Monday, March 31, 2008

Genetic abnormalities in CLL

Although multiple instances of chronic lymphocytic leukaemia in some families, and low frequency of the disease in individuals of Japanese origin, suggest that genetic effects might be stronger than environmental factors in the pathogenesis of chronic lymphocytic leukaemia, the nature of this genetic predisposition remains uncertain and different genes may be involved in different families. A recent paper has identified a family in which a single nucleotide polymorphism down-regulates the expression of DAPK1 transcription. The same polymorphism has been identified in one sporadic case of chronic lymphocytic leukaemia, but not in other familial cases. DAPK1 is a pro-apoptotic protein whose expression is also suppressed in sporadic cases of chronic lymphocytic leukaemia by an epigenetic mechanism. [63] The many unsuccessful attempts to establish genetic linkages have been reviewed by Goldin and Slager.[64] None of the reported genetic aberrations is constant, and whether they constitute initial events or arise during evolution is presently unclear. By contrast with observations in other B-cell malignant diseases, which typically exhibit balanced chromosomal translocations, in chronic lymphocytic leukaemia the most frequent abnormalities are mutations, deletions, or trisomies. Translocations do arise but are usually unbalanced, resulting in loss of genetic material.[65]

Early attempts at karyotyping chronic lymphocytic leukaemia cells identified trisomy 12 and deletions at 13q,[66] but most laboratories were unable to satisfactorily bring chronic lymphocytic leukaemia cells into mitosis. Only in the past few years have cytogenetic techniques been developed that make this proposition feasible.[65] and [67] Döhner and colleagues showed in a series of 325 patients with chronic lymphocytic leukaemia that chromosomal aberrations can be detected in interphase cells by fluorescence in-situ hybridisation (FISH) in 82% of cases. The most frequent alterations are a deletion on chromosome 13q (55%), trisomy 12 (18%), and a deletion on chromosome 11q (16%). A deletion on chromosome 17p, affecting the TP53 protein, is seen less frequently (7%). The presence of a 17p or 11q deletion is associated with poor prognosis and predominates in advanced stages of chronic lymphocytic leukaemia and in patients with unmutated IGHV genes, whereas the 13q deletion or a normal karyotype are associated with good prognosis, initial stages of the disease, and mutated IGHV genes. Controversy exists about whether trisomy 12 is associated with an unmutated status and poor prognosis.[67] and [68] Patients with mutated and unmutated chronic lymphocytic leukaemia differ clearly in terms of prognosis.

Genetic lesions associated with deletions of the short arm of chromosome 17 (del17p13), which encodes the TP53 tumour-suppressor gene, and the long arm of chromosome 11 (del11q23), which encodes the ataxia telangiectasia mutated (ATM) gene, result in a loss of function of TP53. TP53 is a transcription factor activated by strand breaks in DNA. It can trigger apoptosis or cell-cycle arrest. Thus, by controlling repair or elimination of cells with damaged DNA, TP53 maintains the integrity of the genome and prevents clonal progression. ATM is a kinase that regulates TP53. Many cytotoxic drugs require the ATM/TP53 pathway to be intact for them to be effective. A simple screening test that assesses how intact this pathway is has been described.[69] Defects in the ATM/TP53 pathway constitute the strongest independent predictors for disease that is resistant to standard treatment.

Deletions of the ATM gene do not produce such a severe syndrome as do deletions of TP53, with some patients having a fairly benign disease course. Possibly, for ATM function to be impaired, mutations are necessary on the other ATM allele.[70] Conversely, Kalla and co-workers have identified other genes affecting regulation of the cell cycle and apoptosis—namely NPAT, CUL5, and PPP2R1B—in the commonly deleted 11q22-q23 segment, which might underlie the severity of the chronic lymphocytic leukaemia.[71]

The pathogenic role of trisomy 12 in chronic lymphocytic leukaemia remains unresolved.[72] CLLU1—the first disease-specific gene identified in people with chronic lymphocytic leukaemia—has been located to 12q22, but there seems to be no difference in protein expression in patients with or without trisomy 12.[73]

MicroRNA molecules (miRNAs) have an important role in regulation of gene expression during human development. Using a microarray containing hundreds of human precursors and mature miRNA oligonucleotide probes, Calin and colleagues recorded significant differences in miRNA expression between chronic lymphocytic leukaemia B cells and normal CD5+ cells. They showed the absence of two miRNAs (miR15 and miR16) associated with mutations in expressed IGHV genes and with deletions in the 13q14 region.[74] As part of normal control of gene expression, miR15 and miR16 seem to target BCL2, and their absence in chronic lymphocytic leukaemia could be a major factor in prevention of apoptosis.[75] However, Fulci and coworkers [76] have been unable to confirm these findings. They reported low expression of these miRNAs in only 12% of patients, despite 58% having del13q14. All individuals with a deletion of both 13q14 alleles showed striking miR15a downregulation, but such pronounced downregulation of both miRNAs was not paralleled by any significant increase in BCL2 expression levels. Fulci's team also noted overexpression of miR150, miR223, and miR29b and miR29c in IGHV-mutated chronic lymphocytic leukaemia compared with unmutated cases.

Despite clinical and molecular differences, chronic lymphocytic leukaemia is characterised by a common gene-expression signature that differs from other lymphoid cancers and normal lymphoid subpopulations, suggesting that patients with the disease—in agreement with the monotonous phenotypic signature—share a common mechanism of transformation, cell of origin, or both. [77] However, despite sharing a common signature, chronic lymphocytic leukaemias expressing mutated and unmutated IGHV genes differentially express more than 100 genes. Of these, overexpression of genes encoding ZAP70, lipoprotein lipase (LPL), BCL7A, dystrophin (DMD), and gravin (AKAP12) are noted in individuals with aggressive unmutated disease, whereas people with stable mutated chronic lymphocytic leukaemia overexpress WNT3, CTLA4, the gene encoding nuclear receptor interacting protein 1 (NRIP1), ADAM29, and TCF7.[78], [79] and [80] Furthermore, evidence suggests that for particular IGHV genes, such as IGHV1-69 and IGHV3-21, different genomic aberrations might be associated with differential gene expression.[80], [81] and [82] These results indicate that indolent mutated and aggressive unmutated chronic lymphocytic leukaemias constitute two variants of the same disease. The reasons for these striking differences in clinical outcomes remain unsolved.


63 A Raval, SM Tanner and JC Byrd et al., Downregulation of death-associated protein kinase 1 (DAPK1) in chronic lymphocytic leukemia, Cell 129 (2007), pp. 879–890.

64 LR Goldin and SL Slager, Familial CLL: Genes and Environment, Hematology Am Soc Hematol Educ Program 2007 (2007), pp. 339–345.

65 F Dicker, S Schnittger, T Haferlach, W Kern and C Schoch, Immunostimulatory oligonucleotide-induced metaphase cytogenetics detect chromosomal aberrations in 80% of CLL patients: a study of 132 CLL cases with correlation to FISH, IgVH status, and CD38 expression, Blood 108 (2006), pp. 3152–3160.

66 G Juliusson, DG Oscier and M Fitchett et al., Prognostic subgroups in B-cell chronic lymphocytic leukemia defined by specific chromosomal abnormalities, N Engl J Med 323 (1990), pp. 720–724.

67 DG Oscier, AC Gardiner and SJ Mould 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 100 (2002), pp. 1177–1184.

68 A Krober, T Seiler and A Benner et al., V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia, Blood 100 (2002), pp. 1410–1416.

69 K Lin, PD Sherrington, M Dennis, Z Matrai, JC Cawley and AR Pettitt, Relationship between p53 dysfunction, CD38 expression, and IgV(H) mutation in chronic lymphocytic leukemia, Blood 100 (2002), pp. 1404–1409.

70 B Austen, JE Powell and A Alvi et al., Mutations in the ATM gene lead to impaired overall and treatment-free survival that is independent of IGVH mutation status in patients with B-CLL, Blood 106 (2005), pp. 3175–3182.

70 C Kalla, MO Scheuermann and I Kube et al., Analysis of 11q22-q23 deletion target genes in B-cell chronic lymphocytic leukaemia: evidence for a pathogenic role of NPAT, CUL5, and PPP2R1B, Eur J Cancer 43 (2007), pp. 1328–1335.

72 D Winkler, C Schneider and A Krober et al., Protein expression analysis of chromosome 12 candidate genes in chronic lymphocytic leukemia (CLL), Leukemia 19 (2005), pp. 1211–1215.

73 AM Buhl, J Jurlander and FS Jorgensen et al., Identification of a gene on chromosome 12q22 uniquely overexpressed in chronic lymphocytic leukemia, Blood 107 (2006), pp. 2904–2911.

74 GA Calin, CG Liu and C Sevignani et al., MicroRNA profiling reveals distinct signatures in B cell chronic lymphocytic leukemias, Proc Natl Acad Sci USA 101 (2004), pp. 11755–11760.

75 A Cimmino, GA Calin and M Fabbri et al., miR-15 and miR-16 induce apoptosis by targeting BCL2, Proc Natl Acad Sci USA 102 (2005), pp. 13944–13949.

76 V Fulci, S Chiaretti and M Goldoni et al., Quantitative technologies establish a novel microRNA profile of chronic lymphocytic leukemia, Blood 109 (2007), pp. 4944–4951.

77 U Klein, Y Tu and GA Stolovitzky et al., Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells, J Exp Med 194 (2001), pp. 1625–1638.

78 A Wiestner, A Rosenwald and TS Barry et al., ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile, Blood 101 (2003), pp. 4944–4951.

79 Y Vasconcelos, J De Vos and L Vallat et al., Gene expression profiling of chronic lymphocytic leukemia can discriminate cases with stable disease and mutated Ig genes from those with progressive disease and unmutated Ig genes, Leukemia 19 (2005), pp. 2002–2005.

80 D Kienle, A Benner and A Krober et al., Distinct gene expression patterns in chronic lymphocytic leukemia defined by usage of specific VH genes, Blood 107 (2006), pp. 2090–2093.

81 DL Kienle, C Korz and B Hosch et al., Evidence for distinct pathomechanisms in genetic subgroups of chronic lymphocytic leukemia revealed by quantitative expression analysis of cell cycle, activation, and apoptosis-associated genes, J Clin Oncol 23 (2005), pp. 3780–3792.

82 C Haslinger, N Schweifer and S Stilgenbauer et al., Microarray gene expression profiling of B-cell chronic lymphocytic leukemia subgroups defined by genomic aberrations and VH mutation status, J Clin Oncol 22 (2004), pp. 3937–3949.

