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Objectives: A few studies on antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treatments have shown the therapeutic efficacy of mycophenolate mofetil (MMF). However, the therapeutic efficacy of MMF compared with that of cyclophosphamide (CYC) in patients with AAV has not been established. We conducted a systematic review and meta-analysis to assess the efficacy of MMF as a remission induction therapy in patients with AAV comparing it with the efficacy of CYC., Methods: We searched randomised controlled trials (RCTs) comparing the efficacy of MMF with that of CYC in patients with AAV on three different websites: PubMed, Cochrane Library and Google Scholar. We compared the difference in the relative risk (RR) of each outcome based on a Mantel-Haenszel random-effects model., Results: We analysed data from four RCTs with 300 patients for the study. The 6-month remission rate (RR 1.09, 95% CI 0.86 to 1.38, p=0.48), the 6-month ANCA negativity (RR 1.31, 95% CI 0.91 to 1.90, p=0.15) and the long-term relapse rate (RR 1.36, 95% CI 0.80 to 2.31, p=0.26) were all similar between the two treatments. The rates of death, infection and leucopenia were also similar between the two groups (RR 1.05, 95% CI 0.40 to 2.74, p=0.93; RR 1.26, 95% CI 0.79 to 2.01, p=0.33; RR 0.45, 95% CI 0.16 to 1.32, p=0.15, respectively)., Conclusions: We found no difference between the therapeutic efficacy of MMF and that of CYC in patients with AAV. MMF may be an alternative remission induction therapy in patients with non-life-threatening AAV., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

A 66-year-old woman with symptoms of fatigue and headache was diagnosed with giant cell arteritis (GCA). Fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) revealed the strong accumulation of FDG in the descending aorta, abdominal aorta, bilateral subclavian artery, and total iliac artery. Diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) showed signal enhancement at the descending aorta and abdominal aorta. We repeated FDG-PET and DWIBS 2 months after the initiation of therapy with prednisolone. In line with the FDG-PET findings, the signal enhancement of the aortic wall completely vanished on DWIBS. DWIBS may be a novel useful tool for the diagnosis and follow-up of GCA treatment.

A 26-year-old woman with Takayasu's arteritis (TAK) experienced back and neck pain during tocilizumab (TCZ) treatment. The levels of C-reactive protein were normal, and ultrasonography revealed no significant changes. Diffusion-weighted whole-body imaging with background body signal suppression (DWIBS) showed signal enhancement in the walls of several arteries. Contrast computed tomography showed arterial inflammation in the same lesion. After increasing the dose of prednisolone and TCZ, all signal enhancements decreased and continued to decrease, as observed on days 76 and 132. Thus, DWIBS may be a novel imaging modality for assessing the disease activity of TAK, particularly during follow-up.

Objectives: To examine the influence of smoking on biologics treatment against different therapeutic targets, such as TNFα, IL-6, and T cell, in rheumatoid arthritis (RA) and elucidate the underlying molecular mechanism., Methods: The association between drug-discontinuation due to poor therapeutic response and smoking status was analyzed individually in biologics against different therapeutic targets by a multivariable logistic regression analysis using the "NinJa" Registry, one of the largest cohorts of Japanese RA patients. In vitro enhancement of TNFα-induced NF-κB activation and subsequent proinflammatory cytokine production by cigarette chemical components was examined by RT-PCR, qPCR, ELISA, and western blotting using an immortalized rheumatoid synovial cell line, MH7A., Results: The rate of drug-discontinuation due to poor therapeutic response was higher in the current smoking group than in the never- or ever-smoking groups (the odds ratio of current/never smoking: 2.189, 95%CI; 1.305-3.672,P = 0.003; current/ever: 1.580, 95%CI; 0.879-2.839,P = 0.126) in the TNF inhibitor (TNFi) treatment group. However, this tendency was not observed in either the IL-6 or T cell inhibitor treatment groups. Cigarette smoke chemical components, such as benzo[α]pyrene, known as aryl hydrocarbon receptor (AhR) ligands, themselves activated NF-κB and induced proinflammatory cytokines, IL-1β and IL-6. Furthermore, they also significantly enhanced TNFα-induced NF-κB activation and proinflammatory cytokine production. This enhancement was dominantly inhibited by Bay 11-7082, an NF-κB inhibitor., Conclusions: These results suggest a crosstalk between TNFα signaling and AhR signaling in NF-κB activation which may constitute one of the molecular mechanisms underlying the higher incidence of drug-discontinuation in RA patients undergoing TNFi treatment with smoking habits., (Copyright © 2018. Published by Elsevier Ltd.)

