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Iron overload is considered a risk factor for mortality in patients with hematopoietic malignancies. Hepcidin is a key regulator of systemic iron balance. We previously reported dynamic changes of serum hepcidin-25 levels in patients with hematologic malignancies after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this study, we retrospectively analyzed the association of pretransplant hepcidin-25 levels with overall survival (OS), engraftment, and other clinical outcomes of allo-HSCT in patients with hematologic malignancies. A total of 166 patients were divided into two groups depending on their pretransplant serum hepcidin-25 levels; their median age was 49.5 years, and the median follow-up time was 46.8 months. At 3 years, the patients in the high-hepcidin group had a significantly lower OS than those in the low-hepcidin group (49.2 vs. 69.0%, respectively; P = 0.006). Multivariate analysis revealed that pretransplant serum hepcidin-25 level, sex, and disease status were independently associated with OS. The incidence of platelet engraftment was significantly lower in the high-hepcidin group than in the low-hepcidin group, whereas no significant differences were observed in neutrophil and reticulocyte engraftments between these groups. Hence, pretransplant serum hepcidin levels can be a marker for predicting delayed platelet recovery after allo-HSCT., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Virus-associated hemorrhagic cystitis (VAHC) is a formidable complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The standard management of severe VAHC after allo-HSCT has not been established. Intravenous administration of cidofovir (CDV), an acyclic nucleoside analogue with broad-spectrum activity against DNA viruses, has been reported to be effective for VAHC, but it can cause severe renal toxicity. Here we report four cases who achieved clinical responses with intravesical instillation of CDV for severe VAHC after allo-HSCT. Median age was 57 years (40-63), and all were male. The underlying diseases were hematological malignancies. Three had received bone marrow transplantation, and one received cord blood transplantation twice. Conditioning regimen was myeloablative for one, and reduced-intensity for three. The viral types were BK virus and/or adenovirus. Two patients had received CDV intravenously prior to the intravesical therapy. A dose of intravesical CDV was 2-5 mg/kg. In all cases, symptoms of cystitis improved dramatically within a few days without showing any systemic adverse effects. The virological response was observed in two cases. This local therapy was effective even in the cases refractory to the intravenous CDV and a case with severe renal failure. Along with the review of literature, we propose that the intravesical instillation of CDV can be a therapeutic option for severe VAHC after allo-HSCT., (Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a devastating complication of hematopoietic stem cell transplantation. TA-TMA likely represents the final stage of vascular endothelial injury; however, its pathophysiology is largely unknown, making clinical management difficult. Recently, the association of neutrophil extracellular traps (NETs) with the development of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome has been reported. Thus, we explored whether NETs are also relevant to the occurrence of TA-TMA. We retrospectively analyzed post-transplant trends of serum NET levels in 90 patients, 11 of whom developed TA-TMA. Relative to baseline (before the conditioning regimen), elevated serum NET levels either at 4 weeks after transplantation or as early as the day of transplantation were associated with significantly increased risk of TA-TMA. In contrast, thrombomodulin, a potential marker for TA-TMA, was not helpful to predict the occurrence of TA-TMA in our study. In addition, we directly detected glomerular deposition of NETs in 2 TA-TMA patients. Increased NET levels are a significant risk factor for TA-TMA, suggesting that NET level is a useful biomarker for TA-TMA., (Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Studies have suggested an association between pretransplant serum levels of ferritin and C-reactive protein (CRP) and complications of allogeneic hematopoietic stem cell transplantation (HSCT). To evaluate the prognostic impact of these biomarkers on the development of acute and chronic graft-versus-host disease (GVHD), we retrospectively studied 211 patients who underwent allogeneic HSCT for hematologic diseases at our institution. The cumulative incidence rate of chronic GVHD at 3 years was 40.7 %. In the multivariate analysis, elevated CRP levels (≥2 mg/L) were significantly associated with a high incidence of chronic GVHD, whereas high ferritin levels (≥880 ng/mL) showed a tendency, though not statistically significant, to association with a low incidence of chronic GVHD. No significant association was observed between the pretransplant serum ferritin or CRP levels and the incidence of acute GVHD. Multivariate analysis indicated that high pretransplant serum ferritin levels were significantly associated with increases in treatment-related mortality and relapse rates. Overall, an elevated pretransplant serum ferritin level, but not an elevated serum CRP level, is a strong risk factor for overall mortality (hazard ratio, 2.16; P = 0.002). Our results also indicate that pretransplant serum CRP levels may be a useful biomarker for predicting the risk of chronic GVHD.

