Muneo Ohshiro

Absence of pseudomembranes in Clostridium difficile-associated diarrhea in patients using immunosuppression agents.

Objective. Clostridium difficile is a major cause of diarrhea in hospitalized patients. Although pseudomembranes are crucial evidence for diagnosis of C. difficile-associated diarrhea (CDAD), some cases do not show any pseudomembranes. The aim of this study was to verify the hypothesis that pseudomembranes are not generated in immunosuppressed patients because of the absence of immunoreactions. Material and methods. We investigated the endoscopic findings of patients with ulcerative colitis (UC) or who had received hematopoietic stem cell transplantation, and who presented with C. difficile toxin A and had undergone colonoscopy between April 2002 and July 2007 at our institutes. Results. In 4 patients the diagnosis was UC and C. difficile infection, and in another 4 patients the diagnosis was CDAD after hematopoietic stem cell transplantation. None of these cases showed pseudomembranes. Shallow ulcers were found in all four cases with UC. Only non-specific findings were obtained for the CDAD patients after hematopoietic stem cell transplantation. Conclusions. Pseudomembranes, the typical evidence for CDAD, were not detected in any patients using immunosuppressive agents. Additional bacterial examination is therefore essential when UC becomes exacerbated and when patients present with diarrhea after hematopoietic stem cell transplantation, even in the absence of pseudomembranes.

Identification of IGHCδ-BACH2 fusion transcripts resulting from cryptic chromosomal rearrangements of 14q32 with 6q15 in aggressive B-cell lymphoma/leukemia.

In B‐cell malignancies, genes implicated in B‐cell differentiation, germinal center formation, apoptosis, and cell cycle regulation are juxtaposed to immunoglobulin loci through chromosomal translocations. In this study, we identified the BTB and CNC homology 2 (BACH2) gene as a novel translocation partner of the immunoglobulin heavy chain (IGH) locus in a patient with IGH‐MYC‐positive, highly aggressive B‐cell lymphoma/leukemia carrying der(14)t(8;14) and del(6)(q15). Fluorescence in situ hybridization analysis using an IGH/MYC probe detected an IGH‐MYC fusion signal on der(14) and IGH signal on del(6). Genome copy number analysis showed a deletion in the 6q15‐25 region and a centromeric breakpoint within the BACH2 gene. cDNA bubble polymerase chain reaction using BACH2 primers revealed that the first exon of Cδ was fused to the 5′‐untranslated region of BACH2 exon 2. The Cδ–BACH2 fusion transcript consisted of exon 1 of Cδ and exons 2 to 9 of BACH2, encompassing the entire BACH2 coding region, and the BACH2 was highly expressed in this patient. These results indicate that Cδ–BACH2 fusion may cause constitutive activation of BACH2. Although additional screening of 47 samples of B‐cell non‐Hodgkins lymphoma (B‐NHL) patients and 29 cell lines derived from B‐cell malignancies by double‐color fluorescence in situ hybridization analysis detected a split signal with deletion of centromeric region of BACH2 only in a patient with follicular lymphoma, BACH2 was highly expressed in lymphoma cells of the patient and B‐NHL cell lines with IGH‐MYC translocation. These findings suggest that BACH2 plays a critical role in B‐cell lymphomagenesis, especially related to IGH‐MYC translocation in some way.

Cyclosporine A for Chemotherapy-Resistant Subcutaneous Panniculitis-Like T Cell Lymphoma with Hemophagocytic Syndrome

Subcutaneous panniculitis-like T cell lymphoma (SPTL) is a rare subtype of non-Hodgkin lymphoma for which a definitive therapeutic strategy has not been established yet. We report a case of chemotherapy-resistant SPTL with hemophagocytic syndrome (HPS) which was successfully treated with cyclosporine A (CsA) plus methylprednisolone (mPSL), and also reviewed 11 SPTL cases treated with CsA, previously reported in the literature. Our patient was a 38-year-old female with SPTL. The disease progressed despite conventional chemotherapy using cytotoxic agents including alkylators, anthracyclins or purine analogues, and, after 2 months of chemotherapy, was eventually complicated by HPS and disseminated intravascular coagulation (DIC). CsA (4 mg/kg/day) plus mPSL treatment dramatically improved HPS with DIC, reduced subcutaneous tumors within 2 weeks, and finally induced complete remission (CR) after 3 months. Currently, the patient has maintained CR while being treated with CsA for 12 months. In addition to our case, 9 of 11 SPTL cases were successfully treated with CsA, and 8 were induced to CR. Time to first response to CsA was within 2 weeks in most cases, regardless of prior treatment or the co-occurrence of HPS. Our case and this first comprehensive review on CsA for SPTL suggest that CsA may constitute a candidate treatment strategy for SPTL.