Given the hypothesis that inflammation plays a critical role in the progression of cardiovascular diseases, the aim of the present study was to identify new diagnostic and prognostic biomarkers of myocardial proteins involved in early-phase cardiac impairment, using proteomics analysis. Using the two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) combined with MALDI-TOF/TOF tandem mass spectrometry, we compared differences in the expression of proteins in the whole left ventricles between control hamsters, dilated cardiomyopathic hamsters (TO-2), and hypertrophy cardiomyopathic hamsters (Bio14.6) at 6 weeks of age (n = 6, each group). Proteomic analysis identified 10 protein spots with significant alterations, with 7 up-regulated and 3 down-regulated proteins in the left ventricles of both TO-2 and Bio 14.6 hamsters, compared with control hamsters. Of the total alterations, peroxiredoxin 2 (PRDX2) showed significant upregulation in the left ventricles of TO-2 and Bio 14.6 hamsters. Our data suggest that PRDX2, a redox regulating molecule, is involved in early-phase left ventricular impairment in hamsters with cardiomyopathy.

Inflammation enhanced by accumulation of reactive oxygen species plays an essential role in the progression of cardiovascular diseases. Using the 2D-oxyblot analysis and 2D-difference image gel electrophoresis (2D-DIGE), we compared the levels of ROS-induced carbonyl modification of myocardial proteins in the whole left ventricles between 6-week-old hamsters with dilated (TO-2) and hypertrophic cardiomyopathy (Bio14.6) and control hamsters (F1B). Then, 2D electrophoresis combined with MALDI-TOF/TOF tandem mass spectrometry detected 18 proteins with increased carbonyl level in cardiomyopathy hamsters compared with control hamster. Carbonyl modification of proteins related to ATP synthesis, including citric acid cycle and electron transport system, was observed in the hearts of hamsters with both types of cardiomyopathy. Further analysis indicated that left ventricular carbonyl production correlated negatively with succinyl-CoA:3-ketoacid-coenzyme A transferase 1 activity (r 2  = 0.60, P = 0.0007) and ATP concentration (r 2  = 0.29, P = 0.037), suggesting that protein carbonylation has negative effects on the levels of these biomolecules. Furthermore, carbonyl production significantly correlated with plasma Troponin T level (r 2  = 0.33, P = 0.026). Reduction of energy metabolism by oxidative damage may contribute to the development of left ventricular impairment in cardiomyopathy.

Chamobtusin A, a unique diterpene alkaloid isolated from Chamaecyparis obtusa cv. tetragon, is considered to be biosynthesized from an abietane diterpenoid. On the basis of this biosynthetic hypothesis, ferruginol (15) was synthesized from (+)-dehydroabietylamine and then biomimetically transformed into (-)-chamobtusin A in 6 steps (12 steps from (+)-dehydroabietylamine).