Sunday, March 30, 2008

Goya's Ghost

The critics called it a mess, which is probably why we get such rubbish movies in the theaters these days. This is a movie that requires you to concentrate on the plot and listen to the dialogue. You require a modicum of intelligence to understand it and to know a little bit more about the Spanish Inquisition than the fact that it appeared in a Monty Python sketch. This is the first Milos Foreman film since 1999 (remember he made Amadaus and One Flew Over the Cuckoos Nest). It is set over a period of 20 years and uses the character of Goya (played by Stellan Skarsgaard - Good Will Hunting), the famous Spanish painter as a backbone for the story. Brother Lorenzo is played by Spanish actor Javier Bardem (No Country for Old Men). He directs the Spanish Inquisition who hit upon Ines Bilbatua (Natalie Portman) because she refuses pork at a restaurant (she must be a Judaizer). She is also Goya's model and truth be told Lorenzo has the hots for her. On the pretext of aiding her release he seduces her and fathers a daughter on her.

Goya is pressed by her father to get her released, but Lorenzo won't be bribed. When he is himself 'put to the question' by her family he realises that people will admit to anything under torture; such 'confessions' are worthless. He attempts to influence the Cardinal (played by Michael Lonsdale - Day of the Jackal) in vain and became an outcast. Ines remains in prison. Her father goes to the King for aid, but news comes that Napoleon has invaded. In the name of Liberty, Equality, Fraternity, the French army sweeps all before it. The Inquisition is disbanded and prosecuted by none other than Lorenzo, now very secular with a wife and three children. He discovers from Goya that he has another daughter (also played by Portman) who is now a prostitute. He attempts to cover it up and seems to be succeeding. The French turn out to be just as brutal as the Spanish Inquisition and at last they are deposed by the British under Wellington (whose famous painting by Goya was stolen in real life and later turned up in an early Bond film). Lorenzo is captured and when the Inquisition is re-established he is offered redemption if he will repent. He refuses and is executed in a particularly unpleasant way. Ines by now is completely insane, has picked up a stray abandoned baby and follows the cart carrying his corpse while clinging to his dead hand. Her daughter has become the mistress of an English officer and Goya, completely deaf, is still one of the greatest artists of all time. his paintings and etchings provide an impressive backdrop to this film, which is sumptuously realized.

About half the critics gave this movie 4 or 5 stars (out of 5) but a lot gave it only one. It clearly polarizes people, but I think it was wonderful.

Saturday, March 29, 2008

PG Wodehouse

I have been reading the biography of PG Wodehouse by Robert McCrum. Everyone knows of Wodehouse (pronounced woodhouse), the author of Jeeves and Wooster, but few now remember that he was persona non grata for many years because he broadcast over the radio from Nazi Germany. Indeed there was a distinct possibility that he might have been hanged for treason in 1945.

His early life was spent at Dulwich College in south east London, the same public school later attended by Raymond Chandler. His people couldn't afford to send him to Oxford or Cambridge so he went to work in a bank. He wanted to be a writer and eventually by selling short stories he was able to earn enough to leave it. Thereafter he wrote and wrote and sold most of his output. His first successful novels were about schoolboys, but he followed their careers after leaving school and created unforgettable characters such as Psmith, Jeeves, Bertie, Gussie Finknottle, the inhabitants of the Drones club and the denizens of Blandings Castle.

He was extremely successful on both sides of the Atlantic. Quite apart from his novels and short stories he was at the center of the pre-war Broadway scene, collaborating with the Gershwin brothers, Jerome Kern and Cole Porter. He even went to Hollywood when the talkies came in, though the producers didn't quite know what to do with him. In the end MGM paid him a lot of money to keep him on the 'bench'. While there he wrote and revised his stories while making minor adjustments to scripts making a morning's work last three months.

He was peripatetic - largely to avoid double taxation. By the late 1930s he had settled in Le Touquet in France, but got trapped there by the advancing German army. Interned for more than a year, he was let out of prison when an American reporter explained to the Nazis just what an important writer he was. Ensconced in a luxury hotel in Berlin, the German Foreign Office, in the person of ex-Hollywood colleagues, persuaded him that it would be a jolly wheeze to broadcast over the radio his experience of life in an internment camp. In his Edwardian, self effacing manner, he made light of the experience and handed the Germans a propaganda coup. It was probably naivete that led him to fall in with their plans, but also extreme foolishness. Following the war he never again set foot in Britain, but gradually his popularity returned and in his nineties, having lived in Long Island for a long time and become an American citizen, he was eventually restored to the fall and made an honorary knight commander of the British Empire.

I also read 'Mike and Psmith' and early novel from 1913 yesterday. A slight and mildly amusing offering similar to the Billy Bunter novels I read when I was 10.

The B cell receptor

The B-cell receptor

The B-cell receptor is a multimeric complex formed by the assembly of a surface immunoglobulin homodimer and a non-covalently-bound heterodimer Igα/Igβ (CD79A/CD79B). Low expression of the B-cell receptor is the hallmark of lymphocytes in chronic lymphocytic leukaemia.[23]

The mechanisms accounting for poor expression of the B-cell receptor in chronic lymphocytic leukaemia remain elusive. With the exception of one report of mutation in CD79B,[24] no genetic defects in B-cell-receptor components have been recorded.[25] and [26] By contrast with their poor expression at the membrane level, transcription and intracellular synthesis of components of the B-cell receptor are normal,[26] and [27] but they cannot be assembled and transported from the endoplasmic reticulum to the cell surface because of a folding and glycosylation defect of the μ and CD79A chains, although not of the CD79B chain. Poor expression of the CD22 molecule in B-cell chronic lymphocytic leukaemia cells was also shown to result from a folding defect arising in CD79A.[28]

Most B-cell chronic lymphocytic leukaemia cells express CD5 and IgM/IgD and, thus, have a mantle zone-like phenotype of naive cells that, in normal conditions, express unmutated immunoglobulin genes.[29] However, 50–70% of cases of chronic lymphocytic leukaemia have somatic mutations of IGHV genes,[30] as if they had matured in a lymphoid follicle. Presence or absence of somatic mutations is associated with particular IGHV genes. Specific alleles of the IGHV1-69 gene [31] and the IGHV4-39 gene have an unmutated profile.32 Subsequently, workers have reported [32] that more than 20% of patients with chronic lymphocytic leukaemia carry stereotypic B-cell receptors.[33], [34] and [35] Of note, the IGHV3-21 gene shows strikingly homologous IGHV and IGLV gene rearrangements and is associated with poor prognosis, whether expressed in a mutated or unmutated form.[36] and [37] These results strongly suggest that a common antigen epitope is recognised by these highly homologous molecules. With respect to the epitope recognised, research has shown that unmutated chronic lymphocytic leukaemia cells express highly polyreactive antibodies, whereas most mutated ones do not.[38] and [39] Infections with encapsulated organisms might be a trigger for development of chronic lymphocytic leukaemia, and work has shown that individuals with a history of pneumonia are significantly more likely to develop chronic lymphocytic leukaemia than are people without this history, and that the risk increases with number of attacks.[40] and [41]

When stimulated through the B-cell receptor pathway, the response of chronic lymphocytic leukaemia cells is impaired. Low expression of the B-cell receptor correlates with reduced induction of protein tyrosine kinase activity and defective intracellular calcium mobilisation and tyrosine phosphorylation.[42] Individuals have differing responses to IgM ligation, related to IGHV gene status. Findings of one study showed that chronic lymphocytic leukaemia cells expressing unmutated IGHV genes had a better response in most cases to stimulation via the B-cell receptor than did cells expressing mutated IGHV genes.[43]

Unexpectedly, high amounts of ZAP70—a receptor-associated protein tyrosine kinase usually found in T cells and natural killer cells but not in normal circulating B cells—are detected in most patients with unmutated chronic lymphocytic leukaemia.[44] Chronic lymphocytic leukaemia B cells that express ZAP70 are more likely to respond to IgM crosslinking with increased tyrosine phosphorylation and calcium flux than are those that do not express ZAP70. This effect might happen for any or all of the following reasons. First, after B-cell receptor ligation, ZAP70 undergoes tyrosine phosphorylation and becomes associated with surface immunoglobulin and CD79B.[45] Second, ZAP70 mediates inhibition events that terminate the signalling response.[46] Finally, ZAP70 expression is associated with advantageous survival responses because of enhanced access to proliferation centres.[47] Altogether, expression of ZAP70 in chronic lymphocytic leukaemia allows effective IgM signalling in B cells, which might lead to an aggressive disease course.

The apparently anomalous expression of ZAP70 in chronic lymphocytic leukaemia cells is not accounted for completely. Heat-shock protein 90 (HSP90) is a molecular chaperone that catalyses the conformational maturation of many signalling proteins in cancer, known collectively as clients. With inhibitors of HSP90, Castro and colleagues [48] showed that ZAP70 is a client protein in tumour cells, but not in T cells, from patients with ZAP70-positive chronic lymphocytic leukaemia, suggesting that the presence of ZAP70 is an oncogenic event. On the other hand, ZAP70 is expressed at various stages of B-cell maturation and in other B-cell malignant diseases. It is present in normal pre-B cells and pro-B cells and in acute leukaemias derived from them.[49] By studying normal tonsillar cells, Nolz and coworkers [50] and Cutrona and colleagues [51] detected ZAP70-positive B cells, concentrated particularly in germinal centres. ZAP70 seems to be coexpressed with other activation markers. In chronic lymphocytic leukaemia, higher amounts of ZAP70 are expressed by lymph-node cells than by circulating cells.[52] In turn, high levels of ZAP70 expression lead to increased sensitivity to chemokine migratory signals.[53] Whether expression of ZAP70 in chronic lymphocytic leukaemia cells is a result of frequent visits to proliferation centres or is the cause of enhanced access to them is still not clear.

Another unexpected molecule expressed by a subset of chronic lymphocytic leukaemia B cells is CD38. In the B-cell compartment, CD38 is not a lineage marker, but this molecule is expressed at times during B-cell development when cell-to-cell interactions are crucial.[54] Examples include an early bone-marrow precursor cell, cells in the germinal centre, and plasma cells.[55] In chronic lymphocytic leukaemia, expression of CD38 predominates in patients with unmutated IGHV genes and is associated with poor prognosis.18 Expression of CD38 in chronic lymphocytic leukaemia B cells favours B-cell growth and survival through sequential interactions between CD38 and CD31 and between CD100 and plexin B1 (PLXNB1).[56]

The activation-induced cytidine deaminase (AICDA), a B cell-restricted enzyme needed for somatic mutation and isotype switching, is upregulated in unmutated chronic lymphocytic leukaemia cells.[57], [58] and [59] Although evidence exists that AICDA expression could be confined to a small proportion of the clone,[60] AICDA seems to be functional, since unmutated cases of chronic lymphocytic leukaemia can generate isotype-switched transcripts and proteins and mutations in the pre-switch μ region.[57] Upregulation of AICDA could be associated with loss of target specificity, resulting in mutations in non-immunoglobulin genes such as BCL6, MYC, PAX5, and RHOH, which are linked to aggressive disease.[61] and [62]


23 F Vuillier, G Dumas and C Magnac et al., Lower levels of surface B-cell-receptor expression in chronic lymphocytic leukemia are associated with glycosylation and folding defects of the mu and CD79a chains, Blood 105 (2005), pp. 2933–2940.

