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Treatment with azacitidine (AZA), a demethylating agent, prolonged overall survival (OS) vs conventional care in patients with higher-risk myelodysplastic syndromes (MDS). As median survival with monotherapy is <2 years, novel agents are needed to improve outcomes. This phase 1b/2b trial (n=113) was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of panobinostat (PAN)+AZA (phase 1b) and evaluate the early efficacy and safety of PAN+AZA vs AZA monotherapy (phase 2b) in patients with higher-risk MDS, chronic myelomonocytic leukemia or oligoblastic acute myeloid leukemia with <30% blasts. The MTD was not reached; the RP2D was PAN 30 mg plus AZA 75 mg/m2. More patients receiving PAN+AZA achieved a composite complete response ([CR)+morphologic CR with incomplete blood count+bone marrow CR (27.5% (95% CI, 14.6–43.9%)) vs AZA (14.3% (5.4–28.5%)). However, no significant difference was observed in the 1-year OS rate (PAN+AZA, 60% (50–80%); AZA, 70% (50–80%)) or time to progression (PAN+AZA, 70% (40–90%); AZA, 70% (40–80%)). More grade 3/4 adverse events (97.4 vs 81.0%) and on-treatment deaths (13.2 vs 4.8%) occurred with PAN+AZA. Further dose or schedule optimization may improve the risk/benefit profile of this regimen.

There needs to be a less clinical attitude towards the menopause, which is not an illness. There needs to be greater knowledge of the experiences of middle-aged women, with a view to better management of the menopause in a menopause clinic, as the menopause affects different women in different ways. A study of a community group run by women and a menopause clinic run by nurses indicates that women and nurses can decide what services a specialist environment can provide.

Exacta Medica: Reference Tables and Data for the Medical and Nursing Professions by Ian Reid Entwistle Churchill Livingstone, Edinburgh, 1989 (ISBN 0 443 04194 6) 40 pages Price £2.75Sports Injuries edited by Vivian Grisogono Churchill Livingstone, Edinburgh, 1989 (ISBN 0 443 03175 4) 252 pages Price £14.95Outcomes of Artificial Lower Limb Fitting in Scotland by Peter Knight and James Urquhart Health Services Research Reports, Information and Statistics Division, Scottish Health Service, Common Services Agency, Edinburgh, 1989 113 pages Price £ 3.95Changing Ideas in Health Care edited by David Seedhouse and Alan Cribb John Wiley, Chichester, 1989 (ISBN 0 471 92068 1) 236 pages Price £9.95Play Therapy by Virginia Mae Axline Churchill Livingstone, Edinburgh, 1989 (ISBN 0 443 04061 3) 350 pages Price £9.95Anatomy and Human Movement: Structure and Function by Nigel Palastanga, Derek Field and Roger Soames Heinemann Medical Books, Oxford, 1989 (ISBN 0 433 00032 5) 891 pages Price £60.00Manual of Physical Therapy edited by Otto D Payton, Richard P DiFabio, Stanley V Paris, Elizabeth J Protas and Ann F Van Sant Churchill Livingstone, New York, 1989 (ISBN 0 443 08499 8) 761 pages Price $71.95The Management of High Quadriplegia edited by G Whiteneck, D P Lammertse, S Manley, R Menta, C Adler, C Wilmott, R E Carter and K A Wagner Demos Publications, New York, 1989 (ISBN 0 939957 19 1) 367 pages Price $69.95Disabling Diseases: Physical, Environmental and Psychosocial Management edited by A O Frank and G P Maguire Heinemann Medical, Oxford, 1988 (ISBN 0 443 00057 0) 277 pages Price £14.95Kinesiology and Applied Anatomy (7th Edn) by P J Rasch, MD Grabiner, R J Gregor and J Garhammer Lea and Febiger, Philadelphia, 1989 (ISBN 0 8121 1132 X) 286 pages Price £19.00Penguin Nursing Revision Notes: Orthopaedic Nursing (Revised Edn) edited by Patricia A Downie Penguin Books, Harmondsworth, 1989 (ISBN 0 14 077094 1) 113 pages Price £3.99 Linda M King ONC MCSP DipTP Coping with Bereavement by Sandra Horn Thorsons, Wellingborough, 1989 (ISBN 0 7225 1651 7) 128 pages Price £4.99The Sociology of Health and Healing: A Textbook by Margaret Stacey Unwin Hyman, London, 1988 (ISBN 0 04 301233 7) 298 pages Price £12.95Video review An Introduction to Benesh Movement Notation by Helen Atkinson Polytechnic Commercial Development Unit, Donnington House, Trinity Street, Coventry CVI 5FB, UK Price £50.00 plus postage and packing Price to hire £5.00 plus postage and packing

