Yoshiharu Kusano

Absolute peripheral monocyte count at diagnosis predicts central nervous system relapse in diffuse large B-cell lymphoma.

Recently, elevated peripheral blood monocyte counts at diagnosis have been shown to be an independent marker associated with poor prognosis in patients with both non-Hodgkin and Hodgkin lymphoma. In this study, we retrospectively analyzed the data from a total of 550 patients with diffuse large B-cell lymphoma and evaluated the relationship between central nervous system relapse and absolute monocyte counts at diagnosis. Twenty-six patients developed central nervous system relapse. The central nervous system relapse-free survival rate was significantly lower in patients with the absolute monocyte counts ≥0.51×109/L (87.8% versus 96.4%; P<0.001). This association was independently significant after adjusting for other significant factors, including systemic relapse as a time-dependent covariate by multivariate analysis (hazard ratio 2.46; 95% confidence intervals 1.05–5.75; P=0.039). These results suggest that the absolute monocyte count at diagnosis is an independent significant risk factor for central nervous system relapse in patients with diffuse large B-cell lymphoma.

Epstein-Barr virus gastric ulcer associated with ruxolitinib

Dear Editor, The Janus kinase 1 and 2 selective inhibitor ruxolitinib improves splenomegaly and overall survival of patients with primary myelofibrosis (PMF); however, opportunistic infections, although rare, can be a problem [1–4]. Here, we present the case of a patient who suffered from an EpsteinBarr virus (EBV) gastric ulcer due to severe immunosuppression induced by ruxolitinib. We treated the patient with ganciclovir, which proved completely effective against the EBV gastric ulcer. A 77-year-old man with a 2-year history of PMF presented with severe diarrhea. Six months earlier, ruxolitinib had been initiated at 20 mg twice daily. PMF-associated manifestations had improved rapidly, but it had been necessary to taper the amount of ruxolitinib step by step to 5 mg twice daily because of repeated infections, including that of herpes zoster. The number of T cells and activity of natural killer (NK) cells had been decreasing. When his wife brought him to the hospital, he felt only mild discomfort in the epigastric area without tenderness by palpation despite experiencing numerous episodes of diarrhea (approximately 20 times per day). A computed tomography scan showed massive thickening of the gastric wall. An upper gastrointestinal endoscopy revealed multiple opentype gastric ulcers (Fig. 1a). No cytomegalovirus, herpes simplex virus, or EBV was detected in the plasma, but severe impairment of cell-mediated immunity was observed: CD4+ T cells at 123/μL, CD8+ T cells at 159/ μL, and NK cell activity of 7 %. He both HIV-1 and HIV-2 antibodies were negative. Although a stomach specimen showed no indicative features, a viral infection was strongly suspected. Ruxolitinib was discontinued, and empiric ganciclovir administration was initiated. The following day, the frequency of diarrhea diminished to two or three episodes per day. EBV DNA was amplified with polymerase chain reaction from tissue of the gastric ulcer. Fourteen days of ganciclovir improved the patient’s general appearance, and he was discharged. To date, evidence supporting the use of ganciclovir against EBV infections has been limited [5]. However, the gastric ulcer was completely cured with a further 7day treatment with valganciclovir (Fig. 1b). However, although ruxolitinib was discontinued, the level of T cells and NK cell activity continued to decline even after 1 month: CD4+ T cells to 78/μL, CD8+ T cells to 75/μL, and NK cell activity to 1 %. Three months after the discontinuation of ruxolitinib, cell-mediated immunity began to slowly recover but remained low; in particular, NK cell activity remained at 1 %. * Yoshiharu Kusano yoshiharu.kusano@jfcr.or.jp