Expression of Master Regulators of Helper T-Cell Differentiation in Peripheral T-Cell Lymphoma, Not Otherwise Specified, by Immunohistochemical Analysis

The normal counterparts of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) have not been accurately identified. We immunohistochemically analyzed 10 PTCL-NOS cases to examine the expression of the master regulators of T-cell differentiation and of surface antigens, including chemokine receptors. All cases were positive for the master regulator of helper T cells (Th-POK) and the marker of effector T cells (CD45RO). Three cases each were positive for T-Bet and GATA3, which are master regulators of helper T cells (T(H) ) type 1 (T(H)1) and 2 (T(H)2), respectively. Two cases were positive for the surface antigens of central memory (Tcm) (CCR7 and CD62L), and 1 case was positive for follicular helper T-cell (TFH) phenotype (BCL6, CXCL13, and PD-1). The remaining case was negative for all markers of effector T(H) subtypes. These results suggest the postulated normal counterparts of PTCL-NOS identified in 9 of the 10 cases consist of T(H)1, T(H)2, TCM, and TFH.

Risk factors for infection in haematology patients treated with rituximab

Objectives:  Although rituximab therapy is not considered to be closely associated with infection, there have been reports of serious infections in patients treated with rituximab. We performed a statistical retrospective analysis to clarify the risk factors for infection in patients receiving rituximab therapy.

ADAMTS-13 activity can predict the outcome of disseminated intravascular coagulation in hematologic malignancies treated with recombinant human soluble thrombomodulin.

We conducted a multicenter prospective study for evaluating the utility and prognostic markers of recombinant human soluble thrombomodulin (rTM) treatment for acute disseminated intravascular coagulation (DIC) by various types of hematologic malignancies. The study comprised 30 patients with DIC due to hematologic diseases without severe infection. DIC improved in 15 patients and 20 were alive on day 28. Univariate analyses showed that, in comparison with patients who had survived on day 28, patients who had not survived on day 28 showed significantly higher plasma levels of plasminogen activator inhibitor‐I (PAI‐I) and significantly lower plasma activity of a disintegrin and metalloproteinase with a thrombospondin Type 1 motif, member 13 (ADAMTS‐13). Moreover, multivariate logistic regression analysis identified a significant association between plasma ADAMTS‐13 activity before treatment and survival on day 28 (P = 0.034). In particular, patients with lower ADAMTS‐13 activity (≤65%) had a poorer survival rate than those with a higher activity (P = 0.042). These findings suggest that the plasma ADAMTS‐13 activity at the time of DIC diagnosis might help to predict the prognosis of patients treated with rTM for DIC associated with hematologic malignancies. Am. J. Hematol., 2012.

Comprehensive cytogenetic study of primary cutaneous gamma-delta T-cell lymphoma by means of spectral karyotyping and genome-wide single nucleotide polymorphism array.

Primary cutaneous gamma-delta T-cell lymphoma (PCGD-TCL), which originates from activated mature gamma-delta T cells with a cytotoxic phenotype is a rare T-cell lymphoproliferative disease. The prognosis of PCGD-TCL has been rather unfavorable due to poor response to conventional chemotherapy, and its molecular features and pathophysiology underlying disease development remain unknown. We report here a case with primarily treatment-resistant PCGD-TCL featuring highly complex cytogenetic and genetic aberrations detected by spectral karyotyping and genome-wide single nucleotide polymorphism (SNP) array. Chromosomal aberrations included several chromosomal translocations involving breakpoints at 9p21, 14q11.2, 14q32.1, or 16q23.1, suggesting the involvement of WWOX, TCL gene cluster, and BCL11B, which are crucial for tumorigenesis in T-cell lymphomas. SNP analysis also identified genome copy number gains and losses in various regions, which can potently deregulate expression of various pro- and anti-oncogenic genes involved in RAS-related protein pathways, PI3K/AKT/MTOR-related pathways, MYC-related signaling, or TP53-related signaling. Thus, this case report may shed some light on the complex molecular abnormalities involved in the development of PCGD-TCL and on information that can aid the search for druggable target molecules in this disease.

Clostridium difficile-associated diarrhea with hematochezia is associated with ulcer formation.

