Shigeo Mori

Frequent inactivation of A20 in B-cell lymphomas

A20 is a negative regulator of the NF-κB pathway and was initially identified as being rapidly induced after tumour-necrosis factor-α stimulation. It has a pivotal role in regulation of the immune response and prevents excessive activation of NF-κB in response to a variety of external stimuli; recent genetic studies have disclosed putative associations of polymorphic A20 (also called TNFAIP3) alleles with autoimmune disease risk. However, the involvement of A20 in the development of human cancers is unknown. Here we show, using a genome-wide analysis of genetic lesions in 238 B-cell lymphomas, that A20 is a common genetic target in B-lineage lymphomas. A20 is frequently inactivated by somatic mutations and/or deletions in mucosa-associated tissue lymphoma (18 out of 87; 21.8%) and Hodgkin’s lymphoma of nodular sclerosis histology (5 out of 15; 33.3%), and, to a lesser extent, in other B-lineage lymphomas. When re-expressed in a lymphoma-derived cell line with no functional A20 alleles, wild-type A20, but not mutant A20, resulted in suppression of cell growth and induction of apoptosis, accompanied by downregulation of NF-κB activation. The A20-deficient cells stably generated tumours in immunodeficient mice, whereas the tumorigenicity was effectively suppressed by re-expression of A20. In A20-deficient cells, suppression of both cell growth and NF-κB activity due to re-expression of A20 depended, at least partly, on cell-surface-receptor signalling, including the tumour-necrosis factor receptor. Considering the physiological function of A20 in the negative modulation of NF-κB activation induced by multiple upstream stimuli, our findings indicate that uncontrolled signalling of NF-κB caused by loss of A20 function is involved in the pathogenesis of subsets of B-lineage lymphomas.

Prevalence of Epstein–Barr virus in Japan: Trends and future prediction

Epstein–Barr virus (EBV) is the causative agent of infectious mononucleosis and some malignancies including EBV‐associated‐lymphomas. A large portion of adults all over the world are infected with EBV. In children, however, there are geographic variations. Most of the children in Asia and in other developing countries are infected in their early life, before 1u2003year of age (>90% of 5–9‐year‐old children are infected), while the age of primary infection is delayed in Western countries (approx. 50% of 5–9‐year‐old children are infected). The purpose of the present paper was to investigate the recent time trend of the EBV seropositivity among 5–7‐year‐old children living in Tokyo and its neighboring prefectures. Indirect immunofluorescein study for IgG antibody to viral capsid antigen was performed on 442 archival sera. Before the early 1990s, >80% of 5–7‐year‐old children were found to be seropositive, while the positivity rate decreased to 59% (Pu2003<u20030.001) for the years 1995–1999. These results also showed that the delay in the age of primary infection is continuing and that the rate is estimated to be <50% in 2006. This result suggests that the delay will affect the incidence of EBV‐associated disorders in Japan.

Amplification of c-myc and cyclin D1 genes in primary and metastatic carcinomas of the liver.

The c‐myc and cyclin D1 genes are included among the oncogenes the amplifications of which have been detected in cancers of various organs. However, there have been few reports on the amplification of both these genes in primary and metastatic liver carcinomas. In the present study, c‐myc and cyclin D1 gene amplification was examined in 76 primary and metastatic liver carcinomas using formalin‐fixed paraffin‐embedded tissue sections and a differential polymerase chain reaction procedure. c‐myc and cyclin D1 gene amplification was detected in 15 (33%) and two (4%) of 46 hepatocellular carcinomas (HCC), one (10%) and 0 (0%) of 10 intrahepatic cholangiocarcinomas (ICC), one (33%) and 0 (0%) of three combined hepatocellular and cholangiocarcinomas (HCCu2003+u2003ICC), and nine (56%) and three (19%) of 16 metastatic lesions to the liver from colorectal adenocarcinoma (MCA), respectively. The incidence of c‐myc amplification was significantly higher in MCA than in ICC (Pu2003= 0.023), and it tended to be higher in HCC than in ICC. These results indicate that the amplification of the c‐myc proto‐oncogene is not unusual in HCC and MCA, and its detection may have a useful diagnostic significance in differentiating ICC from MCA or HCC from ICC.

