Kyoko Ueda

Frequent BCOR aberrations in extranodal NK/T-Cell lymphoma, nasal type

Extranodal natural killer/T cell lymphoma (ENKTL) is a rare subtype of lymphoma. Recurrent mutations in the JAK‐STAT pathway, recently reported in ENKTL cases, are interesting in terms of both pathogenesis and inhibitor therapy. However, the frequencies of these mutations are low and variable among reports, and other pathognomonic mutations in ENKTL remain to be elucidated. In the present study, targeted capture sequencing of 602 cancer‐related genes from 25 frozen ENKTL samples was performed, 11 of which were matched to normal samples. Several recurrent somatic mutations involving BCOR (32%), TP53 (16%), DDX3X (12%), FAT4 (8%), NRAS (8%), MLL3 (12%), and MIR17HG (8%) were identified. The pattern of BCOR aberrations (1 nonsense and 5 frame‐shift mutations, a mutation leading to a splicing error, and gene loss) suggested that loss of function of BCOR was the functionally important outcome of such changes. The literature was reviewed and the public data on BCOR aberrations was reanalyzed and it was found that the aberrations were frequently found in myeloid neoplasms, but, interestingly, were highly specific to ENKTL among lymphoid malignancies. Given the high frequency and pattern of aberration, BCOR is likely to play an important role in ENKTL pathogenesis as a tumor suppressor gene.

Prospective evaluation of incidence and severity of oral mucositis induced by conventional chemotherapy in solid tumors and malignant lymphomas

PurposeOral mucositis (OM), a complication frequently associated with cancer chemotherapy, may decrease treatment efficacy due to dose reduction or impair the patients quality of life. The purpose was to determine the incidence and severity of OM and its sequelae in patients receiving conventional chemotherapy for various malignancies.MethodsTwo hundred twenty-seven patients (male, 33%; female, 66%) who received chemotherapy for head and neck cancer, esophageal cancer, colorectal cancer, breast cancer, and malignant lymphomas at the Cancer Institute Hospital between January 2007 and December 2008 were examined with questionnaires, prospectively.ResultsThe incidence of OM was highest in patients with breast cancer (76.5%), then head and neck cancer (67.7%), colorectal cancer (63%), esophageal cancer (57.8%), and malignant lymphoma (42.9%). However, patients who experienced severe OM (≥grade 3) were rare: at most 4.8%. The high-risk regimens for OM were TPF (85.7%), FOLFIRI (80%), CAF (78.8%), AC (70.6%), and FOLFOX (60%). OM was associated with gastrointestinal adverse events, anorexia, diarrhea, and dysphagia, which aggravated quality of life. There was no correlation between incidence of OM and prior therapy, PS, oral care, or laboratory data. There was no statistically significant correlation between OM and overall survival. The predictive factor was history of OM in previous chemotherapy.ConclusionOM frequently occurs in patients with various tumors receiving conventional chemotherapy. Despite low-grade OM, they might cause gastrointestinal adverse events. Adequate preventive treatment for OM is required depending on each chemotherapy regimen and each patients OM history.

Bone metastasis and poor performance status are prognostic factors for survival of carcinoma of unknown primary site in patients treated with systematic chemotherapy

BACKGROUND Cancer of unknown primary site (CUP) generally has a poor prognosis, and there is no established standard therapy. There have been no reports of a prognostic model for CUP patients treated with a single regimen of systemic chemotherapy. METHODS Univariate and multivariate prognostic factor analysis for overall survival (OS) were conducted retrospectively in 58 consecutive CUP patients treated with carboplatin plus paclitaxel (Taxol) therapy as a first-line treatment. RESULTS Univariate prognostic factor analysis revealed baseline performance status (PS) of two or more, low serum albumin level, pleural effusion, bone metastasis, and liver metastasis as adverse prognostic factors. Cox proportional hazards analysis showed that poor PS and bone metastasis had the most powerful adverse impact on survival. We developed a prognostic model using those two variables-a good-risk group (PS 0-1 without bone metastasis) and a poor-risk group (PS > or =2 or bone metastasis). The poor-risk group showed significantly poorer OS than the good-risk group (1 year OS 36.8% versus 67.1%, P = 0.0003). CONCLUSIONS Poor PS and bone metastasis were identified as independent adverse prognostic factors in CUP. A simple prognostic model was developed and seems useful for decision making as to whether chemotherapy is indicated for CUP patients.

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.