Background: A phase III trial was conducted to determine whether neoadjuvant chemotherapy (NACT) before radical surgery (RS) improves overall survival., Methods: Patients with stage IB2, IIA2, or IIB squamous cell carcinoma of the uterine cervix were randomly assigned to receive either BOMP (bleomycin 7 mg days 1-5, vincristine 0.7 mg m(-2) day 5, mitomycin 7 mg m(-2) day 5, cisplatin 14 mg m(-2) days 1-5, every 3 weeks for 2 to 4 cycles) plus RS (NACT group) or RS alone (RS group). Patients with pathological high-risk factors received postoperative radiotherapy (RT). The primary end point was overall survival., Results: A total of 134 patients were randomly assigned to treatment. This study was prematurely terminated at the first planned interim analysis because overall survival in the NACT group was inferior to that in the RS group. Patients who received postoperative RT were significantly lower in the NACT group (58%) than in the RS group (80%; P=0.015). The 5-year overall survival was 70.0% in the NACT group and 74.4% in the RS group (P=0.85)., Conclusion: Neoadjuvant chemotherapy with BOMP regimen before RS did not improve overall survival, but reduced the number of patients who received postoperative RT.

Background: The aim of this phase II study was to evaluate the efficacy and toxicity of docetaxel and irinotecan combination chemotherapy in patients with ovarian cancer refractory and resistant to both platinum and taxan treatment., Patients and Methods: Patients who had been treated with platinum and paclitaxel but whose ovarian cancer progressed or recurred within 6 months of treatment (n = 41) received docetaxel 60 mg/m(2) (day 1) and irinotecan 60 mg/m(2) (days 1, 8), repeated every 21 days [Japan Gynecologic Oncology Group (JGOG) study 3015] or every 28 days [West Japan Gynecologic Oncology Group (WJGOG) study 002] until disease progression was observed or unacceptable toxicity. Sixteen patients had platinum/paclitaxel-refractory disease, and 25 patients had platinum/paclitaxel-resistant disease., Results: Thirty-two patients were available for determination of the clinical response. The overall response rate [complete response (CR) + partial response (PR)] was 6.3%, and the disease control rate (CR + PR + stable disease) was 34.4%. Among the 23 patients with resistant tumor, the disease control rate was 47.8%. Ten patients with refractory tumor showed a 10% disease control rate. The median progression-free interval was 12.1 weeks and the median overall survival time was 45.3 weeks. The major toxic adverse effect was neutropenia (grade 4, 56.1%), but the incidence of neutropenic fever was less frequent (4.9%). Neurotoxicity and gastro-intestinal toxicity were mild., Conclusion: Among our patients, a combination of docetaxel and irinotecan was well tolerated. However, this combination may not be a beneficial option for patients with platinum-refractory and -resistant ovarian cancer in terms of response rate and survival.

In this study, we aimed to develop a histological grading system for ovarian clear cell adenocarcinoma (CCA), based on the tumor growth architectures. Cases were defined as Group A if ≥90% of a tumor examined was composed of well-differentiated tubulocystic and/or papillary architectures; Group C if at least 10% of the tumor was composed of very poorly differentiated histology (i.e. solid masses or individual infiltrating tumor cells with no or little glandular/papillary differentiation); and tumors not corresponding to the first 2 descriptions were defined as Group B. The interobserver reproducibility and prognostic value of the assigned groups were analyzed for 159 CCAs from 5 institutions. The level of agreement in assigning the groups between 2 pathologists was 88.7% (=0.82). After consensus was reached, 46 (29%), 79 (50%), and 34 (21%) tumors were classified in Groups A, B, and C, respectively. In early-stage cases [International Federation of Gynecology and Obstetrics (FIGO) stage I-II], Group A tumors had significantly better outcomes (100% 5-yr survival) than Group B tumors (82% 5-yr survival, P=0.024 by log-rank test) or Group C tumors (56% 5-yr survival, P=0.00054 by log-rank test). Moreover, early-stage Group B tumors had significantly better outcomes than Group C tumors (P<0.001 by a generalized Wilcoxon test). In advanced cases (FIGO stage III-IV), Group A tumors had significantly better outcomes than Group C tumors (52% vs. 16% 5-yr survival, respectively, P=0.043). Group A and C tumors defined with our system were identified to have favorable and unfavorable prognostic factors, respectively, independent of the clinical stage of the disease and presence of residual tumors after the initial surgery. The proposed grouping system could divide patients with CCA into 3 subgroups with distinct prognostic indications, providing a 3-tier histological grading system for ovarian CCA.