Japanese phase II study of 90Y-ibritumomab tiuxetan in patients with relapsed or refractory indolent B-cell lymphoma

There is no data about the efficacy and safety of radioimmunotherapy with 90Y‐ibritumomab tiuxetan in patients with relapsed or refractory indolent B‐cell lymphoma pretreated with rituximab‐containing chemotherapy. We focused on this in a Japanese phase II study. Radioimmunotherapy with 90Y‐ibritumomab tiuxetan (11.1 and 14.8 MBq) was evaluated in patients with 100–149 × 109 and >150 × 109 platelets/L, respectively. The primary endpoint was the overall response rate. Forty patients were treated with 90Y‐ibritumomab tiuxetan (18 with 11.1 MBq/kg and 22 with 14.8 MBq/kg). Thirty‐five patients (88%) had been pretreated with rituximab, including 27 (68%) pretreated with rituximab‐containing chemotherapy. The overall response rate was 83% (33/40; 95% confidence interval, 67–93%), and the complete response rate was 68% (27/40; 95% confidence interval, 51–81%). The overall response rates in patients pretreated with rituximab‐containing chemotherapy and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP) were 83% (19/23) and 94% (17/18), respectively. The median progression‐free survival time of the 40 patients who received 90Y‐ibritumomab tiuxetan was 9.6 months. Toxicity was primarily hematological and mostly transient. No grade 4 non‐hematological toxicity was observed. In conclusion, radioimmunotherapy with 90Y‐ibritumomab tiuxetan is safe and highly effective in patients with relapsed or refractory indolent B‐cell lymphoma, including those pretreated with rituximab‐containing chemotherapy. (ClinicalTrials.gov number NCT00220285) (Cancer Sci 2009; 100: 158–164)

Prevalence of ischemic enterocolitis in patients with acute pancreatitis

BackgroundA considerable number of acute pancreatitis cases have been reported to be complicated by nonocclusive mesenteric ischemia. However, no reports have ever referred to the incidence of ischemic enterocolitis in patients with acute pancreatitis, using a series of autopsy cases. Here, we report our review of autopsy cases of patients with acute pancreatitis to examine the incidence of associated ischemic enterocolitis.MethodsThe intestinal and pancreatic slides of 48 autopsy cases of patients with acute pancreatitis were reviewed and the incidence of ischemic enterocolitis was determined. Clinical case records were also reviewed.ResultsThirteen (27%) of 48 autopsy cases of patients with acute pancreatitis were complicated by ischemic enterocolitis. The frequency of shock was significantly higher in patients with ischemic enterocolitis than in those without ischemic enterocolitis. The intestinal lesion was diffuse in many cases and gangrene was not an unusual finding.ConclusionsThe incidence of ischemic enterocolitis in patients with acute pancreatitis was much higher than that in the previous reports. Clinicians who treat patients with acute pancreatitis should consider ischemic enterocolitis as one of the frequent and severe complications of this condition.

Rituximab monotherapy with eight weekly infusions for relapsed or refractory patients with indolent B cell non-Hodgkin lymphoma mostly pretreated with rituximab: A multicenter phase II study

Information regarding rituximab monotherapy with eight weekly infusions for relapsed or refractory indolent B cell non‐Hodgkin lymphoma (B‐NHL), in particular for patients pretreated with rituximab, is limited. To evaluate the efficacy and safety of eight doses of rituximab monotherapy, 52 patients with relapsed or refractory indolent B‐NHL were enrolled in the present study. Forty of 45 eligible patients (89%) had follicular lymphoma and 24 (53%) were at intermediate or high risk group according to the Follicular Lymphoma International Prognostic Index. The median number of prior chemotherapy regimens was 1 (range 1–7). At the median follow‐up of 12.2u2003months, the overall response rate (ORR), complete response rate (%CR), and median progression‐free survival (PFS) were 69% (95% confidence interval [CI] 53%–82%), 47% (95% CI 32%–62%), and 15.6u2003months (95% CI 10.6– months), respectively. In the 33 patients pretreated with rituximab, the ORR, %CR, and median PFS were inferior compared with values for the 12 patients who had not received rituximab previously (64%vs 83% for ORR; 39%vs 67% for %CR; and 13.8 vs 17.5u2003months for median PFS, respectively). All mild‐to‐moderate infusion‐related toxicities were reversible. Grade 3/4 non‐hematologic adverse events occurred in six of the 52 patients. Two patients developed Grade 4 late‐onset neutropenia and a decrease (>50%) in serum immunoglobulin was observed in six patients. In conclusion, rituximab monotherapy with eight weekly infusions is effective in relapsed patients with indolent B‐NHL, with acceptable toxicities, including in patients pretreated with rituximab; however, careful monitoring is recommended for infections associated with late‐onset neutropenia and hypogammaglobulinemia. (University Hospital Medical Information Network no. UMIN000002974.) (Cancer Sci 2011; 102: 1698–1705)

High expression of eosinophil chemoattractant ecalectin/galectin‐9 in drug‐induced liver injury

Abstract: Backgound: Ecalectin/galectin‐9 (ECL/GL9) is an eosinophil chemoattractant isolated from T lymphocytes. Drug‐induced liver injury (DILI), often caused by an allergic mechanism, is occasionally accompanied by eosinophilic infiltration. In this study, we intended to determine whether DILI can induce augmentation of ECL/GL9 expression. Further, we investigated whether this augmentation is associated with tissue eosinophilia.