Primary myelofibrosis is a hematologic neoplasm characterized by bone marrow fibrosis and extramedullary hematopoiesis. A similar clinical condition can occur at late stage of myeloproliferative neoplasms such as polycythemia vera and essential thrombocythemia. Although allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative strategy for both conditions, massive splenomegaly frequently observed in patients with myelofibrosis is considered to be a risk factor for graft failure or engraftment delay after transplantation. A proportion of patients can benefit from splenectomy before transplantation but such procedures have been associated with substantial surgical morbidity. Here, we report two elderly patients with myelofibrosis who received scheduled splenic irradiation for massive splenomegaly immediately prior to allogeneic HSCT instead of undergoing splenectomy. The first patient was a 60-year-old woman who received peripheral blood stem cell transplantation for post-essential thrombocythemia myelofibrosis from an HLA-identical sibling; the second patient was a 60-year-old man who received unrelated bone marrow transplantation for primary myelofibrosis. After receiving fractionated splenic irradiation and fludarabine-based reduced-intensity conditioning regimens, these patients showed remarkable reduction of their splenomegaly at the time of transplantation. They attained successful donor cell engraftment without severe complications related to splenic irradiation, while improvement in splenomegaly was durable. Our experience suggests that splenic irradiation before allogeneic HSCT might be a safe and effective alternative to splenectomy for myelofibrosis patients with massive splenomegaly in terms of reducing the risk of surgical morbidity.

Iron overload is frequently observed in patients with hematologic diseases before and after allogeneic stem-cell transplantation because they usually receive multiple red blood cell transfusions. Elevated pretransplant serum ferritin levels, which are widely used as indicators of body iron status, are significantly associated with a lower overall survival rate and a higher incidence of treatment-related complications; for example, infections and hepatic veno-occlusive disease. As serum ferritin levels are affected, not only by iron loading but also by inflammation, imaging techniques to quantify tissue iron levels have been developed, for example, quantitative MRI using the transverse magnetic relaxation rate, and superconducting quantum interference devices. Iron chelators, such as deferasirox, a new oral iron-chelating agent, reduce iron load in transfusion-dependent patients. Iron-chelating therapy before and/or after transplantation is a promising strategy to improve the clinical outcomes of transplant patients with iron overload. However, further research is needed to prove the direct relationship between iron overload and adverse outcomes, as well as to determine the effects of treatment for iron overload on outcomes of allogeneic stem-cell transplantation.

The association of iron overload with complications of allogeneic hematopoietic stem cell transplantation (HSCT) has been suggested in previous studies. Because hepcidin plays a central role in the regulation of iron homeostasis, we analyzed the association between pretransplant serum hepcidin-25 levels and early infectious complications after allogeneic HSCT. We studied 55 consecutive adult patients with a median age of 47 years (range: 20-64 years) who underwent allogeneic HSCT for hematologic malignancies at our institution. Thirty-two patients had myelogenous malignancies; the remaining 23 had lymphogenous malignancies. The median pretransplant serum hepcidin level of patients in the study was 21.6 ng/mL (range: 1.4-371 ng/mL), which was comparable to that of healthy volunteers (median: 19.1 ng/mL [range: 2.3-37 ng/mL]; n = 17). When cumulative incidences of documented bacterial and cytomegalovirus (CMV) infections at day 100 were compared according to pretransplant hepcidin-25 levels, the incidence of bacterial, but not CMV, infection, was significantly higher in the high-hepcidin group (> or = 50 ng/mL; n = 17) than in the low-hepcidin group (<50 ng/mL; n = 38) (65% [95% confidence interval, 38%-82%] versus 11% [3%-23%]; P < .001). This finding was confirmed by multivariate Cox analysis adjusted for confounders, including pretransplant ferritin and C-reactive protein (CRP) levels. No fungal infection was documented in either group. These results suggest that the pretransplant serum hepcidin-25 level may be a useful marker for predicting the risk of early bacterial complications after allogeneic HSCT. Larger prospective studies are, however, warranted to confirm our findings.

The relationship between serum hepcidin, a key regulator of body iron homeostasis, and erythropoiesis was investigated before and after stem cell transplantation in 31 patients with hematopoietic malignancies. Serum hepcidin-25 was monitored using a liquid chromatography-tandem mass spectrometry-based assay system. Other iron- and erythropoiesis-related parameters and known hepcidin regulators, such as interleukin-6 and growth differentiation factor-15, were also monitored. The serum hepcidin level peaked one week after stem cell transplantation, followed by a gradual decrease with a parallel change in interleukin-6 and a reciprocal change in reticulocyte count. Multivariate regression analysis demonstrated that the serum hepcidin level at four weeks after stem cell transplantation showed significant inverse correlations with erythropoietic activity markers, such as the soluble transferrin receptor, but not with growth differentiation factor-15. These results indicate the existence of an unknown functional erythropoiesis-associated circulating factor, other than growth differentiation factor-15, that negatively regulates hepcidin production in stem cell transplantation settings.

Although intravesical Bacillus Calmette-Guérin ( BCG) instillation is the standard treatment for carcinoma in situ of the bladder, it is generally contraindicated in immunocompromised patients. Here we report the first case, to our knowledge, of BCG treatment for a bladder cancer patient who had received umbilical cord blood stem cell transplantation ( UCBSCT). BCG can be given safely and effectively in select cases where reconstitution of the immune system has been achieved at least 2 years after UCBSCT. [ABSTRACT FROM AUTHOR]