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Background: Interleukin 6 mediates graft-versus-host disease (GVHD) in experimental allogeneic stem-cell transplantation (allogeneic SCT) and represents an attractive therapeutic target. We aimed to assess whether the humanised anti-interleukin-6 receptor monoclonal antibody, tocilizumab, could attenuate the incidence of acute GVHD., Methods: We undertook a single-group, single-institution phase 1/2 study at the Royal Brisbane and Women's Hospital Bone Marrow Transplantation unit, QLD, Australia. Eligible patients were 18-65 years old and underwent T-replete HLA-matched allogeneic SCT with either total body irradiation-based myeloablative or reduced-intensity conditioning from unrelated or sibling donors. One intravenous dose of tocilizumab (8 mg/kg, capped at 800 mg, over 60 mins' infusion) was given the day before allogeneic SCT along with standard GVHD prophylaxis (cyclosporin [5 mg/kg per day on days -1 to +1, then 3 mg/kg per day to maintain therapeutic levels (trough levels of 140-300 ng/mL) for 100 days plus methotrexate [15 mg/m(2) on day 1, then 10 mg/m(2) on days 3, 6, and 11]). The primary endpoint was incidence of grade 2-4 acute GVHD at day 100, assessed and graded as per the Seattle criteria. Immunological profiles were compared with a non-randomised group of patients receiving allogeneic SCT, but not treated with tocilizumab. This trial is registered with the Australian and New Zealand Clinical Trials Registry, number ACTRN12612000726853., Findings: Between Jan 19, 2012, and Aug 27, 2013, 48 eligible patients receiving cyclosporin and methotrexate as GVHD prophylaxis were enrolled into the study. The incidence of grade 2-4 acute GVHD in patients treated with tocilizumab at day 100 was 12% (95% CI 5-24), and the incidence of grade 3-4 acute GVHD was 4% (1-13). Grade 2-4 acute GVHD involving the skin developed in five (10%) patients of 48 treated with tocilizumab, involving the gastrointestinal tract in four (8%) patients; there were no reported cases involving the liver. Low incidences of grade 2-4 acute GVHD were noted in patients receiving both myeloablative total body irradiation-based conditioning (12% [95% CI 2-34) and fludarabine and melphalan reduced-intensity conditioning (12% [4-27]). Immune reconstitution was preserved in recipients of interleukin-6 receptor inhibition, but qualitatively modified with suppression of known pathogenic STAT3-dependent pathways., Interpretation: Interleukin 6 is the main detectable and dysregulated cytokine secreted after allogeneic SCT and its inhibition is a potential new and simple strategy to protect from acute GVHD despite robust immune reconstitution; a randomised, controlled trial assessing tocilizumab in addition to standard GVHD prophylaxis in these patients is warranted., Funding: National Health and Medical Research Council and Queensland Health., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The reconstitution of anti-viral cellular immunity following hematopoietic stem cell transplantation (HSCT) is crucial in preventing cytomegalovirus (CMV)-associated complications. Thus immunological monitoring has emerged as an important tool to better target pre-emptive anti-viral therapies. However, traditional laboratory-based assays are too cumbersome and complicated to implement in a clinical setting. Here we conducted a prospective study of a new whole blood assay (referred to as QuantiFERON-CMV®) to determine the clinical utility of measuring CMV-specific CD8+ T-cell responses as a prognostic tool. Forty-one evaluable allogeneic HSCT recipients underwent weekly immunological monitoring from day 21 post-transplant and of these 21 (51.2%) showed CMV reactivation and 29 (70.7%) developed acute graft-versus-host disease (GvHD). Patients with acute GvHD (grade ≥ 2) within 6 weeks of transplant showed delayed reconstitution of CMV-specific T-cell immunity (p = 0.013) and a higher risk of CMV viremia (p = 0.026). The median time to stable CMV-specific immune reconstitution was 59 days and the incidence of CMV reactivation was lower in patients who developed this than those who did not (27% versus 65%; p = 0.031). Furthermore, a failure to reconstitute CMV-specific immunity soon after the onset of CMV viraemia was associated with higher peak viral loads (5685 copies/ml versus 875 copies/ml; p = 0.002). Hence, QuantiFERON-CMV® testing in the week following CMV viremia can be useful in identifying HSCT recipients at risk of complicated reactivation.

