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The key nuclear export protein CRM1/XPO1 may represent a promising novel therapeutic target in human multiple myeloma (MM). Here we showed that chromosome region maintenance 1 (CRM1) is highly expressed in patients with MM, plasma cell leukemia cells and increased in patient cells resistant to bortezomib treatment. CRM1 expression also correlates with increased lytic bone and shorter survival. Importantly, CRM1 knockdown inhibits MM cell viability. Novel, oral, irreversible selective inhibitors of nuclear export (SINEs) targeting CRM1 (KPT-185, KPT-330) induce cytotoxicity against MM cells (ED50

We have investigated, in a group of regular blood donors, the effect of donating a unit of blood on blood haemoglobin concentration, serum iron and ferritin over a three week study period. The fall in haemoglobin was not significant but the fall in serum iron reached statistical significance (P < 0.05). Serum ferritin fell significantly in the female donors (P < 0.05). We compared the use of Brand' Essence of Chicken, a traditional Chinese remedy for blood replenishment and alleviating tiredness, with placebo in a double-blind study on these changes. Haemoglobin and ferritin were not affected by the essence but serum iron in female donors returned to pre-donation levels at the end of the study only in those taking essence. This response is greater than would be expected from the iron content of the essence and the relevance of this finding is discussed.

Epidemiology data on multiple myeloma (MM) occurrence and outcome is inconsistent whilst a major limitation of randomized controlled trials is selection bias. We present a population-based analysis of patients diagnosed with MM in the South Thames area, which comprises 5.4 million adult inhabitants. A total of 855 cases of MM were ascertained between 1999 and 2000 in a collaborative project involving haematologists and the Thames Cancer Registry. The age-standardized rate was 3.29 per 100 000 and 4.82 cases per 100 000 (World Standard and European Population respectively). The median age was 73 years. The median survival for the whole group was 24 months whist it was 42 and 18 months in those aged less than 65 years and greater than 65 years respectively (P0.001). This population study has shown a higher incidence than previously reported in the UK and Europe and provides a benchmark for future studies. If survival is to be improved, future clinical trials and health care planning should consider patients over 65 years of age.

High dose chemoradiotherapy with autologous peripheral blood progenitor cell transplantation (PBPCT) may improve outcome in myeloma. Melphalan is an effective drug in the treatment of myeloma, but is potentially toxic to progenitor cells. We studied 8 patients receiving intermittent intravenous melphalan (25 mg/m2) as induction therapy before PBPCT to assess engraftment characteristics post-transplantation. Comparison was made with an age-matched control group of patients with non-Hodgkins lymphoma who had not received melphalan during induction therapy. There was correlation (P=0.037) between the dose of melphalan per kg body weight given, premobilization, and days to neutrophil engraftment, but no significant difference between the two groups in neutrophil recovery. The study group had delayed platelet recovery (P=0.01) and required more platelet support post-transplantation (P=0.05). 3-4 weekly melphalan (25 mg/m2) up to 6 courses was delivered to patients who went on to PBPCT without significantly influencing neutrophil recovery but with a negative impact on platelet recovery.

The failure of conventional chemotherapy to eradicate chronic lymphocytic leukaemia cells and induce cure has led many clinicians to investigate the use of high dose chemotherapy and haemopoietic stem cell rescue in this disease. The selection of patients remains a major problem because this is a disease of elderly patients with a median overall survival of 7 years and will only therefore be applicable to a minority of patients. However transplantation is the most likely therapeutic option at this time to lead to cure in this condition. The best type of transplant is not known and not all patients will be able to mobilise adequate numbers of stem cells or have a suitable donor identified. Autologous transplantation relies on the ability of high doses of chemotherapy to eradicate disease whilst allogeneic transplantation attempts to harvest the graft versus leukaemia effect that has been identified in chronic granulocytic leukaemia. However, the high treatment related mortality and morbidity of allogeneic transplants has led to interest in the use of non-myeloablative allografts which hope to maximise the immunological effects of transplantation to achieve durable remissions. To date there have been no randomised clinical trials to compare the efficacy of combination chemotherapy, autologous or allogeneic transplants and this is unlikely to happen in the near future. Other issues that need to be addressed include the timing of transplantation, the source of stem cells, the optimal conditioning regimen and the role of immunomodulation post transplantation. This review attempts to answer some of these questions.

Bone marrow or stem cell transplantation is an established therapy for haematological malignancies. We report a cytomegalovirus (CMV) IgG +ve 56-year-old patient who underwent autologous rescue with CD34(+) selected peripheral blood stem cells as part of consolidation therapy for multiple myeloma and subsequently developed CMV colitis. In contrast to infection secondary to human immunodeficiency virus (HIV), CMV colitis has not previously been described in this context. We discuss this case and issues arising from it related to the use of CD34+ selected stem cells for transplantation.