24 AA Thompson, JA Talley and HN Do et al., Aberrations of the B-cell receptor B29 (CD79b) gene in chronic lymphocytic leukemia, Blood 90 (1997), pp. 1387–1394.

25 B Payelle-Brogard, C Magnac, FR Mauro, F Mandelli and G Dighiero, Analysis of the B-cell receptor B29 (CD79b) gene in familial chronic lymphocytic leukemia, Blood 94 (1999), pp. 3516–3522.

26 A Alfarano, S Indraccolo and P Circosta et al., An alternatively spliced form of CD79b gene may account for altered B-cell receptor expression in B-chronic lymphocytic leukemia, Blood 93 (1999), pp. 2327–2335.

27 B Payelle-Brogard, C Magnac, A Alcover, P Roux and G Dighiero, Defective assembly of the B-cell receptor chains accounts for its low expression in B-chronic lymphocytic leukaemia, Br J Haematol 118 (2002), pp. 976–985.

28 B Payelle-Brogard, G Dumas, C Magnac, AI Lalanne, G Dighiero and F Vuillier, Abnormal levels of the alpha chain of the CD22 adhesion molecule may account for low CD22 surface expression in chronic lymphocytic leukemia, Leukemia 20 (2006), pp. 877–878. )

29 V Pascual, YJ Liu, A Magalski, O de Bouteiller, J Banchereau and JD Capra, Analysis of somatic mutation in five B cell subsets of human tonsil, J Exp Med 180 (1994), pp. 329–339.

30 HW Schroeder Jr and G Dighiero, The pathogenesis of chronic lymphocytic leukemia: analysis of the antibody repertoire, Immunol Today 15 (1994), pp. 288–294.

31 TJ Kipps and DA Carson, Autoantibodies in chronic lymphocytic leukemia and related systemic autoimmune diseases, Blood 81 (1993), pp. 2475–2487.

32 N Chiorazzi and M Ferrarini, B cell chronic lymphocytic leukemia: lessons learned from studies of the B cell antigen receptor, Annu Rev Immunol 21 (2003), pp. 841–894.

33 K Stamatopoulos, C Belessi and C Moreno et al., Over 20% of patients with chronic lymphocytic leukemia carry stereotyped receptors: pathogenetic implications and clinical correlations, Blood 109 (2007), pp. 259–270.

34 BT Messmer, E Albesiano and DG Efremov et al., Multiple distinct sets of stereotyped antigen receptors indicate a role for antigen in promoting chronic lymphocytic leukemia, J Exp Med 200 (2004), pp. 519–525.

35 F Ghiotto, F Fais and A Valetto et al., Remarkably similar antigen receptors among a subset of patients with chronic lymphocytic leukemia, J Clin Invest 113 (2004), pp. 1008–1016.

36 G Tobin, U Thunberg and A Johnson et al., Somatically mutated Ig V(H)3-21 genes characterize a new subset of chronic lymphocytic leukemia, Blood 99 (2002), pp. 2262–2264.

37 M Thorselius, A Krober and F Murray et al., Strikingly homologous immunoglobulin gene rearrangements and poor outcome in VH3-21-using chronic lymphocytic leukemia patients independent of geographic origin and mutational status, Blood 107 (2006), pp. 2889–2894.

38 O Pritsch, C Magnac, G Dumas, C Egile and G Dighiero, V gene usage by seven hybrids derived from CD5+ B-cell chronic lymphocytic leukemia and displaying autoantibody activity, Blood 82 (1993), pp. 3103–3112.

39 M Herve, K Xu and YS Ng et al., Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity, J Clin Invest 115 (2005), pp. 1636–1643.

40 T Hamblin, Is chronic lymphocytic leukemia a response to infectious agents?, Leuk Res 30 (2006), pp. 1063–1064.

41 O Landgren, JS Rapkin and NE Caporaso et al., Respiratory tract infections and subsequent risk of chronic lymphocytic leukemia, Blood 109 (2007), pp. 2198–2201.

42 F Michel, H Merle-Beral, E Legac, A Michel, P Debre and G Bismuth, Defective calcium response in B-chronic lymphocytic leukemia cells: alteration of early protein tyrosine phosphorylation and of the mechanism responsible for cell calcium influx, J Immunol 150 (1993), pp. 3624–3633.

43 S Lanham, T Hamblin, D Oscier, R Ibbotson, F Stevenson and G Packham, Differential signaling via surface IgM is associated with VH gene mutational status and CD38 expression in chronic lymphocytic leukemia, Blood 101 (2003), pp. 1087–1093.
44 A Rosenwald, AA Alizadeh and G Widhopf et al., Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia, J Exp Med 194 (2001), pp. 1639–1647.

45 L Chen, J Apgar and L Huynh et al., ZAP-70 directly enhances IgM signaling in chronic lymphocytic leukemia, Blood 105 (2005), pp. 2036–2041.

46 S Gobessi, L Laurenti, PG Longo, S Sica, G Leone and DG Efremov, ZAP-70 enhances B-cell-receptor signaling despite absent or inefficient tyrosine kinase activation in chronic lymphocytic leukemia and lymphoma B cells, Blood 109 (2007),

47 SJ Richardson, C Matthews and MA Catherwood et al., ZAP-70 expression is associated with enhanced ability to respond to migratory and survival signals in B-cell chronic lymphocytic leukemia (B-CLL), Blood 107 (2006), pp. 3584–3592.

48 JE Castro, CE Prada and O Loria et al., ZAP-70 is a novel conditional heat shock protein 90 (Hsp90) client: inhibition of Hsp90 leads to ZAP-70 degradation, apoptosis, and impaired signaling in chronic lymphocytic leukemia, Blood 106 (2005), pp. 2506–2512.

49 M Crespo, N Villamor and E Gine et al., ZAP-70 expression in normal pro/pre B cells, mature B cells, and in B cell acute lymphoblastic leukemia, Clin Cancer Res 12 (2006), pp. 726–734.

50 JC Nolz, RC Tschumper, BT Pittner, JR Darce, NE Kay and DF Jelinek, ZAP-70 is expressed by a subset of normal human B-lymphocytes displaying an activated phenotype, Leukemia 19 (2005), pp. 1018–1024.

51 G Cutrona, M Colombo and S Matis et al., B lymphocytes in humans express ZAP-70 when activated in vivo, Eur J Immunol 36 (2006), pp. 558–569.

52 J Boelens, J Philippe and F Offner, B cells from lymph nodes express higher ZAP-70 levels than B-CLL cells from peripheral blood, Leuk Res 31 (2007), pp. 719–726.

53 SJ Richardson, C Matthews and MA Catherwood et al., ZAP-70 expression is associated with enhanced ability to respond to migratory survival signals in B-cell chronic lymphocytic leukemia (B-CLL), Blood 107 (2006), pp. 3584–3592.

54 F Malavasi, A Funaro, S Roggero, A Horenstein, L Calosso and K Mehta, Human CD38: a glycoprotein in search of a function, Immunol Today 15 (1994), pp. 95–97.

55 S Deaglio, K Mehta and F Malavasi, Human CD38: a (r)evolutionary story of enzymes and receptors, Leuk Res 25 (2001), pp. 1–12.

56 S Deaglio, T Vaisitti and L Bergui et al., CD38 and CD100 lead a network of surface receptors relaying positive signals for B-CLL growth and survival, Blood 105 (2005), pp. 3042–3050.

57 P Oppezzo, F Vuillier and Y Vasconcelos et al., Chronic lymphocytic leukemia B cells expressing AID display dissociation between class switch recombination and somatic hypermutation, Blood 101 (2003), pp. 4029–4032.

58 P Oppezzo, G Dumas and AI Lalanne et al., Different isoforms of BSAP regulate expression of AID in normal and chronic lymphocytic leukemia B cells, Blood 105 (2005), pp. 2495–2503.

59 H McCarthy, WG Wierda and LL Barron et al., High expression of activation-induced cytidine deaminase (AID) and splice variants is a distinctive feature of poor prognosis chronic lymphocytic leukemia, Blood 101 (2003), pp. 4903–4908.

60 E Albesiano, BT Messmer, RN Damle, SL Allen, KR Rai and N Chiorazzi, Activation induced cytidine deaminase in chronic lymphocytic leukemia B cells: expression as multiple forms in a dynamic, variably sized fraction of the clone, Blood 102 (2003), pp. 375–382.

61 SS Sahota, Z Davis, TJ Hamblin and FK Stevenson, Somatic mutation of bcl-6 genes can occur in the absence of V(H) mutations in chronic lymphocytic leukemia, Blood 96 (2000), pp. 1089–1095.

62 L Reininger, C Bodor and A Bognar et al., Richter's and prolymphocytic transformation of chronic lymphocytic leukemia are associated with high mRNA expression of activation-induced cytidine deaminase and aberrant somatic hypermutation, Leukemia 20 (2006), pp. 1089–1095.

Friday, March 28, 2008

High White Counts

Patients and doctors get very worried about high white counts. Need they be?

I remember one holiday weekend spending days at the hospital with a young 13-year old boy with priapism - a prolonged and painful penile erection - caused by a high white count. What happens in these cases is that the blood vessels get blocked by aggregated white blood cells, so that normal circulation is prevented. We connected the lad up to a cell separator and performed leucocytapheresis on him to rapidly lower the white count. He also had to have a surgical procedure to decompress the organ, but I'm glad to say this combination of treatments was successful and sexual function was restored, although since his disease was chronic myeloid leukaemia (CML)in the days before imatanib and matched unrelated bone marrow transplantation, he eventually succumbed to blast transformation of his disease.

Priapism is a well known complication of CML but is seldom seen in other types of leukemia. It is one version of the leukostasis syndrome. Other features include rapidly progressive breathing difficulties and mental problems. It is thought to be caused very sticky bits of white cells and platelets forming aggregates and thrombi, and blocking the circulation. Some authors distinguish this from the hyperviscosity syndrome which produces similar effects because the blood becomes very viscous or treacly (thick and sticky, not actually sweet). This can be due to high cell content (either red or white) or high protein content (especially IgM or immune complexes). Nowadays, patients are seldom allowed to get high white cell counts except in CLL. The question everybody asks is whether hyperviscosity can occur in CLL. I think that the answer is probably in exceptional cases both hyperviscosity and leukostasis can occur.

Looking back over the old literature, my old mate Eric Preston reported three cases from Sheffield in 1978. The white counts were 500, 647 and 1000 respectively. The symptoms of hyperviscosity were relatively minor, but they did resolve after leucocytapheresis. These three patients did have raised blood viscosity measurements, but the authors noted that CLL does not raise the viscosity by as much as other leukemias for a given white count. There is another report from Kurlander and colleagues of a patient with a white count of 901 who had retinal hemorrhages, which can be a feature of hyperviscosity, though this patient also had hyperkalemia (a high potassium level) and kidney failure, which could also have caused them. Then in 1985 Maria Baer from Nashville reported a study of 16 CLL patients with white counts over 500. In one of them, with a white count of 968 there was a full blown hyperviscosity syndrome with headache, double vision, loss of balance, slurred speech, deafness and other neurological signs, which all recovered after leucocytapheresis (in America people talk about leukapheresis which implies that the machine takes the whiteness out of the blood, like a reverse washing machine). A second patient had what were in retrospect features of hyperviscosity, but she was treated as if she had leukemic meningitis and died. A third patient had retinal hemorrhages, but these can be caused by a lot of different things including high blood pressure. The 16 high white counts were drawn from a series of 210 patients in Nashville.