Peripheral blood platelets were examined in 7 patients who underwent bone marrow ablation with high dose chemotherapy and total body irradiation prior to bone marrow transplantation (BMT). Platelets were studied for 9 days, by which time the platelet counts had fallen to levels at which platelet transfusion support was necessary. Values for 111Indium autologous mean platelet lifespan were similar to those reported in thrombocytopenic patients by other authors. During the period of study, there was no significant change in mean platelet volume or platelet nucleotides. The results indicate that in man, platelet size and platelet nucleotides are not affected when platelets age in the peripheral circulation.

Sekeres: Amgen: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Graux:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavenagh:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Fenaux:Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. DeAngelo:Incyte: Other: Consulting or Advisory Role; Pfizer: Other: Consulting or Advisory Role; Novartis: Other: Consulting or Advisory Role; BMS: Other: Consulting or Advisory Role; ARIAD Pharmaceuticals Inc.: Other: Consulting & Advisory Role; Amgen: Other: Consulting or Advisory Role. Yee:Oncoethix: Research Funding; Astex: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Zhu:Celgene Canada: Membership on an entity's Board of Directors or advisory committees; Novartis Canada: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Valcarcel:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Borbenyi:Novartis: Membership on an entity's Board of Directors or advisory committees. Wegener:Novartis: Employment. Gazi:Novartis Pharma AG: Employment. Acharyya:Novartis Pharmaceuticals Corporation: Employment. Binlich:Novartis: Employment. Ottmann:Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract 4001

Historically, serum protein electrophoresis (SPE), urine protein electrophoresis (UPE) and immunofixation (IFE) have been used to identify and quantify monoclonal proteins (M-proteins). Whilst this approach is adequate for the identification of intact immunoglobulin multiple myeloma (MM), it is not sensitive enough to detect free light chain MM (LCMM). Therefore, an algorithm which utilises SPE, serum free light chain (FLC) immunoassays and IFE for the identification of M-proteins has been suggested. Assays have now been developed which utilise polyclonal antisera raised against the kappa and lambda light chain types of IgG, IgA and IgM immunoglobulins (HLC). Here we report the use of these assays as an alternative to IFE and propose a screening algorithm which utilises SPE, FLC and HLCSerum FLC measurement was added to 1063 requests for SPE, from primary care or from a hospital source. Samples from patients with previously diagnosed MM, Waldenstrom's Macroglobulinemia and lymphoma were, where possible, removed. Sera showing monoclonal proteins or hypogammaglobulinemia (by SPE) or an abnormal FLC ratio were tested further by IFE and IgG, IgA, IgM HLC assays. SPE and IFE were performed on a SEBIA Hydrasys system, and gels were interpreted by experienced clinical chemists. FLC and HLC measurements were performed on a Siemens BN™II nephelometer. HLC results were compared with IFE results and clinical diagnoses. The study was approved by the Wolverhampton, New Cross, NHS Trust Review Board80/1063 patients were identified as having abnormal SPE or abnormal FLC results. 42/80 patients had positive IFE results. 24/42 of these patients were positive by HLC (Table 1), 11/42 had light chain only myeloma/MGUS, the remaining 7/42 were MGUS patients. The 7 MGUS patients (6 IgG and 1 IgM) with normal HLC ratios and positive IFE all had less than 2g/L monoclonal protein measured by SPE densitometry and a normal FLC ratio. Of the 38/80 with normal IFE's all had been investigated further because of abnormal FLC results. 9/38 had abnormal HLC ratios of which 3/9 had confirmed hematological malignancies (1× chronic lymphocytic leukemia (CLL), 1× small lymphocytic lymphoma (SLL) and 1× asymptomatic MM (ASMM)).The use of FLC immunoassays alongside SPE as part of the primary screening protocol identified 10 additional hematological malignancies (1× ASMM, 6×CLL, 2× non-Hodgkin lymphoma, 1× SLL).HLC ratio analysis matched IFE for the identification of all symptomatic haematological malignancies. Abnormal FLC ratios identified 10 additional haematological malignancies of which 3 also had abnormal HLC ratios, which would have been missed using SPE/ IFE. In 7/19 MGUS (6×IgG, 1×IgM) patients there were normal HLC ratios. In all cases the monoclonal protein load was below 2g/L and the FLC ratio was normal; identifying the IgG patients as having a low risk and the IgM patient as having a low/intermediate risk of progression. It may be beneficial not to identify these patients, who do not require therapeutic intervention or justify close monitoring. Another advantage of using HLC analysis instead of IFE is that the HLC ratio has been found to be a prognostic indicator in myeloma and MGUS. It would also form a useful “baseline” comparison if HLC assays were used in monitoring or for the detection of residual disease.HLC analysis identified all symptomatic patients who were IFE positive and in an additional 3 hematological malignancies. Low risk MGUS patients may not be identified using these tests but this might be beneficial to patients and physicians alikeHarding: Binding Site Group Ltd: Employment.