Prognostic value of high thymidine kinase activity in patients with previously untreated diffuse large B-cell lymphoma treated by rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone

Abstract The purpose of this study was to investigate prognostic factors for overall survival (OS) among patients with previously untreated diffuse large B-cell lymphoma (DLBCL) treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). We evaluated four biological parameters, including thymidine kinase (TK) activity. This study included 183 patients. The median level of TK was 14.0 IU/L, which we chose as the cut-off. After a median follow-up time of 50.0 months, the OS rate at 4 years in the high and low TK arm were 46.7% and 66.7%, respectively (p = 0.001). By multivariate analysis, OS was significantly inferior in the high TK arm (hazard ratio 2.705; p = 0.045). The complete response (CR) rate in the high TK arm was significantly worse than in the low TK arm. OS was significantly better in patients who had achieved CR than in those with partial response or less. In conclusion, high TK activity was a strong predictor for short OS and poor response among patients with previously untreated DLBCL treated with R-CHOP.

Non-gastric advanced mucosa-associated lymphoid tissue (MALT) lymphoma has worse prognosis than gastric MALT lymphoma even when treated with rituximab-containing chemotherapy

Abstract The aim of this study was to assess the clinical characteristics, treatment results, and analyze the prognostic factors among patients with extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). We retrospectively reviewed 98 patients with MALT lymphoma consecutively diagnosed at the Cancer Institute Hospital. Eighty-one patients (82%) had localized disease and 17 patients (17%) had advanced disease. The primary site was gastric in 52, and extra-gastric in 46. With a median follow-up of 40 months, the estimated 3-year overall survival (OS) and progression free survival (PFS) of the entire group were 100% and 89%, respectively. Three-year PFS was significantly better in patients with gastric lymphoma than in those with non-gastric lymphoma (95% vs. 82%, p = 0.043). Patients with localized disease had significantly better 3-year PFS than those with advanced disease (94% vs. 73%, p = 0.026). Upon multivariate analysis, non-gastric lymphoma retained prognostic significance for PFS.

R-CHOP with dose-attenuated radiation therapy could induce good prognosis in gastric diffuse large B cell lymphoma

BackgroundThe treatment strategy for gastric diffuse large cell lymphoma (DLBCL) has not been standardized in such as to the cycles of chemotherapy, dose of radiation, or necessity for the surgery. Although the results of CHOP or R-CHOP treatments have demonstrated the good prognosis, the treatments have been controversial in many cases.MethodsWe retrospectively analyzed 40 gastric DLBCL patients receiving chemotherapy with or without radiation in our institute. Those in stages II-IV were treated with six cycles of R-CHOP without radiation; for those in stage I, we administered three cycles of R-CHOP with radiation.ResultsThe three-year overall survival (OS) and progression-free survival (PFS) rates were 95.2 and 91.8%, respectively. Those in stage I obtained 100% of OS. The radiation dose prescribed was 30.6 Gy for CR cases and 39.6 to 40 Gy for PR after chemotherapy. Although survival rates tended to correlate with staging groups or age-adjusted IPI classifications, multivariate statistical analysis did not show clear differences. All 14 patients with initial bleeding were successfully managed without surgery during treatment.ConclusionR-CHOP therapy was very effective for gastric DLBCL. It may be not necessary to use more than 30.6 Gy of radiotherapy in the highly chemo-sensitive cases. Less toxic treatments should be made available to gastric DLBCL patients.

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.

BCL2 expression in DLBCL: reappraisal of immunohistochemistry with new criteria for therapeutic biomarker evaluation

Overexpression of the BCL2 is associated with a poor prognosis in diffuse large B-cell lymphoma (DLBCL). The assessment of MYC immunohistochemistry (IHC) is becoming optimized, whereas the criteria for BCL2 positivity are highly variable. Furthermore, data on the frequency and prognostic value of BCL2 positivity are conflicting. We aimed to evaluate BCL2 expression by IHC and assess the prognostic significance of the histopathologically scored BCL2 expression in 456 patients with DLBCL uniformly treated with standard immunochemotherapy (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, R-CHOP). We initially designed 4-grade BCL2 scoring criteria, from 0 to 3+, and found that ∼40% of DLBCL showed strong BCL2 expression (score 3+). The scores from the pathologists visual estimation were confirmed to be reliable using a digital image analysis. A retrospective survival analysis revealed that BCL2 score 3+ was a significant prognostic factor independent of the international prognostic index (IPI), the IHC-determined cell of origin, and the MYC protein/rearrangement status in a training set (n = 218). The adverse prognostic impact of BCL2 score 3+ was confirmed in a validation set (n = 238). We also developed a prognostic model consisting of 3 groups with a combined BCL2 score and MYC protein/rearrangement status. Patients with BCL2 score 3+ showed a higher treatment failure rate; therefore, alternative therapeutic strategies should be considered for these patients. A highly selective BCL2 inhibitor, venetoclax, was recently introduced as breakthrough therapy. Our BCL2 scoring system could readily be used by pathologists to evaluate patients with DLBCL who might benefit from BCL2-targeted therapies.