One of the problems about the early CLL papers is that before good immunophenotyping we could not be sure that the patient actually had CLL – it could have been mantle cell lymphoma or a variant. A study from Sweden published in 1992 said this:

In order to evaluate the effects of different cell types of leukaemic cell origin on skin capillary circulation we have studied patients with (a) chronic lymphocytic leukaemia (CLL) (n = 6) and (b) acute non-lymphocytic leukaemia (ANLL) (n = 6) or chronic granulocytic leukaemia (CGL) (n = 5). Capillary blood cell velocity (CBV) in fingernail-fold capillaries was measured by videophotometric capillaroscopy. After a 1-min arterial occlusion at the finger base, the post-occlusive reactive hyperaemia was evaluated by measuring the peak (p) CBV and the time to pCBV. In patients with ANLL/GGL, both resting CBV and pCBV were lower than in healthy control subjects. In the CLL patients these values were not significantly different compared to controls.

More recently there have been occasional patients with very high white counts due to CLL that have caused either hyperviscosity or leukostasis, but they are so rare that they are almost certain to be reported in the literature.

In Paris in 1988:
A 50 year old man with chronic lymphocytic leukemia (CLL) and extreme hyperleukocytosis (600 x 10(9)/liter) presented with a respiratory distress syndrome, congestive heart failure with cardiomegaly, endotoxic shock and anuria. Examination revealed nodes in all areas and hepatosplenomegaly; laboratory studies showed hypoxemia and a chest X-ray diffuse bilateral alveolar infiltrates. He was treated twice by leukapheresis using a cell separator. This procedure removed 10.1 x 10(10) white blood cells with marked clinical improvement and resolution of air-space diseases over the subsequent 48 hours.

In Germany in 1991
An 82-year-old woman with CLL developed acute neuropsychiatric signs (confusion, disorders of speech and vision) together with ataxic gait and left hemiparesis mainly affecting the lower limb. Her white count was 1,300, most of the cells being morphologically atypical lymphocytes. Significant reduction of leucocyte count with considerable improvement in clinical signs was achieved after three doses of vincristine and prednisone together with one cycle of COP

In the Netherlands in 1996
The authors mistook pulmonary infiltrates with CLL cells for leukostasis. The white count was only 153.

In Poland in 1999
A severe leukostasis syndrome was observed in a case of CLL with peripheral lymphocyte count of 1,120. Typical symptoms of respiratory and central nervous system were developed (tachypnoe, hypoxia, headache, slurred speech, somnolence and confusion). Leukapheresis decreased the lymphocyte count to 305 rapidly and reversed the leukostasis syndrome.

And in Israel in 2002
We describe a 73-year-old woman who presented with newly diagnosed CLL, leukostasis, and hyperleukocytosis (2000 x 10(9)/l), affecting the respiratory and nervous system. We hypothesize that in our patient the extreme number of circulating lymphocytes resulted in an abnormal accumulation of lymphocytes possibly causing stasis and occlusion of a larger vessel, which resolved after leukapheresis.

In CLL patients with high white counts there are usually other reasons to begin treatment, but in patients without symptoms there should be no urgency to begin treatment just because the white count has reached 100 or 200 or 300 or 400 or even 500 because of the possibility of leukostasis or hyperviscosity. This makes CLL different from other types of leukemia, where a high white count carries its own dangers.

Thursday, March 27, 2008

CLL: Diagnosis and Pathophysiology

Clinical diagnosis of chronic lymphocytic leukaemia is defined by absolute lymphocytosis of at least 5×109/L mature-appearing lymphocytes and an appropriate immunophenotype (figure). [13] These characteristics distinguish chronic lymphocytic leukaemia from mantle-cell lymphoma and splenic marginal-zone lymphoma, the diseases that most frequently mimic chronic lymphocytic leukaemia. [14] In a few individuals, tumour is confined to lymph nodes or other tissues without blood or bone marrow involvement. In these people, the disorder is known as small lymphocytic lymphoma: histological findings and immunophenotype are identical to chronic lymphocytic leukaemia and management should be the same.[15] Individuals without involvement of lymph nodes or other tissues, who have a population of small lymphocytes immunophenotypically similar to chronic lymphocytic leukaemia cells in blood or bone marrow below the threshold necessary for diagnosis of chronic lymphocytic leukaemia, are designated as having monoclonal B-cell lymphocytosis.[16] Molecular and cellular markers have been identified that could predict disease progression. In particular, the mutational profile of immunoglobulin genes[17] and [18] and some cytogenetic abnormalities [19] show strong prognostic value. However, these biological differences do not separate chronic lymphocytic leukaemia into two different disorders; it remains one disease with heterogeneous features. [20]


Despite the ready availability of tumour cells in chronic lymphocytic leukaemia, up to now, very little has been known about the pathophysiology of the disease. The cells themselves are remarkably inert in vitro. Most, if not all, cell lines attributed to chronic lymphocytic leukaemia are either from patients with mantle-cell lymphoma masquerading as chronic lymphocytic leukaemia or B-cell lymphoblastoid lines from contaminating normal lymphocytes. [21] Until the past few years, no animal model had existed for chronic lymphocytic leukaemia. The TCL1 transgenic mouse develops a CD5+ B-cell lymphoproliferative disease that serves as a model for aggressive forms of chronic lymphocytic leukaemia but not for the frequent indolent form. [22]

The discovery that the mutational status of IGHV genes affects profoundly the prognosis of chronic lymphocytic leukaemia has acted as such a spur to our understanding of the disease's pathology, but full review of this topic is not possible within the space confines of this Seminar. Instead, we will concentrate on three topics: the B-cell receptor; genetic abnormalities revealed by interphase cytogenetics; and the balance between proliferation and apoptosis.


13 JL Binet, F Caligaris-Cappio and D Catovsky et al., Perspectives on the use of new diagnostic tools in the treatment of chronic lymphocytic leukemia, Blood 107 (2006), pp. 859–861.

14 E Matutes, K Owusu-Ankomah and R Morilla et al., The immunological profile of B-cell disorders and proposal of a scoring system for the diagnosis of CLL, Leukemia 8 (1994), pp. 1640–1645.

15 HK Muller-Hermelink, E Montserrat, D Catovsky and NL Harris, Chronic lymphocytic leukaemia/small lymphocytic lymphoma. In: ES Jaffe, NL Harris, H Stein and JW Vardiman, Editors, World Health Organization classification of tumours: pathology and genetics of tumours of haematopoietic and lymphoid tissues, IARC Press, Lyon (2001), pp. 127–130.

16 GE Marti, AC Rawstron and P Ghia et al., Diagnostic criteria for monoclonal B-cell lymphocytosis, Br J Haematol 130 (2005), pp. 325–332.

17 TJ Hamblin, Z Davis, A Gardiner, DG Oscier and FK Stevenson, Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia, Blood 94 (1999), pp. 1848–1854.

18 RN Damle, T Wasil and F Fais et al., Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia, Blood 94 (1999), pp. 1840–1847.

19 H Döhner, S Stilgenbauer and A Benner et al., Genomic aberrations and survival in chronic lymphocytic leukemia, N Engl J Med 343 (2000), pp. 1910–1916.

20 T Hamblin, Chronic lymphocytic leukaemia: one disease or two?, Ann Hematol 81 (2002), pp. 299–303.

21 HG Drexler, WG Dirks, Y Matsuo and RA MacLeod, False leukemia-lymphoma cell lines: an update on over 500 cell lines, Leukemia 17 (2003), pp. 416–426.

22 R Bichi, SA Shinton and ES Martin et al., Human chronic lymphocytic leukemia modeled in mouse by targeted TCL1 expression, Proc Natl Acad Sci USA 99 (2002), pp. 6955–6960.

Wednesday, March 26, 2008

TP53: is it such a big deal?

Everyone knows that p53 abnormalities bode ill for patients with CLL. Generally such leukemias are resistant to fludarabine, cyclophosphamide, chlorambucil, penatastatin, cladribine, and rituximab. Although responsive to high dose steroids and Campath and sometimes to Revlimid, most patients with this abnormality have very short survivals. The data on this come from randomized clinical trials like LRF CLL4. However, not all patients need treatment and these trials lack representation from unreated patients. So I have examined my database for patients with del 17p (the chromosomal abnormality that most commonly causes p53 deletion. Have a look at these graphs:

What they tell us is that patients with mutated IgVH genes who also have del 17p usually don't require treatment, just like other patients with mutated IgVH genes.

Epidemiology of CLL

The incidence of chronic lymphocytic leukaemia varies with the age and sex structure of the population. Analysis of the Surveillance, Epidemiology, and End Results (SEER) database notes the US incidence as being 3·5 per 100 000 per year (men 5·0, women 2·5).[1] In the Leukaemia Research Fund data collection study, researchers gathered data from individual haematologists responsible for laboratories covering about a third of the population of England and Wales and reported an incidence of chronic lymphocytic leukaemia in the UK of 6·15 per 100 000 per year, although this value concealed a variation between 1·3 and 13·7 per 100 000 per year in different health districts, dependent largely on how interested the local haematologist was in the disease.[2] Since, in our experience, more than three-quarters of patients with chronic lymphocytic leukaemia are discovered because of an incidental blood count, the exact prevalence of the disease depends clearly on how assiduous is the case finding.

Chronic lymphocytic leukaemia is rare in people younger than 50 years, but after this age a fairly rapid rise in incidence takes place. According to SEER data, the median age for diagnosis of the disease is 70 years for men and 74 years for women, and median age at death is 76 years and 81 years, respectively. White American individuals have a slightly higher incidence than those of African-American origin (3·9 vs 2·8 per 100 000 per year), but in American people of Chinese, Japanese, and Filipino extraction, incidence is about five times lower, even in those who have adopted a fully American lifestyle.[3] Early data put the incidence of chronic lymphocytic leukaemia in Jewish people at twice that of non-Jewish North American individuals.[4]

Chronic lymphocytic leukaemia can arise in families.[5] and [6] First-degree relatives of patients with the disease are three times more likely to have chronic lymphocytic leukaemia or another lymphoid neoplasm than the general population.[7] With a four-colour flow-cytometric assay, Rawstron and colleagues [8] noted that 3·5% of healthy individuals older than 40 years had a population of monoclonal lymphocytes in their blood, with the immunophenotypic characteristics of chronic lymphocytic leukaemia cells, at concentrations lower than 3·5×109/L; in first-degree relatives of patients with familial chronic lymphocytic leukaemia, the prevalence of such cells is between 13·5% and 18%.[9] and [10] The relation between subclinical chronic lymphocytic leukaemia and full-blown disease is a matter of intense investigation in several laboratories.