Survival of elderly patients with de novo acute myeloid leukemia (AML) is poor. A single published study on patients with AML aged 80 years and above (DeLima et al., Br. J. Haematol. 1996; 93: 89) concluded that chemotherapy was not indicated since median overall survival (OS) of 29 treated patients was 1 month, 9 patients reached complete remission (CR) of 3 months median duration, and only two survived over 1 year: for 15.5 and >18 months. The aim of our study was to identify the characteristics of elderly AML patients who may reach CR by standard chemotherapy. We analyzed 9 consecutive patients with de novo AML aged 80–90 (median 83) years treated by us in 1992–2007. All bone marrow films were hypercelullar with 48–92 (median 80) % leukemic cells, classified as FAB types: 2 M2, 6 M4, and 1 M5. Six patients, all with hypertension and five with ischaemic heart disease (IHD), received chemotherapy, while 3 patients (82–87 years old) opted for supportive or palliative therapy and survived 1–4 months. Cytosine arabinoside (Ara-C) 100 mg/sqm/12 h in 3-h infusion for 7 days and 3 doses of daunorubicin (DNR) 45 mg/sqm/d i.v. (D+A, 1 case) or mitozantrone (MTZ) 10 mg/sqm/d i.v. (M+A, 3 cases) was given to 4 patients. The remaining two patients received D+A with thioguanine (TG) 100 mg/sqm/12 h p.o. for 7 days (TAD). Their WHO performance status (PS) was 4x PS3, 1x PS2, 1x PS1, and median WBC 58 (17.9–97.8) × 10^9/L. Three patients with AML M4 and normal karyotype reached CR. Maintenance therapy consisted of 4-day courses administered in intervals of 5–12 (median 8) weeks according to the patient's clinical status and tolerance until relapse. Courses containing Ara-C 60 mg/sqm/12h s.c. with TG 70 mg/sqm/12h p.o. were repeated 3x. The fourth course was 1+4 containing a single dose DNR or MTZ as described and Ara-C. The outcomes: An 85 year-old female with IHD and LVEF 25 % reached CR with TAD. She was on maintenance in CR for 17 months when severe heart arrhythmia developed. She refused a pacemaker implantation and died 3 days later. Her OS was 18.6 months. An 80 year-old male reached CR with M+A and was on maintenance therapy when relapsed after 19.7 months. He refused further chemotherapy and his OS was 28 months. An 80 year-old female (PS1, Flt3-ITD neg.) reached CR after D+A 3+7 and got one cycle D+A 2+5 without further maintenance. Her CR lasted 10.1 months. She was further treated with 2 cycles of low-dose Ara-C and her OS was 16.5 months. Three other patients, two with normal karyotype, did not reach CR after chemotherapy. A 90 year-old male with AML M4 died of mycotic pneumonia on the 24thday of TAD induction. An 83 year-old male with AML M5, PS2, experienced nonQ myocardial infarction after M+A induction and did not reach CR. He was further treated with hydroxyurea with OS of 2.7 months. An 80 year-old female with AML M2, complex karyotype, renal insufficiency and sepsis died after 7thhemodialysis in septic shock on 10thday of M+A induction. All three patients who reached CR did not exhibit dysplasia in erythroblastic or megakaryocytic lineage showing that only granulocyte-macrophage lineage was involved in the leukemic clone (single–lineage AMLs). In contrast, all 3 patients who did not reach CR exhibited megakaryocytic dysplasia in a half or more of megakaryocytes and two had erythroblastic dysplasia in more than 26% erythroblasts. They represent a different biological category of AMLs with multi-lineage involvement. In summary, we defined a biological category of single-lineage AML patients over 80 years of age who may benefit from standard dose chemotherapy in spite of their poor performance status.

