Yasunobu Takeoka

Impact of relative dose intensity (RDI) in CHOP combined with rituximab (R-CHOP) on survival in diffuse large B-cell lymphoma

BackgroundRecently, maintaining higher relative dose intensity (RDI) of chemotherapeutic drugs has become a widespread practice in an attempt to achieve better outcomes in the treatment of aggressive lymphoma. The addition of rituximab to chemotherapy regimens has significantly improved outcome in diffuse large B-cell lymphoma (DLBL). However, it is unknown if higher RDI in chemotherapy when combined with rituximab leads to a better outcome in aggressive B-cell lymphoma.MethodsWe retrospectively evaluated the impact of the RDI of initial chemotherapy (consisting of cyclophosphamide, doxorubicin, vincristine and prednisolone with rituximab (R-CHOP) on outcome in 100 newly diagnosed DLBL patients.ResultsA multivariate Cox regression model showed that RDI trended towards a significant association with mortality [hazard ratio per 0.1 of RDI = 0.8; 95% confidence interval 0.6–1.0; P = 0.08]. Additionally, on multivariate logistic analysis, advanced age was a significant factor for reduced RDI.ConclusionOur data suggest that in DLBL patients, mortality was affected by RDI of R-CHOP as the initial treatment, and the retention of a high RDI could therefore be crucial.

Prognostic value of serum surfactant protein D level prior to transplant for the development of bronchiolitis obliterans syndrome and idiopathic pneumonia syndrome following allogeneic hematopoietic stem cell transplantation.

Bronchiolitis obliterans syndrome (BOS) and idiopathic pneumonia syndrome (IPS) cause high mortality and impaired survival after allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Early recognition of patients at high risk of developing BOS/IPS may lead to improving the outcome of allo-HSCT. We retrospectively analyzed serum surfactant protein A, D (SP-A, -D) and Kerbs von Lungren 6 Ag (KL-6) levels before allo-HSCT in 56 patients who survived more than 90 days after allo-HSCT and compared values of these serum markers and other transplant factors in BOS/IPS patients with those in non-BOS/IPS patients. Five patients developed BOS and two developed IPS at a median interval of 303 and 117 days (range, 100–452 and 95–153) from transplantation. As a result of univariate analysis, pretransplant serum SP-D levels but not SP-A, KL-6 in BOS/IPS patients were significantly lower than those in non-BOS/IPS patients (P=0.03). In multivariate analysis, the patients with lower pretransplant serum SP-D level had a trend toward frequent development of BOS/IPS (P=0.08). Constitutive serum SP-D level before allo-HSCT may be a useful, noninvasive predictor for the development of BOS/IPS.

Efficacy and safety of intravenous itraconazole as empirical antifungal therapy for persistent fever in neutropenic patients with hematological malignancies in Japan

Recently, empirical antifungal therapy with intravenous itraconazole (ITCZ) for neutropenic patients with antibiotics-resistant fever has been approved by Japanese Ministry of Health, Labour and Welfare on the bases of previous multicenter trials of foreign countries. In this study, we conducted a single-arm, multicenter, prospective study in order to evaluate the efficacy of empirical ITCZ injection on Japanese patients. Sixty-eight patients with hematological diseases who underwent anticancer chemotherapy or stem cell transplantation were enrolled. In this study, we found that the overall clinical response rate to ITCZ injection was 67.6% and success rate of achieving composite endpoints including survival, defervescence during neutropenia, no breakthrough fungal infections, and no premature discontinuation of drug was 50.0%. Mild adverse reactions were observed in 6 patients (8.8%). Further analysis revealed that possible/probable deep fungal infection according to the 2002 and 2008 criteria defined by EORTC/MSG were found in 19.1 and 7.5% of the patients, respectively. Interestingly, response rate to ITCZ injection of possible/probable cases according to the 2002 and 2008 criteria was 61.5% (8/13) and 100% (5/5), respectively. These results not only proved the good efficacy and safety of empirical ITCZ injection for Japanese patients, but also indicated a utility of the drug on future “presumptive” approach.

Primary refractoriness to platelet transfusion caused by Naka antibody alone

Anti‐Naka, a platelet‐specific antibody, occasionally causes platelet‐transfusion refractoriness (PTR) together with human leucocyte antigen (HLA) antibodies. Anti‐Naka usually appears after frequent platelet transfusions or pregnancy. We report the first case of PTR caused by anti‐Naka alone.

Virus-associated hemophagocytic syndrome due to rubella virus and varicella-zoster virus dual infection in patient with adult idiopathic thrombocytopenic purpura

Abstract. A 26-year-old woman with idiopathic thrombocytopenic purpura (ITP) was admitted to our hospital because of fever and rash. Blood tests revealed thrombocytopenia, liver dysfunction, coagulopathy, and hyperferritinemia. Bone marrow examination revealed many atypical lymphocytes and some histiocytes with hemophagocytosis. On admission she was diagnosed with rubella virus-associated hemophagocytic syndrome (VHAS), but on laboratory examination, she was seropositive for varicella-zoster virus (VZV)-IgM as well as rubella virus-IgM. She was therefore diagnosed with dual infection by rubella virus and VZV. Her simultaneous rubella virus and VZV infection may have been related to the VAHS pathogenesis. She was treated with prednisolone and gamma globulin therapy and recovered completely.

Two cases of ampulla (takotsubo-shaped) cardiomyopathy associated with hemophagocytic lymphohistiocytosis.