No consistent evidence is available to link chronic lymphocytic leukaemia with environmental exposure to either radiation or chemicals, except in the case of agricultural workers and herbicides. On Jan 23, 2003, the US National Academy of Sciences' Institute of Medicine published a report concluding that there is “sufficient evidence of an association between exposure to Agent Orange, a herbicide used in Viet Nam, and the development of chronic lymphocytic leukaemia”. [11] Although ionising radiation has traditionally been absolved from causing chronic lymphocytic leukaemia, recent studies have suggested that this may be unwarranted.[12]

1 National Cancer Institute, SEER cancer statistics review 1975–2001

2 RA Cartwright, SM Bernard and CC Bird et al., Chronic lymphocytic leukaemia: case control epidemiological study in Yorkshire, Br J Haematol 56 (1987), pp. 79–82.

3 NS Weiss, Geographical variation in the incidence of the leukemias and the lymphomas, Natl Cancer Inst Monogr 53 (1978), p. 139.

4 B MacMahon and EK Koller, Ethnic differences in the incidences of leukemia, Blood 12 (1957), pp. 1–10.

5 MS Linet, ML Van Natta and R Brookmeyer et al., Familial cancer history and chronic lymphocytic leukemia: a case-control study, Am J Epidemiol 130 (1989), pp. 655–664.

6 GS Sellick, D Catovsky and RS Houlston, Familial chronic lymphocytic leukemia, Semin Oncol 33 (2006), pp. 195–201.

7 J Cuttner, Increased incidence of hematologic malignancies in first degree relatives of patients with chronic lymphocytic leukemia, Cancer Invest 10 (1992), pp. 103–109.

8 AC Rawstron, MJ Green and A Kuzmicki et al., Monoclonal B lymphocytes with the characteristics of “indolent” chronic lymphocytic leukemia are present in 3·5% of adults with normal blood counts, Blood 100 (2002), pp. 635–639.

9 AC Rawstron, MR Yuille, J Fuller, M Cullen, B Kennedy and SJ Richards, Inherited predisposition to CLL is detectable as subclinical monoclonal B-lymphocyte expansion, Blood 100 (2002), pp. 2289–2290.

10 GE Marti, P Carter and F Abbasi et al., B-cell monoclonal lymphocytosis and B-cell abnormalities in the setting of familial B-cell chronic lymphocytic leukemia, Cytometry B Clin Cytom 52 (2003), pp. 1–12.

11 Committee to review the health effects in Vietnam veterans of exposure to herbicides (fourth biennial update), Veterans and Agent Orange: 2002, National Academic Press, Washington, DC (2003), pp. 373–377.

12 TJ Hamblin, Have we been wrong about ionizing radiation and chronic lymphocytic leukemia?, Leuk Res 32 (2008), pp. 523–525.

Tuesday, March 25, 2008


"If Barack gets past the primary," said the Rev. Jeremiah Wright to the New York Times in April of last year, "he might have to publicly distance himself from me. I said it to Barack personally, and he said yeah, that might have to happen."

Calculating or what?

Monday, March 24, 2008

BBC caught out regurgitating propaganda

Remember before the fall of the Soviet union when Gorbachev was captured by the KGB and held in Georgia he said that he only knew what was happening because he listened to the BBC? The BBC can no longer be trusted to tell the truth about what is happening in the world.

In a news item on March 7, following the Mercaz Harav Yeshiva attack, the BBC showed a bulldozer demolishing a house, while correspondent Nick Miles told viewers: "Hours after the attack, Israeli bulldozers destroyed his family home. Later, mourners set up Hamas and Islamic Jihad banners nearby."

The house, however, was not demolished; the BBC was embarrassed when news reports from other broadcasters showed the east Jerusalem home intact and the family commemorating their son's actions.

Last week, the BBC apologized live on its news program, admitting it had used footage of another house being demolished.

News anchor Geeta Guru-Murthy said: "Now, we would like to clarify a report we heard at this hour last Friday about the attack by a Palestinian gunman on a Jewish seminary in Jerusalem. In the report, the day after the attack, BBC World said that the gunman's home in east Jerusalem had been demolished by the Israeli authorities. That was not correct, and the images broadcast were of another demolition."

The fabrication was exposed by Boston-based media monitor CAMERA, which revealed that the images used by the BBC were similar to photos taken by the Palestinian news agency Maan from the demolition of the house belonging to Islamic Jihad leader Muhammad Shehadeh in Bethlehem on March 7.

In a second incident, in a news item entitled "Israel jets strike northern Gaza" on March 14 on their News Web site, the BBC reported that Israel was deliberately targeting civilians in an operation targeting Kassam rocket launch sites in Gaza, and claiming that the United Nations secretary-general had described it as an attack on civilians.

"The Israeli air force said it was targeting a rocket firing team... UN Secretary-General Ban Ki-moon has condemned Israel's attacks on Palestinian civilians, calling them inappropriate and disproportionate," the report said.

In a letter to the BBC, Manchester Jewish community member Jonathan Hantman wrote,

"It is one-sided for the report to describe Israel's operations as 'attacks on civilians' while not describing the Palestinian rocket attacks, to which Israel was responding, as 'attacks on civilians' or 'acts of terrorism.'"

Hantman also pointed out that Ban's attributed comments were made weeks earlier to the UN Security Council and not in reference to that particular attack. He added that it was also wrong to mention the UN secretary-general's condemnation of Israel without mentioning his condemnation of Palestinian rocket attacks in the same statement.

"Ban's statement, made some two weeks ago, did not refer to yesterday's attack and did not describe Israel's operations on Gaza as 'attacks on civilians,'" Hantman noted. "He did, however, describe Palestinian rocket attacks as 'acts of terrorism.'"

In his statement to the UN Security Council on March 1, Ban said: "While recognizing Israel's right to defend itself, I condemn the disproportionate and excessive use of force that has killed and injured so many civilians, including children... I condemn Palestinian rocket attacks and call for the immediate cessation of such acts of terrorism."

Apologizing for the error, the BBC said in its response, regarding the speech: "We accept we should have made reference to what [Ban] said about Palestinian rocket attacks as well as to the 'excessive use of force' by Israel. We have amended the report, also removing the reference to Israeli 'attacks on civilians.'"

I have repeatedly said that I am not a Zionist nor a Jew. I do not believe that there is a divine right for the Jews to build a nation in Palestine. I think that blowing up the King David Hotel in 1948 was a terrorist act for which there was no justification. However, the world is the way it is and no amount of violence on behalf of the Palestinians is going to change it. Some members of the BBC have fallen for the Palestinian cause and regularly swallow whole the stories put out by their well-oiled propaganda machine. One would have thought that the fuss over the faked photographs from last year's Hezbollah war in Lebanon would have taught the BBC a lesson.

Sunday, March 23, 2008

Third day: Nathaniel's tale

Cowed, we sat in that upper chamber and considered our options. Some of the women had gone to the grave before daybreak and found it empty. It certainly was empty, Cephas and Jonah had gone to confirm, but was it the right grave? We never saw where they had buried him so we just have the women’s word for it. One of women said she had actually seen him, but who can believe a woman? They’ll see things that aren’t there and say the first thing that comes into their head. Quite rightly the Law regards the testimony of a woman as less than believable.

Then there were those two who were on their way home to Emmaus. They fell in with this travelling preacher who conned his way into a meal at their expense. After they’d had a few they somehow got it into their heads that it was Jesus that they were eating with. I ask you, if they didn’t recognize him when they were sober how are we going to believe what they think they saw when they were sozzled? They burst in on us while we were here in John Mark’s house. To me they didn’t look in control of themselves.

The inner three – Jacob and Jonah Bar-Zebedee and Cephas – then said, “Yes, we know, Cephas has seen him too.”

That was news to me. Why were they keeping it to themselves? Cephas is one for shooting his mouth off, saying the first thing that comes into his head. He said nothing to Andrew, even, and now others come in saying, “We have seen the Lord,” and good old Cephas, not wishing to be beaten, claims, “I saw him first.”

You know me, I’m a straight talker. The Lord himself called me an Israelite in whom there is no guile. Not like our father Israel – there was a real trickster. Well, I grant you that the whole thing is highly suspicious. Nobody in their right mind would believe a hysterical woman and Cephas is an impulsive idiot. But I am someone who doesn’t put his name to something unless I’m sure it’s true. I am not joshing you. This is exactly what happened.

We had the locked the door after Cleopas and his mate gatecrashed the meeting. We were still arguing over what they had told us when suddenly Jesus stood in the midst of us. The door hadn’t opened; it was still locked. He just said, “Shalom,” the way that you do when you greet someone. My goodness, it was a shock. He wasn’t there and then he was there. If it was a trick, I can’t work out how he did it. There was nowhere he could have been concealed.

Of course, some of them thought he was a ghost. But he offered his hands and I felt them. They were real flesh and blood. You could even see the holes in his wrists where the nails went through. Same with his feet. He even ate a fish sandwich.

Then he said it again, “Shalom,” but this time it wasn’t a greeting. He was emphasizing the meaning. “My peace I give to you.” And, do you know, we felt it. After all the worry and turmoil of the last few days this tremendous feeling of calm came over us. I was struck by the enormity of it. It was wonderful to see him, of course, but he had been dead and now he is alive!

All he had been telling us at last made sense. When I first met him I had been contemplating our father Israel’s dream at Bethel. He knew what I was thinking. It was as though he could read my mind. I knew then that he was the son of God. Now he has revealed himself. Great things are going to happen. You see, the peace he offered us was peace with God. Ever since Adam sinned God had dealt with us under sufferance. We had to keep killing lambs and bulls, even pigeons to show that we submitted to his judgement. And on that condition his judgement was held at bay.

I keep thinking of that old servant song, “The punishment that brought us peace was upon him…the LORD has laid on him the iniquity of us all.” The Rabbis have argued down the ages about who the servant was supposed to be, but it’s all clear now. The servant is the son of God. Even the resurrection is predicted. I never saw it before, but what else can “After the suffering of his soul he will see the light of life and be satisfied” mean? So much that he said to us makes sense now. “In a little while you will see me no more, and then after a little while you will see me.” What else could that mean? Why didn’t we realize it at the time? And the best of it is this: because he is alive, the punishment is complete. Death has spat him out. He was too big to swallow.

He blew on us, as if to say take my breath into the whole world. It’s no longer a secret. Death is defeated; the last enemy is conquered. Something great is surely coming.

Saturday, March 22, 2008

Second day

We have had these periods of silence before. There is nothing you can do about it; you just have to wait. On Andros III the moons are so arranged that the orbiter is out of contact with the ground station for a little under 24 earth-hours every nineteen weeks. Captain Newman could explain the physics of it if he were here, but I am a mere physician and everyone knows that we become doctors because we can’t do the math.

How I got to be alone on a small shuttle at the back end of the Galaxy is a long story. For now, let’s just say that I happened to be in the shuttle bay loading medical equipment when the main ship exploded and my orbiter was flung clear. If I knew how to fly the thing I might try to go somewhere, but not having the navigation skills I know neither where I would be coming from or where I would be going to. I just have to wait until I get into radio contact again.

