, then I wouldn't have to try and remember what exactly that item 'Staples £3-98' actually was.

I won't comment more about the task except to say it might have been worse; I could be an accountant.

This has been the worst summer in England since 1956, though that did have some redeeming features. We retained the Ashes against Australia and Jim Laker took 19-90 at Old Trafford. No sporting redemption this year; the cricketers have lost to India, the rugby players have lost to France, the footballers have been struggling, the tennis players are out of form, and the only athlete to win a gold medal at the IAAF World Championships is someone who missed three off-season drug-testing appointments.

Blair has gone and we gave had a summer of Brown. What is it like in England now?

We have had a lot of floods. Brown has handled the press well; he hasn't fallen into the traps set for Bush over Katrina. He was helped by David Cameron fulfilling a long planned foreign trip while his own constituency was under water. The reasons for the floods - too much house building without the necessary infrastructure - can hardly be laid at the feet of an incoming prime minister.

The economy remains strong; although the 'footsie' fell with the American sub-prime crisis, it seems to have recovered and stabilized. The cash-for-honors crisis seems to have gone quiet - I suppose it is regarded as Tony Blair's dirty washing. John Prescott, the boorish Deputy Prime Minister and constant source of embarrassment has gone too. There have been no financial or sexual scandals surrounding Brown.

The big test, of course, remains Iraq. He packed his cabinet with Bush-haters, yet seemed amiable enough when he visited Camp David, pledging friendship and support. While the surge seems to be showing some benefit in the north, the carnage has got worse in Basra. There has been criticism of the British forces in the south from some of the American armchair generals (I suppose in Patrick O'Brien's world they would be Admirals of the Yellow). In the press today are rejoinders by retired British Generals blaming Rumsfeld for the whole sorry mess.

Of course, the situation in Iraq is more complex than we are told. The success of the surge is related to the war against Al-Qaeda. The Americans have successfully separated Sunni leaders from the Sunni Al-Qaeda and have begun to undo the mistake of assuming that all Saddam supporters were fervent Baathists. They were careerists backing the winning horse. In the south Al-Qaeda is not a factor; they are all Shi'ites. The question there is how much influence Iran will have over their fellow Shi'ites. The anti-Iran conflict is a particularly American one that the British have never fully bought in to. I can understand that Americans still want pay-back for the hostage crisis of the 1970s and don't trust the Ayatollahs but in the real world you have to deal with things as they are, not how you would like them to be.

The truth is that politics in Basra is unlike anything in the West since Al Capone was defeated in Chicago. Unless there is a serious intention of recreating the Untouchables, and there is no political mandate or will to do that, we are better off out of there.

We hear of a six-month truce from the Mahdi army. Presumably some sort of deal has been done between Muqtada al Sadr and the British Foreign Office. You want us to leave and we want to leave. We can't go if there are IEDs going off every day. Give us some peace and quiet and we will declare that we have successfully handed over to Iraqi forces, which, as you know, are largely manned by your militia. Why would he demur?

Afghanistan is also a problem. There are criticisms that the government has sent men out to fight with inadequate equipment - a charge that can be laid at Brown's door since the ex-chancellor may well have penny-pinched on the Army budget. The poppy harvest has not been reduced. Again, I see the hand of the Foreign Office here. There is a worldwide shortage of morphine, so it makes no sense to reduce the source of the raw material. Winning the battle against the Taliban means winning hearts and minds. You hardly deny the Taliban a sanctuary by making the farmers who could hide them penniless.

At home there is a crisis in the prisons. Because they are overflowing they are letting prisoners out two weeks earlier than they should. One newspaper is keeping a record of new crimes committed by prisoners so-released. 59 so far. Crime statistics are so easily manipulated as to be meaningless. The government spins them to put themselves in the best light. Concealed in the current figures is a fourfold increase in the numbers of killings and injury from guns. One Chief Constable defends the figures because they are nothing like as bad as in American cities. But owning guns is illegal in the UK and legal in America. Of course, it is not as bad, but it's not comparing like with like. With the police so defeatist what can you expect?

Brown has a 10 point lead in the polls and might call an early election apart from one thing - Europe. The European Constitution was defeated by referenda in France and Holland. Tony Blair had promised a referendum, but didn't have to deliver because the whole thing was hit into the long grass by the French and Dutch defeats. The European leaders had a second go and produced a 'Treaty' that is 95% the same as the Constitution. This does not require a referendum they said it can be agreed by local parliaments. Brown has told us we won't have a referendum, but a large majority of the public want one and a large majority would vote against. If he were to call an election now, it would become in effect a referendum on Europe, which he would certainly lose despite his lead in the Opinion Polls. So no election yet, I think.

Oh, and Barclays are in trouble since I took my money out and transferred it to teh Halifax.