Objective. Clostridium difficile-associated diarrhea (CDAD) is a well-known iatrogenic infection with typical endoscopic features including pseudomembranes and intervening normal mucosa. Clinically, diarrhea frequently occurs, but occurrence of hematochezia is rare. The objective of this study was to investigate the background and endoscopic features of CDAD patients with hematochezia. Material and methods. The endoscopic and clinical findings in 12 patients who showed evidence of C. difficile toxin A and who underwent colonoscopy between April 2002 and July 2007 were investigated retrospectively. Results. Eight patients were diagnosed as having CDAD and 4 patients had a diagnosis of ulcerative colitis. Six of the patients with CDAD presented with hematochezia, and 4 of them were diagnosed with hematological malignancies and received anticancer chemotherapy. Colonic ulcer was demonstrated in all CDAD patients with hematochezia, and bleeding from the ulcer was endoscopically confirmed in all of them. Conclusions. CDAD accompanied by hematochezia is closely associated with ulcer formation. Ulcers are thought to occur during recovery from nadir after anticancer treatment, and white blood cells appear to be essential for their formation. Physicians should therefore pay close attention to the occurrence of colonic ulcer, especially in patients with CDAD during recovery from nadir.

Favorable Event Free-Survival of High-Dose Chemotherapy Followed by Autologous Hematopoietic Stem Cell Transplantation for Higher Risk Diffuse Large B-Cell Lymphoma in First Complete Remission

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has been applied to patients with diffuse large Bcell lymphoma (DLBCL); it is well established that ASCT shows significant survival benefits for chemosensitive relapse. However, half of relapsed patients are resistant to salvage chemotherapy, indicating that they are not suitable for ASCT. We retrospectively analyzed the clinical records of 47 patients with DLBCL classified as high or high-intermediate (higher) risk, according to the International Prognostic Index, who underwent upfront ASCT in first complete remission (CR1). Compared with 10 patients with similar characteristics who did not receive ASCT, event free survival at 5-year was significantly superior in ASCT group. Toxicity of ASCT was acceptable and therapy-related death was not observed. We therefore propose that upfront ASCT for higher risk DLBCL in CR1 might provide survival benefit, probably because the high-dose therapy removes minimally resided tumor.

Bortezomib for post-allogeneic hematopoietic stem transplantation relapse and GVHD in multiple myeloma: a single institute experience.

Allogeneic hematopoietic stem cell transplantation (alloSCT) can result in remission and long-term survival for multiple myeloma (MM), but its effect has been often hampered by high rates of therapy-related death by graftversus-host diseases (GVHD), disease progression, or infection [1]. We retrospectively investigated the efficacy and safety of Bortezomib (Bor) alone or with dexamethasone (Dex) (BD) for MM patients with disease progression following allo-SCT. Six MM patients were treated with Bor alone or with BD as the salvage treatment for disease progression following allo-SCT, while 32 patients with relapsed/refractory MM without allo-SCT were also treated with BD at our institute between October 2003 and July 2009. The median age was 39.5 years old for the allo-SCT cohort and 67.5 for the non-allo-SCT cohort. None had prior exposure to Bor. In six post-allo-SCT patients, two underwent a conditioning regimen with high-dose cyclophosphamide (60 mg/kg) plus total body irradiation (10 Gy), while four were treated with a reduced intensity-conditioning regimen using fludarabine (90–125 mg/m) plus melphalan (140–200 mg/m) (Table 1). According to the International Myeloma Working Group response criteria, the best response for alloSCT was complete remission (CR) in one, very good partial response (VGPR) in two and stable disease (SD) in three patients. Bor (1.3, 1.0, or 0.7 mg/m/day) was administered on days 1, 4, 8 and 11, and Dex on days 1, 2, 4, 5, 8, 9, 11 and 12, every 21 days. The dosage of either agent was adjusted by the attending physician in the light of the patient’s condition. Among the six post-allo-SCT patients, one received Bor alone and five received BD, while all patients in the non-allo-SCT cohort received BD. The median number of cycles of Bor alone or BD was 3 (1–7 cycles) for the post-allo-SCT cohort and 2 for the non-allo-SCT cohort. The median interval between allo-SCT to Bor or BD was 12.5 months (6–22 months). All presented acute and chronic GVHD. Three patients received thalidomidecontaining therapy for post-allo-SCT disease progression prior to Bor (Table 2). For the six post-allo-SCT patients, the overall response rate (ORR) was 50.0%, including two VGPR and one PR, while two died of MM progression and one of bacterial pneumonia complicated with bronchiolitis obliterans, a late complication of allo-SCT. Although ORR for the allo-SCT cohort was inferior to that of the non-alloSCT cohort (68.8%), the median overall survival (OS) (912 days) and median progression-free survival (PFS) (71 days), 2-year OS (66.7%) and 2-year PFS (33.3%) from the start of Bor-containing treatment for the allo-SCT cohort did not seem significantly different from those for the non-allo-SCT cohort, although the statistical analysis was not applicable due to the small number of patients (Supplementary Fig. 1). Our findings thus seem to provide further supportive evidence that Bor or BD constitutes a promising salvage treatment even for heavily treated Electronic supplementary material The online version of this article (doi:10.1007/s12185-010-0709-3) contains supplementary material, which is available to authorized users.