Phase I/II and pharmacokinetic study of cladribine with 2‐h infusion in Japanese patients with relapsed indolent B‐cell lymphoma mostly pretreated with rituximab

We conducted a phase I/II study to investigate the toxicity, pharmacokinetics, and efficacy profiles of cladribine with 2‐h intravenous infusion for five consecutive days every four weeks in Japanese patients with relapsed indolent B‐cell lymphoma. This was a dose‐escalation study to confirm the safety of the doses which have been recommended for Caucasian patients (phase I), and to further evaluate the efficacy and safety (phase II). In the phase I portion for nine patients, no dose‐limiting toxicities were observed at levels 1 (0.09 mg/kg/day, n = 3) and 2 (0.12 mg/kg/day, n = 6). No appreciable accumulation of plasma cladribine concentration was suggested. We enrolled a total of 20 patients, and an additional 14 patients in the phase II portion at level 2 (0.12 mg/kg/day). Eighteen patients, including 13 with follicular lymphoma, were eligible for efficacy evaluation, and 15 (83%) were pretreated with rituximab. The overall response rate was 50% (9/18; 80% confidence interval, 35–65%), with 11% (2/18) complete response. With a median follow‐up of 296 days, the estimated median time to progression for 18 eligible patients was 382 days. The most frequent adverse events were hematologic toxicities, including grade 4 neutropenia. Non‐hematologic toxicities were mild. In conclusion, cladribine with 2‐h intravenous infusion for five consecutive days every four weeks is effective with acceptable toxicities for Japanese patients with relapsed indolent B‐cell lymphoma, including those pretreated with rituximab. (Cancer Sci 2009; 100: 1344–1350)

Gastrointestinal stromal tumor in the duodenum exhibiting hemangiopericytoma‐like histological pattern

Reported herein is a gastrointestinal stromal tumor (GIST) that exhibited a hemangiopericytoma (HPC)‐like histological pattern. Such a morphological variant of GIST has not been described previously. A 57‐year‐old woman presented with bloody stools. On upper digestive tract endoscopy a submucosal tumor of diameter 2u2003cm was detected at the duodenal bulb, and enucleated. Grossly, the tumor was well‐circumscribed, grayish to whitish, and solid, and its central portion was ulcerated. Histology indicated round to fusiform tumor cells that had proliferated around branching vessels that had a staghorn configuration. Immunohistochemistry showed that the tumor cells were diffusely positive for vimentin and KIT; partially positive for CD34 and muscle actin; and negative for α‐smooth muscle actin. On mutation analysis a 42u2003bp deletion was found from codons 560 to 573 of exon 11 of the KIT gene, which is a mutational hot spot of GIST. In diagnosis of gastrointestinal tract tumors with an HPC‐like histological pattern, pathologists should consider the possibility of GIST.

Integration of HIV-1 Caused STAT3-Associated B Cell Lymphoma in an AIDS Patient

Signal transducer and activator of transcription 3 (STAT3) is a DNA-binding transcription factor activated by multiple cytokines and interferons. High expression of STAT3 has also been implicated in cancer and lymphoma. Here, we show a case of B cell lymphoma in which a defective human immunodeficiency virus 1 (HIV-1) integrated upstream of the first STAT3 coding exon. The lymphoma cells with anaplastic large cell morphology formed multiple nodular lesions in the lung of an acquired immunodeficiency syndrome (AIDS) patient with Kaposis sarcoma. The provirus had a 5 long terminal repeat (LTR) deletion, but the 3 LTR had stronger promoter activity than the STAT3 promoter in reporter assays. Immunohistochemistry showed increased expression of STAT3 in the nuclei of lymphoma cells. Transfection of STAT3 resulted in transient cell proliferation in primary B cells in vitro. Although this is a very rare case of HIV-1-integrated lymphoma, these data suggest that up-regulation of STAT3 caused by HIV-1 integration resulted in the development of B cell lymphoma in this special case.