That’s if there is anyone to get in contact with. The honey virus epidemic has affected three quarters of the colonists and although I now have the vaccine ready I’m reliant on the radio beam to guide me down to the survivors. If that were all, I would be happy to sit it out. In just under twenty-four hours I would be able to lock on to the beam and the computer would fly the thing down to them. The thing is, I don’t understand why the ship exploded. And if I don’t know that then I’m not sure it’s safe to go down there at all.


It’s been six hours now. I’ve tried to sleep but sleep won’t come. For some reason the only books on the computer are what they used to call ‘chick lit’ – historical classics by Jane Austen and Helen Fielding. Don’t they realize that there are still some male doctors? Another eighteen hours to go. The computer has beaten me at 3D chess seventeen times and I’m tired of Suicide Sudoku. I keep coming back to the explosion.

All I can remember is absolute panic. People were screaming over the radio. The whole ship was shaking. I jumped into the orbiter and slammed the hatch. Then everything went black and I passed out. When I awoke, twenty minutes had passed. I was alone and everything was silent. Through the upper port I could see Iskios, the largest moon, but through the other ports, nothing but stars.

Was the explosion some sort of accident? Or was it the result of enemy action? We’ve been fighting against the Kathgoros for centuries now. They seldom reach this far out in the Galaxy, but Captain Newman is an important person. It would be a fine coup for them to take him down if they could locate him. There have been rumors that the Kathgoros are behind the honey virus; certainly there have been signs of their activity wherever it has turned up throughout the Empire, but there has never been any conclusive evidence that they engineered it. They are like that, though. Elusive. If only they would stand and fight, I’m sure that we could defeat them. There used to be a term for it – asymmetric warfare.

We don’t even know what they look like. They’re shape-shifters, of course. They seem to be able to take on the shape of any human for a limited time – usually for less than an hour, but they seldom need more to spread their chaos. People are deceived by them and once they have their hooks into us, we seem to swallow all sorts of poison as if it were true.


I must have dozed off. Another three hours have gone by. I was playing “Parto, parto, ma tu ben mio” from La clemenza di Tito on the audio and I drifted into sleep. It’s six centuries since Mozart wrote it and it still has the power to calm the anxious heart. It was supposed to goad Sesto into starting the revolution, but Mozart is a soother not a goader.

We are no longer in the shadow of Iskios, but now Jragma shields us from the planet. After Jragma it will be Aspia and so on. Nearly fifteen hours of it.

I was always suspicious of Judy. That’s Judy Skaros, Newman’s PA. She gave herself airs, that one. Newman is a great man, no doubt about it. He was the brains behind the new vaccine, I just followed his instructions. But what is Judy? Just a glorified secretary. She organized his appointments, kept him on schedule; but she controlled who could see him. He was always accessible if you could get past her, always welcoming. He always had something interesting to say; a new way of looking at your problem. I thought she was taking bribes. Some of the people who got to se him latterly were really the dregs. Oh, they were rich enough, but how did they get their money? And she seemed dress more sharply every time I saw her. You don’t get that rich as a captain’s PA.

Not that I had much time for any of his unit. He seemed to attract losers. That Peter Ceffus was about the best of them, but he was always shooting his mouth off. He was going to do this; he was going to beat that; I reckon he’d be nowhere without Newman.

Anyway that’s one explanation. If the Kathgoros did get to Newman I suspect Judy had a hand in it.


If the Kathgoros blew up the ship it probably isn’t safe to go own to the surface. They would only risk the ship if they wanted to wipe out the colonists. They are probably down there waiting right now.

On the other hand it could all have been an accident. I’m assuming the ship was totally destroyed, but perhaps the damage was limited to my part and I was launched automatically in the orbiter. In which case perhaps the rest are fine and they think that I am the only lost one. But if that is the case why haven’t they come looking for me? Perhaps the ship was disabled but not damaged. Why then not send a shuttle to find me? But I was in the shuttle bay, perhaps that’s where the damage occurred and they can’t launch another shuttle. Yes, perhaps that’s it. In another 12 hours I come out of radio silence and everyone will know where I am. I’ll be rescued.


This waiting is killing me. Time seems flexible. When you are enjoying yourself it travels at light speed but waiting stretches it. I keep looking at my chronometer. I can’t believe that only two minutes has passed. If I only knew what I was waiting for. The longer the radio silence persists the more I expect disaster. Should I attempt to fly this thing? It can’t be that difficult. If only I had worked harder at the math. Molecular engineering is no pushover; it can’t be that difficult to work out co-ordinate geometry. But where to start?

Of course, the computer does most of the flying; all I have to do is punch in the co-ordinates of the start and finish, but that’s what I don’t know. Without a solid reference point I’m helpless. I’d just be wasting fuel and I need the fuel to re-generate the oxygen. I can certainly survive longer if I don’t go anywhere, but what’s the point of surviving if I don’t go anywhere?

Kathgoros means ‘accuser’ in English. The accuse us of contaminating the Galaxy. They were here before us, of course, but I can’t see how that gives them squatters’ rights. Surely there is room in the Universe for both of us? They seem to think that the presence of humans spoils things for everyone else. Their ambition seems to be to confine us to ‘Prisonship Earth’.

Captain Newman isn’t everybody’s cup of tea. A lot of the corporations don’t like him. They say his ways diminish profits. But then, the government isn’t that keen on him either. They appreciate his general law-abiding principles, but they don’t like his being free of their control. They see him as loose canon. They certainly didn’t approve of his coming to Andros III. They have problems much closer to home and they want him there. They though this was a foolhardy mission – they’d cast the colonists adrift.

Newman couldn’t resist a lost sheep. So he came. We worked on the vaccine together and by now we should be down on the planet inoculating everyone. Instead, I’m stuck in this stupid orbit and he’s been blown to smithereens. I would certainly carry on the vaccinations if it were possible, but somehow I think it’s a lost cause. What a waste of a brilliant potential: to perish on a mercy mission to a few thousand backwoodsmen. It won’t even merit a footnote in galactic history. I doubt if more than one person in a million on Earth has even heard of Andros III.


It won’t be long now. In half an hour I shall come out of the shadow of Sabano and be able to see the planet. This has been the longest 24 hours in my life. I’ve imagined every scenario. I think it’s most likely that the radio silence will continue. The ship will be completely gone and all its crew killed. I expect that the colony will be destroyed and if anyone is waiting for me it will be the Kathgoros. More likely, no-one will be there. I, only I, will be left. I have enough oxygen to last 3 days, or three hours if I attempt to fly the thing down to the planet. If I try that, most likely I will crash. I have a small chance of making it, but I suppose even a 1% chance is better than the certain death of staying up here. On the other hand, if I do survive the flight I shall be alone on an unpopulated. planet. Why wait forty years for death if there is no prospect of company? This far out in the Galaxy the prospect of further colonists is remote. What a choice!


Ten minute ago Captain Newman ‘beamed’ aboard. I thought that technology was impossible, a figment of the imagination of sci-fi writers of the twentieth century. Don’t ask me for an explanation. He suddenly appeared in the co-pilot’s seat, smiled at me, set the co-ordinates, fired up the engine and set us going. The he said, “I’ll see you later,” and disappeared again.

The orbiter seems to be approaching the planet on an orderly course. No doubt in time I will get an explanation.

Friday, March 21, 2008

Violent death

The accompanying document has recently come to light among the scrolls and papyri found near the Wadi Qumran. Unlike the majority of these documents, it was written in Latin and it may therefore be an attempt by local Bedouin to cash in on these discoveries. The Bedouin tribe of Ta’ammireh is well known for its cunning and sharp business practices, so it may well be a forgery. I have made a rough translation which I present for your judgement.

Report of post-mortem examination of prisoner MCMLXVII known as Yeshua Ben-Adam.

Hail Tiberius Caesar!

The body is that of a male Sephardic Jew aged between XXX and XL years, of average build and swarthy complexion. The hair is long and plaited and the beard unkempt. There are numerous facial injuries as detailed below.
(i) swelling over both eyebrows.
(ii) torn right eyelid.
(iii) large swelling and discoloration below right eye.
(iv) swollen nose, the nostrils filled with old blood clot.
(v) triangular shaped wound on right cheek with apex pointing towards nose (this appears to have arisen from an attempt to pluck out the prisoner’s beard)
(vi) swelling of left cheek.
(vii) swelling and contusion of left side of jaw.
(viii) IX separate puncture wounds in the scalp arranged in a ring around the crown of the head. The longest of these admits a probe the distance of the terminal bone of a man’s thumb.

On the dorsal surface of the body there are numerous wounds extending from the shoulders, across the back and buttocks down to the backs of the thighs. Each wound is slightly longer than the terminal bone in a man’s thumb and dumbbell shaped. They are arranged in groups of III and extend diagonally across the back in both directions. I counted CXVII separate wounds. These wounds are consistent with a scourging with a flagra properly administered.

There is an area the size of a man’s hand over the right shoulder which shows blistering and abrasions. Over one part of the knees are numerous excoriations.

There are puncture wounds in both wrists consistent with a large nail having been hammered through the skin crease between hand and wrist. In both cases the wound has passed between the small bones of the wrist without damaging them, but in both cases it has transected the median nerve. There is an exit wound on the back of the wrist.. There are similar wounds in each foot. In this case the wound passes between the proximal ends of the second and third metatarsals.

There is one further would. There is an elliptical slit the length of a man’s thumb between the ribs V and VI on the right hand side of the front of the chest. It is clear that blood has flowed from this. Unusually for those executed by crucifixion in the province of Judea no bones are fractured.

Internal examination was most interesting for the findings in the thorax. The left pleural cavity was filled with a straw colored fluid with some blood streaks. There was enough of this fluid to half fill a centurion’s helmet which I was leant for the purpose. The left lung showed contusions on the surface and was collapsed. The cut surface was frothy. I have seen such fluid before in prisoners who have died following a flogging.

The left pleural cavity contained very little fluid. Presumable it had drained through the wound in the anterior chest wall. I examined the track of this wound, the depth of which was about the breadth of a man’s hand. The wound passed through the pleural cavity, through the collapsed lung and into the right atrium of the heart which was empty of blood. The wound could have been made by a Roman soldier’s short lance.

The other organs of the body showed no gross abnormalities apart from the fact that all were covered with small petechiae and there was a good deal of unaltered blood in the bowel. A curious finding was the complete absence of clotted blood. Indeed blood flowed freely from the vessels when cut. I collected a sample of blood in an earthenware jar and although I stored it for several hours the blood would not coagulate. I have noticed this finding before in prisoners who have met a violent death. I would like to propose that such blood be collected and instilled into those who, because of a deficiency of blood, are weak and cowardly.

I find the cause of death to be suffocation caused by accumulation of fluid in the thorax during judicial crucifixion. Owing to the inability of the blood to coagulate it is possible that the lance wound occurred post-mortem and thus was both blood and pleural fluid lost from the body.