Klebsiella pneumoniae primary liver abscess associated with ruxolitinib

Dear Editor, Pyogenic liver abscess is an uncommon intra-abdominal infection associated with high mortality. The liver is in contact with massive quantities of blood from systemic and portal circulation. Therefore, any breakdown of its immune system can directly cause lethal infections. Patients with Klebsiella pneumoniae primary liver abscess (KPPLA) have higher incidences of diabetes or glucose intolerance compared to those with other pyogenic liver abscess, but it is unknown how diabetes influences the liver’s immunity including Kupffer’s cells. Here, we present a case with primary myelofibrosis (PMF) suffering from KPPLA during the course of ruxolitinib, a JAK1 and JAK2 inhibitor. A 78-year-old man had a diagnosis of JAK2V617F+ PMF. Treatment with ruxolitinib 20 mg twice daily was initiated in May 2015. At the 2-month follow-up, he was suffering from herpes zoster and thrombocytopenia, so the dosage of ruxolitinib was reduced to 10 mg twice daily. Since dosage was reduced, absolute hemoglobin and thrombocyte counts had been stable. In January 2016, he presented with fatigue, fever with chills, and persistent right upper quadrant pain. Blood pressure was 91/50 mmHg, pulse was 120 beats per minute, respiratory rate was 26 breaths per minute, and oxygen saturation was 98 % while he was breathing a room air. A laboratory blood test showed elevated biliary and liver enzymes, prothrombin time (PT), activated partial thromboplastin time, and fibrinogen degradation products (FDP), whereas hemoglobin and platelets were decreased due to disseminated intravascular coagulopathy (DIC), which was score 4 based on DIC diagnostic criteria (systemic inflammatory response syndrome, platelet count of 8.5 × 10/μL, FDP>10 μg/ml, and PT-international normalized ratio > 1.2). The absolute neutrophil count and immunoglobulin levels were normal. Abdominal contrast-enhanced computer tomography scans showed an abscess with a 5-cm radius (Fig. 1). Percutaneous catheter drainage of abscess was performed, and piperacillintazobactam 4.5 mg thrice daily was initiated. An alleviation of fever was observed from the next day, and the volume of the abscess dwindled considerably in 14 days. Klebsiella pneumoniae was detected from the pus. Magnetic resonance imaging did not reveal any predisposing intra-abdominal factors for abscess formation. The catheter was removed and the patient was discharged from hospital continuing on cefcapene 100 mg trice daily for another 3 weeks. Ruxolitinib interferes with a variety of immune cells and their function [1–3]. In fact, the number and activity of immune cells were diminishing in our case: B cells, 28/μl; CD4+T cells, 50/μl; CD8+ T cells, 53/μl; and NK-cell activity, 4 % (normal 18–40). With severe impairment of the number and activity of NK cells, JAK mutations and STAT Key Message JAK mutations and STAT deficiency can cause lack circulating T and NK lymphocytes. We need to warrant not only viral infection but also severe bacterial infections such as pyogenic liver abscess that can be induced by immunosuppression by ruxolitinib, a JAK1 and JAK2 inhibitor.

Myelomatous meningitis: a case report.

A 65-year-old man with 4-year history of extramedullary multiple myeloma refractory to novel-agent containing chemotherapy presented with dysarthria. Fluorescence in situ hybridization did not reveal any cytogenetic abnormalities. Brain computer tomography scan and magnetic resonance imaging also did not reveal the causes of the dysarthria; however, plasma cells were found in the cerebrospinal fluid. Whole-brain radiotherapy (30 grays) improved the patient’s symptoms; however, speech disturbances eventually reappeared due to the progression of the disease, despite treatment. At 1-month follow-up, he died of myeloma (Fig. 1).

Gastric involvement, a rare site for extramedullary myeloma

Dear Editor, Gastric involvement of multiple myeloma (MM) is rare. It accounts for 7 % [1, 2] of total extramedullary plasmacytomas. Patients with MM present gastric carcinoma in 3 % of cases. We present here a case that gastric involvement of MM was diagnosed soon after endoscopic submucosal dissection against gastric carcinoma. A 64-year-old man was referred for further evaluation of renal impairment, hypercalcemia, and anemia. His general condition was scored 3 according to EOCG performance status. Physical examination showed dry skin and pallor conjunctiva. Both serum and urine immunofixation electrophoresis revealed monoclonal IgG elevation and lambda chain restriction. Bone marrow aspirate showed an infiltration of 60% monoclonal plasma cells. Positron emission tomography showed numerous bone fractures. Based on these results, the diagnosis of symptomatic MM was confirmed. On the other hand, early-stage gastric adenocarcinoma was found coincidentally. Treatment priority was put onMM, and he started on chemotherapy with bortezomib plus dexamethasone (BD). Efficacy of BD was observed gradually; however, he experienced numerous infectious events. First, he suffered from a cytomegalovirus (CMV) infection. He usually presented diarrhea after bortezomib administration. Although diarrhea usually stopped in several days, diarrhea occurring 10 times per day sometimes continued for a week. He also presented fatigue due to volume depletion and was admitted. Laboratory test showed elevated CMV IgM. And CMV retinitis was also diagnosed. Gancyclovir 5 mg/kg per 12 h was administered. Following a total of 14 days administration, CMVretinitis and gastroenteritis were completely cured without any complications. Second, Clostridium difficile (CD) toxin was found, associated with gastroenteritis. When he complained of a sore throat at another clinic, the physician prescribed antibiotics. He presented with diarrhea as usual after bortezomib administration, but his diarrhea did not disappear for a week. CD toxin was verified and diarrhea ended by vancomycin, which was continued for 10 days. The third was a varicella virus infection due to immunosuppression caused by bortezomib. When the seventh cycle of BD was finished, he achieved partial response, but the amount of M protein gradually increased with many postponements of BD. Endoscopic submucosal dissection was performed and gastric cancer was removed completely. However, 1 month later, multiple bull’s-eye lesions emerged in the greater curvature of the stomach (Fig. 1a, indigo carmine staining), found during a routine checkup. Pathological findings confirmed plasmacytoma (b, hematoxylin and eosin staining; c, highlighted with lambda chain staining; d, highlightedwith CD138 staining). At that time, he became ineligible for a transplant due to his age and instead was supposed to receive bortezomib, melphalan, and dexamethasone (VMP). Nevertheless, he eventually died of acute coronary syndrome. Prior study showed only 0.9 % had gastric involvement in 2584 MM patients [3]. Our case had gastric carcinoma coincidently. Kyle reviewed 869 MM patients and concluded that 3 % had other kinds of solitary tumors [4]. Especially, several cases in which MM and gastric cancer were diagnosed * Yoshiharu Kusano yoshiharu.kusano@jfcr.or.jp