We evaluated the efficacy of recombinant human interleukin-3 (rhIL-3) in reducing the number of platelet transfusions and major infections after autologous bone marrow transplantation (ABMT) in patients with malignant lymphoma. 198 patients with non-Hodgkin's lymphoma (NHL, n = 111) and Hodgkin's disease (HD, n = 87) were randomized to receive rhIL-3 10 microgram/kg/d (n = 130) or placebo (n = 68) for a maximum of 28 d after ABMT. Several well-known conditioning regimens were used. From day 1 after ABMT patients were treated with placebo or rhIL-3 at a dose of 10 microgram/kg/d by continuous i.v. infusion for 7 d and then by s.c. administration for 21 d or until platelet (50 x 109/l) and neutrophil (0.5 x 109/l) recovery had occurred. Treatment was completed in 54% of the patients in the rhIL-3 group versus 75% in the placebo group (P < 0.004). Adverse events were the main reason for premature discontinuation in the IL-3 group (23% IL-3 v 5% placebo). The median number of platelet transfusions was not significantly different between the IL-3 group and the placebo group (8.0 IL-3 v 6.0 placebo, P = 0.09). Platelet engraftment (>/= 20 x 109/l) was not significantly faster in the IL-3 group (28 d in the IL-3 and 27 d in the placebo group, P = 0.06) and the incidence of haemorrhagic complications was similar in both groups. In patients receiving the full intended dose of rhIL-3, platelet engraftment to >/= 20 x 109/l was delayed (P = 0.007). The median time to neutrophil engraftment was 23 d in the IL-3 and 25 d for the placebo group (P = 0.39). There was no difference in the incidence of major infections. We conclude that treatment with IL-3 has no clinical benefit in patients receiving ABMT for malignant lymphoma.

Little information has been published concerning the severity of pain experienced by bone marrow donors or the use of local analgesia following bone marrow harvesting procedures. The aims of this study were to assess duration and severity of pain experienced by bone marrow donors and the effectiveness of bupivacaine as a local analgesic agent following bone marrow harvest. During a single blinded randomised study of 24 bone marrow donors, 10 ml of 0.5% bupivacaine was infiltrated either into the right or left posterior iliac crest of the donor immediately following bone marrow harvest. Donors were requested to record the level of pain experienced at the right and left harvest sites on a pain rating score sheet (0-10) at time intervals of 4, 8, 12, 24, 48 and 72 h following harvest. A significant reduction in pain was experienced at the harvest site infiltrated with bupivacaine when compared with the control site during the first 3 days post-harvest. It is recommended that bupivacaine be infiltrated routinely into the harvest sites of all bone marrow donors to reduce the pain experienced in the 3 days following harvest.

We evaluated the role of rest and exercise left ventricular diastolic filling parameters as a marker of cardiotoxicity in 25 consecutive patients 1 year following BMT. Ten age- and sex-matched subjects served as controls. Patients were evaluated in toto and in three sub-groups according to chemotherapy. Left ventricular ejection fraction (EF), peak filling rate (PFR) and time to peak filling (TTPF) were assessed at rest and at peak exercise. EF and PFR were similar at rest and at peak exercise in patients and controls. TTPF was significantly prolonged at rest in patients compared to controls (200 +/- 65 vs 131 +/- 26 ms, P = 0.003) and at peak exercise was markedly longer in patients (142 +/- 40 vs 54 +/- 19 ms, P < 0.001). Sub-group analysis demonstrated abnormal resting TTPF in those patients who had received either combination anthracycline and CY or anthracycline and melphalan, while those patients who received CY alone had normal resting TTPF. However, exercise TTPF was abnormally prolonged in all patient groups. While all controls demonstrated a normal decrease in TTPF during exercise, four of the 25 patients had a paradoxical increase in TTPF during exercise. Exercise diastolic function may provide evidence of cardiotoxicity in long-term survivors of BMT.

We report the use of octreotide in 10 patients with severe diarrhea, refractory to loperamide, following bone marrow transplantation (BMT). Five patients had regime-related toxicity (RRT) and 5 were suffering from acute intestinal graft versus host disease (GvHD). Complete responses were observed for all patients with RRT, with optimal response being observed in the patients with dose escalation to 250 micrograms tds. Only partial responses were observed in the patients with intestinal GvHD. Increased doses of systemically administered cyclosporin-A (CSA) were necessary to maintain therapeutic levels for 2 patients. Octreotide is very effective in controlling RRT diarrhea. It is less effective in the control of GvHD-related diarrhea. CSA levels require close monitoring, whether the drug is administered systemically or orally.

Aplastic anaemia is a rare complication of systemic lupus erythematosus (SLE). The mechanism is unclear but is thought to be related to an autoantibody to bone marrow precursors of haematopoiesis. We report a case of SLE related aplastic anaemia in which therapy with methylprednisolone and high dose cyclophosphamide followed by prednisolone and azathioprine resulted in complete clinical and haematological remission. Bone marrow cultures showed inhibition of erythropoiesis when incubated with acute and remission serum. Myeloid colony growth was not affected by either serum. The serum inhibitor we demonstrated was only active in vitro, and we postulate that the mechanism for marrow aplasia may have been an autoimmune cellular process.