I would finally like to protest at the treatment of this prisoner. Although the wounds to the back and limbs are consistent with scourging and crucifixion properly and legally carried out, the wounds to the head are a different matter. There is no doubt in my mind that this prisoner was illegally beaten while in custody. Eye witness testimony suggests that this took place not only in the custody of the Roman Procurator, but also in that of the Tetrarch Herod Antipas and indeed in the custody of the Jews themselves.

This, Sir, is not what Roman justice is about. I should further like to protest that I was prevented from continuing my examination of the body by its disappearance. I have no doubt that this was ‘engineered’ by someone in authority to cover up evidence of penal atrocities. Despite extensive enquires I have been unable to find any trace of the corpse.

Signed Lucas Mortico, state pathologist.

The document has an addition in a different hand:
File. No further action. Not to be referred to higher authority. Lucas Mortico to be posted to Britannia or somewhere equally cold and unpleasant.

Signed: Pilatus, Procurator of Judea.

I think that this document is highly unlikely to be genuine, but it is interesting to note that the Soviets also observed the inability of blood to clot in those meeting a violent end. Apparently something triggers the fibrinolytic enzymes. They are on record as using cadaver blood donations to bolster their transfusion service in the time of Joseph Stalin.

Thursday, March 20, 2008

Maundy story

Ward rounds were occasions of terror. In our short white coats we trooped behind the gods and demi-gods and tried to escape notice. Sir John Perkins was especially terrifying. He was tall, grey-haired and always dressed in black; black jacket and waistcoat, black trousers with a fine pin-stripe and sword-edge creases and black shoes reflecting their surroundings like a looking glass. Finely spoken and austere, his slim presence brought silence to the room as we waited for wisdom to emerge from his thin lips.

In those days we had Nightingale wards; long narrow rooms with beds lined up on either side, each with its own set of curtains. Half an hour before Sir John arrived Sister Carstairs had every patient settled in bright white sheets, hospital corners immaculate. Every bed was square with its fellow, every surface polished, every odour dispelled.

On this particular morning curtains were drawn around a bed at the far end of the ward. Sir John’s eye fixed upon it first. “An emergency, Sister? Is someone in need of my attention?”

Sister Carstairs looked unaccustomedly flustered, “A visitor, Sir John, an interloper. A brief admission from Casualty because they were short of beds. A lodger, merely. Gone tomorrow.”

“Nevertheless…” said Sir John and marched to the end of the ward and pulled back the curtains to reveal O’Brien. Those of us who had done stints in Casualty recognised O’Brien. The Irish drunk was a frequent visitor, but it was rare for him to con his way into a bed for the night.

Once the curtains were drawn the smell became noticeable and as Sir John drew back the bedclothes it intensified. “So, Patrick,” said Sir John, “It’s the feet, is it?”

It was the feet. O’Brien was wearing a hospital gown that left his legs exposed. He was not an attractive man; unshaven, obese, unwashed, hairy and malodorous. His feet were black with ingrained dirt and his ankles ulcerated. Sir John stripped off his jacket and handed it to Keith Pritchard, his Senior Registrar. He turned on his heel and marched in his shirtsleeves to the sluice. Shortly afterwards he reappeared with a towel wrapped around his waist and carrying a yellow plastic bowl filled with warm water. He set it down on the floor and kneeling before O’Brien proceeded gently to wash his feet. He took the towel and dried them. “Some talcum powder, Sister, I think.” he said.

Then he dismissed us; the students, the junior doctors, the nurses, almoner and the rest.
“Some coffee, perhaps, Sister Carstairs?” and he and she retired to her office.

Six months later Sir John Perkins died of lung cancer. We had not known that he smoked. He was succeeded as consultant surgeon at that famous teaching hospital by Keith Pritchard who learned from Sir John how to dress well and how to inspire respect in his students. He later became Surgeon to the Queen. Tony Baldini, the Senior House Officer, also became a consultant surgeon. He had learned to terrify his students and was notorious for humiliating them in front of their friends. Liam Murphy, my friend who had cowered with me at the back of the crowd, became a consultant obstetrician in Cork and the father of seven children, all boys. Sister Julia Carstairs never married. I learned never to think of myself as better than my patients.

Monday, March 17, 2008

That pig Paul.

The evangelist was scheduled to take a religious education lesson in a girls' secondary school. As he walked into the classroom he was greeted by the teacher who said, "We have decided that St Paul was male chauvinist pig."

After shooting upwards an arrow prayer for help he asked the girls, "How many of you would like to be married and have a family?" All their hands shot up.

"How many would like to marry a man like your father?" All the hands stayed down.

"Why not?" One girl suggested, "He expects my mum to wash and iron his clothes, to cook his meals and wash up the dishes, to do his shopping for him, to wait on him hand and foot. He's turned her into his house-slave."

"Who would like to marry a man like this? His love is patient, his love is kind. His love never envies, he is never rude. He is never proud; he does not boast. His love is not easily angered. His love keeps no record of wrongs. His love hates evil and loves the truth. His love always protects, always trusts, always hopes always keeps on tyring. His love never fails."

Every hand shot up.

"That's the kind of man that St Paul recommends."

I am grateful to Ian Leitch for the story.

Dying well.

Some people have horrible deaths. The author of this article suggests that it is all down to money, but I don't accept that. Money doesn't buy care, only the semblance of care. It's like relying on a prostitute for love; it may look like love, but it is all an act that finishes when the money runs out.

Arthur Hugh Clough's 'Thou shall not kill but needst not strive officiously to keep alive' was meant ironically, but it was written at a time when physicians could do next to nothing to prolong life anyway. I have noticed in my younger colleagues an unwillingness to let go. It's as if a patient's death is a personal insult. I believe doctors are generally terrified of their own deaths and as a consequence fear death of a patient. Thus they fail to prepare patients for their deaths and persist with useless treatments to a point when they are causing harm rather than benefit.

They have forgotten the part of their job that is about relieving suffering. There is also an unwarranted reticence to use morphine in proper doses. For Christians the doctrine of double effect – relieve the suffering even if it shortens life - should absolve them from responsibility for a patient's death.

Some would blame Christian ethics for this cruel attitude to the dying. They suggest that a belief that life must be preserved at all costs condemns patients to prolongation of their suffering, but it is not Christian ethics that are responsible for the callousness of health providers. Christians are supposed to be patient, kind, loving, good, faithful, gentle, peaceful, joyful and self-controlled. Other attitudes are perversions. Dame Cecily Saunders, the mother of the modern hospice movement understood that.

Blood Diamond

On Saturday night we watched Blood Diamond, the thriller set in Sierra Leone starring Leonardo DiCaprio. As a thriller it was excellent fun. Usually the action in these things is interrupted for what we used to call as kids, 'kissing bits'. Blood Diamond was mercifully free of these. The language was rather ripe - no doubt the film-makers would say that it reflects reality. I never thought that thrillers had to reflect reality.

The civil war in Sierra Leone began in 1991 and was fueled by the illegal exprt of diamonds. It was ended in 2000 following the intervention of British troops .

This took place during a short window when it was seen as acceptable to interfere in the internal workings of another country


Today I took the notes of all my private patients into the hospital and distributed them among my colleagues. While there I reported two bone marrow biopsies that have been sitting in my in-tray. That's it. Finished.

When I got home my wife said, "On to pastures new?"

"More like pastors new," I said. I have just been asked to chair a search committee looking for a new pastor at the Church. Two of our pastors are leaving this year and our first task is to find a minister for pastoral care.

Sunday, March 16, 2008

Androcles, you never can tell.

This week we watched two more of the GBS plays. 'Androcles and the Lion' starred Billy Connolley as Androcles, Anna Calder Marshall as Lavinia and Bernard Bresslaw as Ferrovius. Michael Holdroyd directs. This is a gentle and rather lightweight production originally produced for BBC Schools and not broadcast for 21 years. The story is based on the Aesop fable and written by Shaw to demonstrate different types of Christians.

Rather more fun was 'You never can tell' an early comedy (1897). The only reviewer on Amazon, was not impressed, but I rather approved of it. Robert Powell starred with Cyril Cusack and there was an appearance of Warren Clarke as a young and rather good looking man. He now plays Andy Dalziel in Dalziel and Pascoe as a plug ugly policeman.

Saturday, March 15, 2008

New Clinical Trials

I was at the UKCLL Forum Clinical Trials Meeting yesterday. Here are some of the trials up and running or in development in the UK.

CLL6 is in preparation. It needs funding from the Health Technology Assessment Board. It asks a question about cost, namely, do we need such a large dose of rituximab. It compares FCR with FCmini-r + mitoxantrone in a non-inferiority study. This is a randomized phase II study. The dose of rituximab in mini-r is 100mg as opposed to 500mg/sq meter for FCR. Such a small dose can be given quicker and save time an money in the hospital. With small doses there is also the possibility of sc delivery which also saves money.

The use of mini-r derives from the work of Ron Taylor about which I have reported previously. Antigen shaving means that higher doses of rituximab have no CD20 to latch on to. If FCr+M is not inferior to FCR in response rate then a three way randomization of FCR v FCr+M v FCRM would be undertaken. Obviously the pharmaceutical companies will not fund a mini-r trial in case it is as good as full doses and their sales were gut to a fraction of present sales.

Since the German trial shows FCR to be better than FC (although this is from the Roche website and not from a peer reviewed publication) trials with FC as the comparator are non-starters now. However we do not expect publication of the German CLL8 until ASH this year and peer review won't happen to 2009. Therefore NICE will not pronounce until 2010/11. British patients will therefore not get rituximab until then.

As a consequence Roche have offered to fund a FCR v FCRM trial in the UK (using oral FC). This would enable British CLL patients to get free rituximab until NICE pronounces. It could also be seen as an interference ploy by Roche to prevent the mini-r trial from accruing. A cynic might suggest that Roche might be lobbying HTA to stop the funding for mini-r. There is certainly a message coming down from National Cancer Research Institute (NCRI) that they want to encourage participation in industry sponsored trials. Industry also has an interest in demonstrating that FCR with oral FC is as good as with iv FC.

In this context I ought to report that Pete Hillmen's phase II study showed that FCM-R was better than FCM in terms of response rate and quality of response. Historically, we know that FCM produces equivalent responses to FCR is separate phase II trials.

On the question of trials for older patients and those with co-morbidities, we looked at teh possibility of bendamustine trials. However, we thought that this was rather like going back to driving a Trabant when you had previously driven a Ford Focus. We decided to stick with chlorambucil, though given at a proper dose of 70mg/sq m/month rather than the 40mg/sq m/month used in American trials. Roche is supporting a phase II trial using this dose of chlorambucil with rituximab in conventional doses. 50 patients will be recruited in a maximum of 12 months. So far 10 sites are actively recruiting with 11 patients registered. CLL7 might be a randomized phase III comparing Chlorambucil plus or minus rituximab, but GSK have offered an alternative randomized phase III using ofatumumab (HuMax CD20) instead of rituximab.