Bearing 19q13 aberration predicts poor prognosis in non-germinal centre type of CD5+ DLBCL

Patients with CD5 positive (CD5) diffuse large B cell lymphoma (DLBCL) are frequently resistant to chemotherapy and have a poor prognosis (Yamaguchi et al, 2002; Ennishi et al, 2008; Johnson et al, 2009). In some literature, the clinical features of CD5DLBCL resemble activated B cell-like (ABC) DLBCL and the gene profiling analysis has demonstrated some similar gene expression patterns (Tagawa et al, 2005; Suguro et al, 2006). However, the data was heterogeneous and no common gene aberration has been detected. In this study, we retrospectively investigated 350 DLBCL cases treated at our hospital between 2000 and 2015, sub-classifying them as germinal centre B cell-like (GCB) and non-GCB (NGC) type by immunohistochemical staining with CD10, BCL6 and MUM1 (Hans et al, 2004; Hwang et al, 2013), and then comparing the prognoses. This protocol was approved by our Institutional Review Board and Genomic Review Board. Patients with central nervous system disease at diagnosis were excluded. Patients with stage I disease were given three cycles of R-CHOP therapy (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) followed by involved-field radiotherapy, and patients with stage II disease or higher received six cycles of R-CHOP therapy. In the enrolled DLBCL patients, 41 (11 7%) were CD5 and 309 (88 3%) were CD5 (Table SI). There was no significant difference in sex, stage and International Prognostic Index (IPI) score between these two groups. In the CD5 group, the cell of origin was NGC type in 30 cases (73 2%); the ratio of NGC type in the CD5 group was higher than that in the CD5 group (P = 0 023) (Table SI). With regard to outcome, there was no statistically significant difference in the complete remission (CR) rate between the CD5 and CD5 groups (73 1% and 87 7%, respectively, P = 0 4757; Table SII). However, there were significant differences in CD5 status for cases with progressive disease (PD: CD5, 24 4% vs. CD5 , 6 8%, P = 0 0013) or relapse (CD5, 14 2% vs. CD5 , 11 8%, P = 0 0031) (Table SII). Furthermore, when these groups were subdivided into GCB or NGC type, the GCB type showed no significant differences between the CD5 and CD5 groups regarding CR, PD or relapse rate (Table SII). For the NGC type, CR cases showed no significant differences between CD5 and CD5 status (70 0% and 87 5%, respectively, P = 0 4747, P = 0 0859). However, PD was significantly increased in the CD5 group compared to CD5 group (26 7% and 6 3%, respectively, P = 0 0042).

O1-15-1Azacytidine is effective in the therapy related myelodysplastic syndrome

The comprehensive genomic analysis by Next generation sequencing can make us find many oncodriver gene mutations. And at the same time, we can find many gene structural mutations outside of oncodriver gene mutations. Most of such gene mutations are not identified about the pathologic significance, so that they are called variants of uncertain significant (VUS) gene mutations. And evaluations of their function are important for patient treatment. Recently, we had experienced an adult pancreatoblastoma case. Using commercially available the cancer panel, OncoDeep, we found a missense mutation in APC gene, which has not been reported in the UMD-APC mutations database. Immunohistochemically analysis revealed nuclear accumulation of the b-catenin protein. Because CTNNB1 was not mutated in this case, these results indicated that the missense mutation of APC lost its function and caused Wnt signal activation. To identify the structure mutation of APC gene in germ line, we have done target sequence of DNA extracted from oral mucosa. We found heterozygous of APC gene. It was assumed that loss of heterozygosis of APC gene causes Wnt signal activation in pancreatoblastoma cells in this case. The patient harboring pathological APC gene mutations in germ line generally develop colon polyposis, but this patient did not have the past history of colon polyposis. To make clear the APC mutation we found in this case causes functional loss, we have done functional assay with cell line model. The results indicated the APC gene mutation in this case causes partial loss of suppression of Wnt signal activation. This is a very important case report in NGS era in which we found many VUS gene mutations. We will present detail analyzed data together with clinical course.

Study of patient risk factors for febrile neutropenia in non-Hodgkin lymphoma receiving R-CHOP regimen: STOP FN single institution analysis in Japan.

e21605Background: Cyclophosphamide, doxorubicin, vincristine, prednisone, and rituximab (R-CHOP) is standard therapy for patients (pts) with CD20 positive non-Hodgkin lymphomas (CD20+NHLs). America...