There is increasing evidence that perturbations in chromatin structure contribute to the pathogenesis of AML raising the possibility that modulators of chromatin structure may be of therapeutic benefit. Sodium valproate (VPA) is a potent histone deacetylase inhibitor (HDI) and in conjunction with ATRA induces apoptosis of primary AML blasts in vitro. It has been postulated that induction of pro-apoptotic genes including p21 and TRAIL play a critical role in determining the tumor selectivity of HDIs. We have therefore conducted a Phase I/II study of combined VPA/ATRA therapy in patients with high risk AML ineligible for chemotherapy and correlated clinical response with alterations in chromatin structure, induction of pro-apoptotic genes and in vitro sensitivity to VPA. In light of evidence that modulating cAMP levels may increase rexinoid responsiveness theophylline was added in patients who had failed to respond to 28 days combined VPA/ATRA therapy. A total of 20 patients (median age 72 yrs) have been treated to date including 12 patients with relapsed AML, 6 with previously untreated disease and 2 with primary refractory disease. Nine patients completed treatment for at least 8 weeks. Four patients (all with relapsed AML) demonstrated a haematological response. One patient achieved a complete remission and two a partial remission. Myeloblasts isolated from trial patients prior to the commencement of therapy demonstrated varying sensitivity to VPA and ATRA in vitro which correlated with clinical response. Combined treatment with VPA and ATRA resulted in increased levels of histone acetylation and methylation and induced expression of p15, p16 and p21 in myeloblasts from treated patients. Induction of TRAIL was documented in three patients-two of whom demonstrated a clinical response. p21 induction was documented in all responding patients. Induction of p21 and TRAIL was most marked in the patient who achieved a CR. There was no apparent correlation between induction of p15 or p16 and response. We have previously documented that exposure of AML cell lines to HDIs results in specific changes in HDAC expression patterns with selective up-regulation of HDAC11 and to a lesser extent HDAC9 and SIRT4. Similar changes in HDAC expression were documented in myeloblasts from patients after 28 days treatment with VPA/ATRA. This study demonstrates that VPA, in combination with ATRA and theophylline, has significant clinical and biological activity and identifies possible mechanisms underlying the tumor-specific activity of VPA in AML in vivo.

Sir.—We read with interest the recent editorials1,2 and article3 on bicycle injuries in children. We report an additional complication of this pursuit seen in hemophiliac patients attending the Birmingham Children's Hospital in England.Patient Reports.—Over the 12 months preceding this report, four patients with severe hemophilia (VIII:C, &lt;0.01 U/mL) presented with obscure perineal or adductor compartment hematomas. All four patients had recently acquired BMX bicycles as Christmas or birthday presents, and their "spontaneous" bleeds were associated with BMX bicycle usage. There was no other history of trauma. Restriction of BMX bicycle activities prevented recurrence of the lesions. Many of our hemophiliac patients have bicycles, but this particular injury is rare and has been seen only in BMX riders. This may be due in part to the design of the saddle and in part to the athletic nature of BMX bicycle riding.Comment.—We would like