The human BK and JC polyomaviruses are known to be reactivated and excreted in the urine following bone marrow transplantation (BMT). A proportion of patients who excrete BK virus following BMT experience a haemorrhagic cystitis (HC), which may persist for many months. We report a case of human polyomavirus-associated HC, in whom treatment with vidarabine was associated with a dramatic response.

Acquired cystic disease of the kidney (ACDK) in patients with end-stage renal failure can be associated with development of polycythaemia. The relationship between plasma erythropoietin levels and ACDK in 17 patients on long-term haemodialysis treatment was studied. There was a significantly higher level of plasma erythropoietin in patients with multiple renal cysts than in those patients with less than five cysts or no cysts. Haemoglobin tended to be higher in the ACDK group, but the difference was not significant. These results indicate that the development of renal cysts results in increased secretion of erythropoietin.

The erythrocyte sedimentation rate has previously been identified as an important prognostic factor in Hodgkin's disease. The plasma viscosity has replaced the ESR measurement in many laboratories, but doubts exist about its clinical relevance. In this study plasma viscosity at presentation/diagnosis was studied in 107 patients with Hodgkin's disease. A multivariate analysis of factors influencing prognosis and relapse-free survival identified plasma viscosity and number of disease sites as being highly significant. The risk of relapse increases initially with a rise in plasma viscosity, but after a value of about 2.0 mPa.s no further increase in risk is observed. When all of the prognostic factors are made available to the proportional hazards model, treatment modality and plasma viscosity are selected as the best set for predicting time to first relapse. This study demonstrates that measurement of plasma viscosity at presentation is an important prognostic factor in Hodgkin's disease, in terms of predicting outcome or risk of relapse.

A 33 year old man developed fever, malaise, jaundice, pancytopenia, coagulation abnormalities, hepatomegaly, pleural effusions and a subcutaneous lump. Biopsies revealed a lobular panniculitis with the presence of cytophagic histiocytes; erythrophagocytosis was also demonstrated in the liver and bone marrow. Despite the use of chemotherapy (CHOP) his clinical condition deteriorated and he died 5 months after presentation. This illness is consistent with the recently described syndrome of histiocytic cytophagic panniculitis.

We describe a case of neutrophil aplasia in a woman with recurrent myasthenia gravis and a past history of thymoma. Bone marrow showed virtually absent granulopoiesis but normal erythropoiesis and megakaryopoiesis. Bone marrow cultures showed no growth of granulocyte/mononuclear cell progenitors (CFU-GM). She was treated with immunosuppression including azathioprine, and her neutrophil count returned to normal. Serum before treatment, and also an IgG fraction thereof, inhibited CFU-GM growth both in autologous 'remission' marrow and in allogeneic marrow. She remains in complete remission 36 months after starting azathioprine. This association is extremely rare, and was formerly associated with a grim prognosis.

A method for the detection of immunoglobulin light chain mRNA by situ hybridization has been applied to routine bone marrow trephines, from patients suspected of having multiple myeloma. The principle aim was to define monoclonal populations even in cases lacking a paraprotein or an obvious atypical plasma cell proliferation. The expression of light chain mRNA in plasma cells in routine bone marrow trephines from 14 patients with suspected myeloma was studied. Plasma cells in the marrow ranged from 4% to 99%. Clonal populations based on light chain restriction were delineated in 12 patients, using biotinylated probes to kappa and lambda mRNA and visualized using an alkaline phosphatase/fast red naphthol capture method. Normal tonsil and bone marrow trephines were used as controls. In situ hybridization was found to be a specific, safe and rapid technique. It could be applied to both fixed and fresh tissue. It was found to lack the background staining of interstitial immunoglobulin, particularly in sclerotic cases, which is so often encountered with immunocytochemistry. Additionally, this technique will type plasma cell neoplasms (undetected by routine immunocytochemistry) in post-transcriptional block or non-secretory myeloma.

A 22-yr-old man with aplastic anaemia was treated with high dose methylprednisolone. A month later he developed severe epistaxis which was not controlled by regular platelet transfusions. A balloon catheter inserted into the left nostril caused necrosis of the left ala nasi accompanied by gross facial oedema. He received treatment with horse ALG for aplastic anaemia but developed gross facial oedema and anaesthesia of incisor and canine teeth on the right side. Radiographs initially showed thickening of the maxillary antral mucosa and later erosion of the maxilla over the anaesthetic region. A biopsy specimen of this region contained hyphae of zygomycetes. He was treated with amphotericin B and a second course of antilymphocyte globulin followed by oxymetholone. He has made a satisfactory clinical and haematological recovery.