Efficacy and safety of mepolizumab in Japanese patients with severe eosinophilic asthma

Background

The MENSA trial assessed the efficacy and safety of mepolizumab in patients with severe eosinophilic asthma. This report describes the efficacy and safety of mepolizumab in Japanese patients from MENSA.

Japanese version of The Cancer Genome Atlas,JCGA, established using fresh frozen tumors obtained from 5143 cancer patients

This study aimed to establish the Japanese Cancer Genome Atlas (JCGA) using data from fresh frozen tumor tissues obtained from 5143 Japanese cancer patients, including those with colorectal cancer (31.6%), lung cancer (16.5%), gastric cancer (10.8%) and other cancers (41.1%). The results are part of a single‐center study called “High‐tech Omics‐based Patient Evaluation” or “Project HOPE” conducted at the Shizuoka Cancer Center, Japan. All DNA samples and most RNA samples were analyzed using whole‐exome sequencing, cancer gene panel sequencing, fusion gene panel sequencing and microarray gene expression profiling, and the results were annotated using an analysis pipeline termed “Shizuoka Multi‐omics Analysis Protocol” developed in‐house. Somatic driver alterations were identified in 72.2% of samples in 362 genes (average, 2.3 driver events per sample). Actionable information on drugs that is applicable in the current clinical setting was associated with 11.3% of samples. When including those drugs that are used for investigative purposes, actionable information was assigned to 55.0% of samples. Germline analysis revealed pathogenic mutations in hereditary cancer genes in 9.2% of samples, among which 12.2% were confirmed as pathogenic mutations by confirmatory test. Pathogenic mutations associated with non–cancerous hereditary diseases were detected in 0.4% of samples. Tumor mutation burden (TMB) analysis revealed 5.4% of samples as having the hypermutator phenotype (TMB ≥ 20). Clonal hematopoiesis was observed in 8.4% of samples. Thus, the JCGA dataset and the analytical procedures constitute a fundamental resource for genomic medicine for Japanese cancer patients.     

Predictive role of anti-gp210 and anticentromere antibodies in long-term outcome of primary biliary cirrhosis

Because some of the autoreactive T-cell clones specific for human PDC-E2 cross-react to mimicry peptides having an EIExDK motif derived from nuclear antigens such as human gp210 and sp100, we studied the clinical significance of antinuclear antibodies (ANA) in primary biliary cirrhosis (PBC) patients registered to the National Hospital Organization Study Group for Liver Disease in Japan (NHOSLJ). We found that there are two different types of progression in PBC; one is a hepatic failure-type progression which is represented by positive anti-gp210 antibodies and the other is a portalhypertension-type progression which is represented by positive anticentromere antibodies. We discuss the predictive role of these ANA in the long-term outcome of PBC and the mechanisms by which two different PBC progression types occur based on molecular mimicry and aberrant expression of nuclear antigens.     

Prevalence of and risk factors for low bone mineral density in Japanese female patients with systemic lupus erythematosus

To examine the prevalence of and risk factors for low bone mineral density (BMD) (osteoporosis or osteopenia) in Japanese female patients with systemic lupus erythematosus (SLE). We performed BMD measurements by dual X-ray absorptiometry at the lumbar spine and the hip and collected basic and lifestyle-related, clinical and treatment characteristics among 58 SLE patients. Odds ratios (ORs) and their 95% confidence intervals (CIs) were assessed for associations between low BMD and selected factors among SLE patients. The mean BMD?±?SD was 0.90?±?0.17?g/cm² at the lumbar spine and 0.76?±?0.17?g/cm² at the hip. The prevalence of osteopenia (2.5 SD?<?T score?<?1 SD) was 50.0% and that of osteoporosis (T score?<?2.5 SD) was 13.8% in our SLE patients. After adjustment for age and disease duration, we found the number of deliveries (OR?=?5.58, 95% CI?=?1.31?C26.06; P?=?0.02) to be a risk factor for overall low BMD (T score?<?1 SD) and a maximal dosage of >50?mg/day of oral corticosteroids (OR?=?0.25, 95% CI?=?0.07?C0.91; P?=?0.035) as a preventive factor for low BMD at the lumbar spine. Reduced BMD, especially in spinal trabecular bone, was pronounced in Japanese female patients with SLE, particular in those with a history of delivery. A history of high-dose oral corticosteroids was associated with the preservation of BMD at the lumbar spine, however, further study is needed considering the limited sample size.     

Appendiceal intussusception due to an appendiceal malignant polyp — An association in a patient with peutz-jeghers syndrome: Report of a case

A 40-year-old woman with Peutz-Jeghers syndrome and an appendiceal intussusception is reported. In this patient, the lead point was a large sessile, appendiceal polyp. The invaginated and inverted portion of the appendix resembled the long stalk of a pedunculated polyp on roentgenography and endoscopic examination. Histologically, the appendiceal polyp was a villous adenoma with mild to severe atypia and focal carcinoma in situ. In patients with Peutz-Jeghers syndrome, hamartomatous polyps and colorectal adenomatous polyps with highly malignant potential can coexist and must be managed appropriately. Therefore, when evaluating a polypoid or a pedunculated lesion in the cecal lumen, the possibility of an appendiceal intussusception should also be investigated.     

Predictors of survival after liver transplantation for hepatocellular carcinoma associated with Hepatitis C.