CLL8 looks at the Campath consolidation question. The aim of this trial is to determine the rate of achieving MRD negativity as determined by 4 color flow cytometry in patients with low levels of MRD following conventional therapy or who relapse at MRD level after a previous MRD negative remission; and to assess the safety of alemtuzumab in the MRD positive setting. The recent CALGB trial had 5 deaths after Campath which has put the wind up Bayer, who bought Schering AG. However, this degree of toxicity is anomalous and may be a reflection on the community oncologists entering patients in that trial.

MRD positive patients will receive alemtuzumab 3 times a week for a total of 6 weeks. Patients whose CLL has disappeared will stop treatment. Patients whose CLL levels have not changed since before the start of treatment will stop treatment. Responding patients who have detectable CLL at the end of 6 weeks will continue treatment for 6 more weeks. MRD negative patients will be monitored every 3 months until they become MRD positive at which point they will be eligible to receive treatment with alemtuzumab.

Up to 54 patients will be recruited over a two year recruitment period and so far 15 patients are registered.

CLL206 is a phase II trial of Campath and high dose methylprednisolone in 17p deleted cases. There was a high MRD negative response rate and this will come to publication shortly. CLL10 asks a Revlimid question in the same group. Even MRD negative patients relapse so Revlimid maintenance will be examined in this study.

CLL203 ask a Revlimid question in high risk p53 or ATM deleted patients. The principle aims of the study would be to determine 1. Response (according to 2008 IWCLL criteria plus MRD eradication, 2. Safety and dosing schedule, 3. Time to next treatment. This question has been a thorny question with us. We have looked at the possible use of FC, FCR, rituximab, alemtuzumab and now Revlimid in this context. The figures for this group are so bad, however, that we feel that something must be done. Rituximab does not depress the immune system nor cause DNA damage - though it does have other unpleasant side effects.

We are also considering an FC plus or minus ofatumumab trial in relapsed disease. This would be commercially sponsored and therefore iv FC, which is a disadvantage, but would cost nothing and give us something to offer until NICE looks at FCR. It competes directly with the FCR plus or minus luxililimab trial, but this is not generally popular in the UK.

Friday, March 14, 2008

Travails of the NHS

Multi-disciplinary teams (MDT) are the means by which the NHS seeks to eliminate mavericks and make sure that patients receive the best treatment. The idea is that every new patient is discussed by a group of specialists and decisions are taken by several heads being put together.

Recently a patient with CLL appeared in a district hospital with a lymphocyte count of over a million. Prognostic markers were done and the patient was found to have a p53 deletion. The MDT was consulted and recommended that possible courses of treatment were alemtuzumab or leucapheresis. The local team instead decided to use CHOP. The following week the patient had a lymphocyte count of 1.2 million. The Hb was only 4g/dl. Again different members of the MDT recommended different courses of action. One consultant, who has an international reputation in the treatment of this disease and who chairs the committee that draws up treatment guidelines, again recommends alemtuzumab. He is aware that the patient has large lymph nodes, but the urgent element for treatment is the severe bone marrow suppression and surely this needs to be remedied before worrying about the lymph nodes. Instead, the local team decide on leucapheresis despite the low Hb and the patient dies while connected up to the cell separator.

Another patient, a young bodybuilder, appears with enlarged lymph nodes from his CLL. He too has a p53 deletion. The correct treatment is clearly alemtuzumab and high dose steroids. Because there is no specific budget for this, the case has to be put to the primary care trust (PCT). This group of public health doctors, GPs and pharmacists of course knows nothing about CLL. So they read the literature. "I have been reading about this subject for two hours" says one, "I am now an expert in the condition." "Campath is contraindicated where there are bulky nodes," says another. "Where are the guidelines recommending this?" asks another. My friend produces a recent paper and admits that the guidelines do not yet recommend this, but the ones in preparation will. He knows because he has the job of writing them. Of course a prophet is not without honor save in his own country. Eventually they are part persuaded and will pay for two courses of the drug.

Both examples of inappropriate bureaucracy hindering treatment.

Another example. The European Clinical Trials directive decrees that the same standard of oversight should be applied to academic trials as to pharmaceutical trials. So the MHRA dispatches inspectors to hospitals to examine the notes to ensure that the protocol has been properly followed. One famous hospital is taken to task because for one patient there is no record in her notes that she has been counselled about taking effective contraception during her chemotherapy. The patient is 73 years old.

A man from Zimbabwe has a blood test which shows a white count of 20,000 and a platelet count of 7. The cells are typical acute promyelocytic leukemia (APML) cells. This disease is curable if treated but he is in imminent danger of bleeding to death if he is not treated. This is explained to him, but he declines admission to hospital. The doctor realizes that he is probably an illegal and reassures him that he is not going to snitch to the authorities. He still refused to come into hospital. A week later his 'brother' brings him into the A&E department unconscious and then leaves him. He dies a few hours later; he has had a cerebral hemorrhage. the address his 'brother' has left is a false one.

I am so glad I no longer work for the NHS

Thursday, March 13, 2008

stem cell transplants - a personal history

I was first involved in a bone marrow transplant (BMT) in 1970. We attempted to transplant bone marrow into a toddler with aplastic anemia from an identical twin. It did not take and the child dies. Such a transplant is called a syngeneic transplant and I have never been involved in one since.

In 1983 I got involved in a an autologous bone marrow transplant (ABMT). This was a woman with untreatable ovarian cancer. The idea was to increase the dose of chemotherapy that we gave her. The most sensitive tissue to the toxicities of the alkylating agents is bone marrow, so we thought we could take this out of the equation by storing it in the fridge while she had a big dose of melphalan. The technology worked but the chemotherapy did not damage the cancer.

In 1985 I was given a grant to pursue the idea of ABMT in lymphoma. We had access to Campath - at that time a rat monoclonal antibody. The problem with ABMT in lymphoma is that there is often lymphoma in the bone marrow, so we thought we would be able to launder the marrow with Campath to clean out the lymphoma. This was more successful and we did our first CLL/SLL transplant in 1985. He was cured of his CLL/SLL but died 13 years later of lung cancer.

We transplanted several other patients at this time and some of these were very successful ans some are still alive. For patients with very heavily contaminated bone marrow, even Campath could not get it clean. We then saw a paper by Martin Korbling who described a patient with Burkitt lymphoma who had been treated by a stem cell transplant using stem cells harvested from the peripheral blood (PBSCT). We thought we could try the same thing, especially since I was President of the European Society for Haemapheresis at this time and new all about harvesting cells from the blood.

In fact stem cells had been harvested from the blood before in chronic myeloid leukemia, but that was thought to be a special case, where the disease seemed to consist of bone marrow spilling out into the blood. No-one had suspected that you could get marrow stem cells from the blood in other diseases.

In 1986 we had a patient whose bone marrow was solid with lymphoma (mantle cell lymphoma in fact) We were trying a new chemotherapy regimen, IMVP16, and we had the idea that during the recovery phase from the chemotherapy, stem cells might shower into the peripheral blood as they had with Korbling's case. Sure enough, we had an assay for bone marrow progenitor cells (CFU-GM) as after chemotherapy we found large numbers of these cells appearing. By this time Chris Juttner in Adelaide had done a stem cell transplant in AML so we went ahead in our patient. It was a great success and we put him into a complete remission that lasted for 18 months. This was the first PBSCT in the UK and we think the third or fourth in the world. We did two further such transplants and then published the three cases in a paper in the B J Haem. The important finding was that the neutrophils recovered much more quickly after a PBSCT than after an ABMT, 15 days compared to 24.

We then started doing autografts in myeloma. Having already given high doses of melphalan in this disease and nursing patients through 6 weeks of pancytopenia, we though we would be able to manage this safely. In order to generate the stem cell harvest we had to give 7g per square meter of cyclophosphamide, a huge dose, but the patients negotiated this safely. Again this was very successful, though others were worried about the large dose of chemotherapy, we found that we were able to harvest enough stem cells to do a double autograft in some patients.

Then an Italian group published the fact that instead of chemotherapy you could generate stem cells in the blood by giving the growth factors G-CSF or GM-CSF the whole field took off. In fact, even allogeneic transplants used peripheral blood stem cells as a preference. Because bone marrow transplants and peripheral blood stem cell transplants tend to get lumped together a new term was coined - human stem cell transplants (HSCT) which encompasses both.

We did our first allograft in 1985. She was a young mother with high count acute lymphoblastic leukemia. This disease has a terrible prognosis and we decided that she needed a transplant. Because the past 4 transplants that we had sent to London had all died of the procedure we decided that we couldn't do worse if we did it ourselves. In fact we did rather better, because at least the patient got home for a while. Unfortunately, she developed graft versus host disease and then interstitial lung disease and died a few months later. I met her daughter a few months ago. there were no recriminations; she though that we had done the best for her mum. She left the hospital in a white Rolls Royce in a blaze of publicity.

In this case her sister had been the donor - it was a matched sibling transplant. We went on to do several more transplants which were more successful, but unfortunately the powers that be decided that resources should be concentrated in a different center.

When I started going to Kings College Hospital, I linked up with the biggest transplant center in the UK, one run by my old research fellow who had done our first allograft with us back in 1986. The majority of transplants done there are matched unrelated transplants (MUD) where the donors come from a volunteer donor panel. Sometimes these are known as volunteer unrelated donor transplants (VUD). To some extent this has made transplants more available, but still, because most hematologic diseases occur in older patients, most are unsuitable for standard transplants.

I remember going to a lecture about 10 years ago when the lecturer proposed that transplants work not by rescuing patients after a massive dose of chemotherapy, but by an immune attack on the tumor, the so-called graft-versus-leukemia effect. Therefore it wasn't really necessary to blast the patient with radiotherapy, simply to immunosuppress him enough for the graft to become established. This 'mini-tranplants' began. These are sometimes known as reduced intensity conditioning (RIC) transplants, and sometimes non-myeloablative grafts. There are various regimens used for the conditioning. In Seattle they use low-dose total body irradiation, but in other centers they rely on a small dose of fludarabine to immunosuppree, and in the UK they often use Campath. Patients up to the age of 70 can be safely transplanted, which brings patients with MDS and CLL into the transplantable range.

Still to be solved is the problem of ethnic minority volunteer donors. One solution seems to be cord-blood donors. Cord blood doesn't need to be so tightly matched and one or two mismatches are often perfectly acceptable. This extends the number of possible donors and even with patients who are half Serb and half Nigerian a donor can be found. Kings has started a cord blood program. Often the graft is not large enough for an adult transplant and in these cases two cords must be used. Only one will transplant, but the second sustains the first while it is expanding. One disadvantage of cord transplants is the risk of EBV driven lymphomas which occurs in 20%. The risk can be elimnated if rituximab is given with the graft, but this will likely make the recipient hypogammaglobulinemic for life.

Transplants are getting better all the time but the problems are not yet solved. There are patients that sail through the procedure with little problem, for others the procedure is lethal. We know some of the factors that influence outcome, but not all. Because the risk is uncertain we are reluctant to recommend it except where the alternative is definitely worse, but often that is a matter of judgement.