There have been many reports of patients with ampulla cardiomyopathy described as takotsubo-shaped cardiomyopathy in the cardiovascular field. This unique cardiomyopathy is characterized by transient apical ballooning and hypokinesis of the left ventricle. We describe 2 cases of ampulla cardiomyopathy associated with hemophagocytic lymphohistiocytosis (HLH). In both of the patients, ventricular dysfunction suddenly occurred during the active phase of HLH. In each case, the findings on ECG, echocardiogram and left ventriculogram were compatible with ampulla cardiomyopathy. To our knowledge, this communication is the first to report cases of ampulla cardiomyopathy associated with HLH. Our cases suggest that HLH hypercytokinemia may have a role in causing ampulla cardiomyopathy.

Serum Cytokine Profiles at the Onset of Severe, Diffuse Alveolar Hemorrhage Complicating Allogeneic Hematopoietic Stem Cell Transplantation, Treated Successfully with Pulse Intravenous Cyclophosphamide

A 59-year-old man with lymphoma-type adult T-cell leukemia/lymphoma was admitted to hospital for treatment of a skin relapse on day 398 after allogeneic hematopoietic stem cell transplantation (allo-HSCT). To induce a graft-versus-adult T-cell leukemia/lymphoma effect, we discontinued methylprednisolone and tacrolimus. About a month after the discontinuation, he developed grade II acute graft-versus-host disease (GVHD) with a high fever. Soon after the development of GVHD, all the skin lesions regressed in size and finally vanished. However, he developed diffuse alveolar hemorrhage (DAH), which was resistant to high-dose corticosteroid therapy. He was intubated for respiratory insufficiency on day 451. Cyclophosphamide pulse therapy was administered at a dose of 1 g per day for 2 days and his oxygen saturation then improved, and ventilatory support was released on day 465. On analysis of cytokine profiles at the onset of DAH, we found elevated serum levels of T-helper 2 cytokines as well as T-helper 1 cytokines, suggesting that both T-helper 1 and T-helper 2 cytokines might play a role in the occurrence of DAH following allo-HSCT. Pulse cyclophosphamide treatment might be very effective in suppressing the exaggerated allogeneic immune response in DAH.

A case of a long-time survivor with chronic active Epstein-Barr virus infection.

Epstein–Barr virus (EBV) is associated with hypersensitivity to mosquito bites (HMB) and fatal EBV‐associated hemophagocytic syndrome (HPS). The prognosis of patients with chronic active EBV infection (CAEBV) is very poor. We report a rare case of an adult woman patient with a 28‐yr history of HMB, who developed EBV‐HPS. EBV genome was detected in the serum and peripheral blood lymphocytes. Clonal proliferation of EBV was demonstrated by Southern blot analysis using an EBV genome terminal‐repeat probe. This is a very rare case of a long‐term survivor with CAEBV. The patient was initially treated with immunochemotherapy and achieved complete remission. However, the patient immediately relapsed and underwent allogeneic bone marrow transplantation (BMT) from her HLA‐matched brother. Peripheral blood cell recovered well, and EBV genome disappeared from the peripheral blood. Allogeneic BMT may be effective in eradicating EBV‐HPS. Unfortunately, the patient died of graft vs. host disease on the 92nd day after BMT.

Promising therapeutic option for cutaneous plasmacytosis: 308-nm excimer lamp

Figure 1. (a) The patient, a 74-year-old man. On his trunk, 10–15-mm multiple infiltrating erythemas had presented. (b) The 311-nm narrowband ultraviolet B (NBUVB) therapy was performed once a week at an initial irradiation dose of 0.2 J/cm. The dose was gradually increased at each visit, and reached 0.8 J/cm 20 weeks after the start of treatment. In March 2017, the 311-nm NBUVB therapy at a total 58 J/cm showed only a slight effect on the cutaneous plasmacytosis (CP). (c) The 308-nm excimer lamp therapy was performed once a week at an initial irradiation dose of 100 mJ/cm. The dose was gradually increased at each visit, and reached 220 mJ/cm 12 weeks after the start of treatment. In November 2017, the 308-nm excimer lamp therapy at a total of 9 J/ cm showed a full effect on the CP. No obvious adverse events were observed. (d,e) Perivascular, periadnexal and lobular infiltrations of mature plasma cells were observed in the dermis to subcutaneous fat, histopathologically (hematoxylin–eosin, [d] scanning magnification, [e] 9400). (f,g) No light chain restriction was detected by in situ hybridization for Igjand Igk-chain (j/k ratio, 0.6; [f] Igj 9200; [g] Igk 9200).

Refractoriness to platelet transfusion in acute myeloid leukemia correlated with the optical density of anti-platelet factor 4/heparin antibodies

A small number of reports have described cases of heparin-induced thrombocytopenia complicating hematological disorders with impaired platelet production. We describe the case of a 66-year-old woman with acute myeloid leukemia who exhibited unexplained refractoriness to platelet transfusion, while receiving heparin flushes, and was found to have anti-platelet factor 4 (PF4)/heparin antibodies with high optical density (OD) values (>2 units) detected by an enzyme-linked immunosorbent assay. After cessation of heparin flushes, her refractoriness to platelet transfusion resolved. We retrospectively confirmed that the OD values for anti-PF4/heparin antibodies declined gradually; refractoriness to platelet transfusion resolved when the OD values fell below 1.0 units. Given the absence of any other evident explanation for this phenomenon, and the correlation between the OD values for anti-PF4/heparin antibodies and the efficacy of platelet transfusions, we conclude that the patient’s refractoriness to platelet transfusion was most likely caused by anti-PF4/heparin antibodies that had platelet-activating properties.