Fluconazole is widely used as antifungal prophylaxis but it is ineffective against Aspergillus. Itraconazole has a broader spectrum of activity but the capsules give erratic bioavailability in neutropenic patients. We compared itraconazole oral solution (which has an improved pharmacokinetic profile) with fluconazole for antifungal prophylaxis. Adults with haematological malignancies receiving chemotherapy or bone marrow transplants were randomly allocated 5 mg/kg/d itraconazole (itra) solution (288 episodes) or 100 mg fluconazole suspension (flu) (293 episodes) from before the onset of neutropenia until neutrophil recovery or suspected fungal infection. Outcomes were assessed by independent reviewers unaware of the prophylaxis allocation. More proven systemic fungal infections occurred in flu (Aspergillus four, Candida tropicalis one, C. krusei one) than itra (C. albicans one) and more of these were fatal (four versus nil). This difference reached statistical significance when first study episodes were considered separately (six flu versus nil itra, P = 0.03). Significantly more deaths of presumed fungal origin occurred in flu than itra (seven versus nil, P = 0.024). There were significantly more cases of proven aspergillosis in flu than itra (six versus nil, P = 0.038, 5/6 cases were fatal) if those occurring outside the study period are included. Significantly more patients receiving flu required amphotericin B (58 v 39, P = 0.043) but this may have been affected by the fact that the study was not blinded. There were 11 proven mucosal candidal infections in flu and four in itra. Itraconazole solution and fluconazole provide effective prophylaxis against Candida but itraconazole affords greater protection against fatal aspergillosis.

Tests for folate and vitamin B12 deficiency are frequently requested by clinicians in many different specialties. An audit of folate assay methodology was undertaken to establish the number of tests and types of assay performed in different centres, and to analyse the indications for these investigations, with a view to advising on the most appropriate assay for use in the laboratory. A questionnaire was sent to 30 centres, 24 (80%) of which participated in the audit. The types of folate assay performed, number of requests, reference range and method of analysis differed between centres. The major specialty users of the service were general practitioners, general physicians and geriatricians. A detailed analysis of 1,259 consecutive requests for folate assays from a single representative laboratory showed a significant correlation between serum and red cell folate levels (r = 0.49, p < 0.001). However, in patients with low serum folate, there was no correlation with red cell folate in the absence of macrocytosis. The major indication for folate analysis was for haematological abnormalities but 36% of cases were for nonspecific indications. A haematologist with an interest in folate metabolism was invited to moderate the results at an audit meeting of haematologists. The consensus was that the most appropriate screening test for folate deficiency is the serum assay, which can be combined easily with vitamin B12 assay.

Summary The metabolism and antagonism of vitamin K has been studied in cultured fibroblasts. Monolayers of 3T3 mouse fibroblasts (grown in the absence or presence of warfarin or other putative antagonists) were incubated for 24 h with [1′, 2′-3H2]phylloquinone (K1) or [1′,2′-3H2]phylloquinone epoxide (K1O), the cells harvested and lipid extracts fractionated by high performance liquid chromatography. [3H]K1 was converted to [3H]K1O (about 20% of [3H] lipids) and to unidentified polar metabolites (30%). [3H]K1O was converted to [3H]K1 (3%) and to polar metabolites (50%). Cells grown with warfarin showed a marked increase in the [3H]K1O:K1 ratio and in the proportion of polar metabolites. The metabolic interconversion of K1 and K1O and inhibitory response to warfarin provide evidence for a fibroblast pathway analogous to the vitamin K-epoxide cycle in the liver. From the K1O:K1 ratios it was possible to grade the antagonism of vitamin K epoxide reductase activity by known and suspected inhibitors. Inhibitory ratios were seen for racemic warfarin down to 10−8m. S-warfarin was a more potent antagonist than the R-enantiomer. Consistently low K1O:K1 ratios were observed for N-methyl-thiotetrazole and antibiotics with (moxalactam) or without (cefotaxime) this side chain suggesting that none of these compounds are direct inhibitors of vitamin K epoxide reductase. Fibroblasts grown in cell culture provide a useful model to study the extrahepatic role of vitamin K and the mode of action of vitamin K antagonists.

The intracytoplasmic inclusions seen in most cells from a patient with B prolymphocytic leukaemia were analysed using both light and electron microscopy. They consisted of a dense homogeneous structure and were surrounded by a membrane, which had no continuity with the Golgi cisternae or the endoplasmic reticulum; some inclusions had a clear association with small lysosomal granules. Immunofluorescence and immunoperoxidase studies using light microscopy failed to elucidate completely the nature of the inclusions, but immunocytochemical reactions performed using electron microscopy suggested an immunoglobulin nature. All inclusions were negative for acid phosphatase and periodic acid Schiff. The nature of the inclusions described in the prolymphocytes of this patient were compared with those previously recorded in B prolymphocytic leukaemia.