The efficacy of orthotopic liver transplantation (OLT) for hepatocellular carcinoma (HCC) associated with hepatitis C virus (HCV) is not well defined. This study examines the variables that may determine the outcome of OLT for HCC in HCV patients. From 1990 to 1999, 463 OLTs were performed for HCV cirrhosis. Of these patients, 67 with concurrent HCC were included in the study. Univariate and multivariate analyses considered the following variables: gender, pTNM stage, tumor size, number of nodules, vascular invasion, incidental tumors, adjuvant chemotherapy, preoperative chemoembolization, alpha-fetoprotein (AFP) tumor marker, lobar distribution, and histological grade. Overall OLT survival of HCV patients diagnosed with concomitant HCC was significantly lower when compared to patients who underwent OLT for HCV alone at 1, 3, and 5 years (75%, 71%, and 55% versus 84%, 76%, and 75%, respectively; P < 0.01). Overall survival of patients with stage I HCC was significantly better than patients with stage II, III, or IV (P < .05). Eleven of 67 patients developed tumor recurrence. Sites of recurrence included transplanted liver (5), lung (5), and bone (1). Twenty-four of 67 patients (36%) died during the follow-up time. Causes of deaths included recurrent HCC in 8 of 24 patients (12%) and recurrent HCV in 3 of 24 patients (4.5%), whereas 13 (19.5%) patients died from causes that were unrelated to HCV or HCC. Both univariate and multivariate analysis demonstrated that pTNM status (I versus II, III, and IV; P < .05) was a reliable prognostic indicator for patient survival. Presence of vascular invasion (P = .0001) and advanced pTNM staging (P = .038) increased risk of recurrence. Multivariate analysis showed that pretransplant chemoembolization and adjuvant chemotherapy reduced risk of death after OLT in HCC recipients. In conclusion, this study demonstrates the effectiveness of OLT for patients with HCC in a large cohort of chronic HCV patients. Advanced tumor stage, and particularly vascular invasion, are poor prognostic indicators for tumor recurrence. Early pTNM stage, adjuvant chemotherapy, and preoperative chemoembolization were associated with positive outcomes for patients who underwent OLT for concomitant HCV and HCC.     

Improvement of porcine islet isolation by inhibition of trypsin activity during pancreas preservation and digestion using α1-antitrypsin

Porcine islets are considered to be a promising resource for xenotransplantation. However, it is difficult to isolate porcine islets because of the marked fragility and rapid dissociation. Endogenous trypsin is one of the main factors to damage islets during the isolation procedure. Recent studies have suggested that trypsin inhibitors during the preservation of pancreas or the collagenase digestion can improve the result of islet isolation. In this study, we examined whether α1-antitrypsin (Aralast?), which inhibits several endogenous proteases and has immunomodulatory properties, can protect islets from the proteases and improve the results of porcine islet isolation. Twelve porcine pancreata were divided into three groups: without Aralast group (standard, n = 5), preserved with Aralast using the ductal injection (DI) method (DI, n = 3), and with Aralast using the DI method and in the collagenase solution (DI+C, n = 4). Efficacy of islet isolation was assessed by islet yields, purity, and viability. The trypsin activity of the preservation and the digestion solution during the isolation procedure was measured. During islet isolation, the trypsin activity in DI+C group was significantly inhibited compared to the standard group, whereas DI group showed less effect than DI+C group. The average of postpurification islet equivalents (IEQ) per pancreas weight in the DI+C group was significantly higher than the standard group (standard: 3516 ± 497 IEQ/g, DI: 4607 ± 1090 IEQ/g, DI+C: 7097 ± 995 IEQ/g; p = 0.017 between standard and DI+C). In the DI+C group, stimulation index was higher than in other groups, although there was no significant difference. The presence of Aralast in both DI solution and collagenase solution markedly inhibited trypsin activity during pancreas digestion procedure and improved the porcine islet isolation. Inhibition of trypsin activity by Aralast could improve porcine islet isolation.     

Islet purification method using large bottles effectively achieves high islet yield from pig pancreas

Porcine islets are a promising resource for xenotransplantation. However, low efficacy of islet isolation because of their marked fragility remains a problem. Recently we found that the standard purification method using COBE 2991 cell processor (COBE) with Ficoll density gradient solution damaged islets mechanically by high shearing force. In this study, we evaluated our new purification method using large plastic bottles for the efficacy of islet purification. Ten porcine pancreata were used. The average warm ischemic time was over 40 min; therefore, these pancreata were considered to be in a marginal condition. After digestion, the digested tissue was divided into three groups. Each group was purified using either top loading method with bottle (top group) or bottom loading method with bottle (bottom group) or standard COBE method (COBE group). Islet yield per pancreas weight (IEQ/g) and the rate of postpurification recovery in the top group were significantly higher than the COBE group (top: 8060 ± 1652 IEQ/g, bottom: 4572 ± 614 IE/g, COBE: 3900 ± 734 IE/g. p < 0.02 in top vs. COBE; top percentage of recovery: 99.3 ± 12.3%, bottom: 62.6 ± 8.8%, COBE: 49.5 ± 6.7%, p < 0.02 in top vs. bottom and COBE). The average sizes of purified islets in the top and bottom groups were significantly larger than COBE group (Average diameter top: 156 ± 8 μm, bottom: 147 ± 6 μm, COBE: 119 ± 6 μm, p < 0.01 in top vs. COBE and in bottom vs. COBE), which indicated that bottle method can reduce shear force during purification. Our new purification using top loading bottle method enabled us to obtain a high yield of porcine islets from marginal pancreata.