In this study, we aimed to determine whether the presence of poorly differentiated histologic components in ovarian clear cell adenocarcinoma (CCA) affects patient prognosis. Pathologic slides from 159 patients with CCA were studied, and the tumors were classified as Por(+) in the event of poorly differentiated histology; that is, if solid masses or cords, or individual infiltrating tumor cells with little or no glandular/papillary differentiation were present in >5% of the tumor area examined. All other tumors were classified as Por(-). The prognostic value and interobserver reproducibility of this assignment were analyzed. The agreement level in the assignment between 2 pathologists was 93.7% (κ=0.86). After a consensus was reached, 53 (33%) and 106 (67%) tumors were classified as Por(+) and Por(-), respectively. Patients with Por(+) tumors showed a significantly worse outcome than those with Por(-) tumors, both in the early stages (stages I/II, 5-year survival rate 53.9% vs. 96.3%, P<0.0001 by log-rank test) and advanced stages (stages III/IV, 5-year survival rate 26.5% vs. 49.2%, P<0.001 by generalized Wilcoxon test). Por(-) tumors showed an effective response to postoperative platinum-based first-line chemotherapy more frequently compared with Por(+) tumors (48% vs. 14%, P=0.042). The Por(+) tumor was found to be an independent prognostic factor for survival irrespective of the clinical stage or presence of residual tumor after the initial surgery. These results suggest that the tumor with a poorly differentiated histology is an adverse prognostic subgroup in ovarian CCA. On the basis of the prognostic impact and interobserver reproducibility, the present binary classification system for CCAs was deemed to be highly superior to the compared conventional histologic grading system.

GEX1A is a microbial product with antitumor activity. HeLa cells cultured with GEX1A accumulated p27(Kip) and its C-terminally truncated form p27*. GEX1A inhibited the pre-mRNA splicing of p27, producing p27* from the unspliced mRNA containing the first intron. p27* lacked the site required for E3 ligase-mediated proteolysis of p27, leading to its accumulation in GEX1A-treated cells. The accumulated p27* was able to bind to and inhibit the cyclin E-Cdk2 complex that causes E3 ligase-mediated degradation of p27, which probably triggers the accumulation of p27. By using a series of photoaffinity-labeling derivatives of GEX1A, we found that GEX1A targeted SAP155 protein, a subunit of SF3b responsible for pre-mRNA splicing. The linker length between the GEX1A pharmacophore and the photoreactive group was critical for detection of the GEX1A-binding protein. GEX1A serves as a novel splicing inhibitor that specifically impairs the SF3b function by binding to SAP155.

Pathologic slides from 150 patients with clear cell adenocarcinoma from the collaborating institutions were reviewed independently by 2 pathologists, and each tumor was graded histologically using the Shimizu-Silverberg and International Federation of Gynecology and Obstetrics (FIGO) grading systems. For the Shimizu-Silverberg grading system, 3 parameters-architectural pattern, nuclear pleomorphism, and mitotic activity-were assessed and scored as 1 to 3. When the summed scores of these parameters were 3 to 5, 6 to 7, and 8 to 9, grades 1, 2, and 3 were assigned, respectively. The FIGO grade was based on the ratio of glandular/papillary growth versus solid growth: grade 1, less than 5% solid tumor; grade 2, 5% to 50% solid tumor; grade 3, greater than 50% solid tumor. Interobserver agreement levels for assignment of both gradings were fair (κ=0.32 and 0.24, respectively). After consensus had been acquired, 82 (55%), 56 (37%), and 12 (8%) tumors were classified as grades 1, 2, and 3 by the Shimizu-Silverberg grading system, and 88 (59%), 38 (25%), and 24 (16%) were classified as grades 1, 2, and 3 by the FIGO grading system, respectively. Survival analyses indicated that patients with grade 3 tumors, as defined by both the grading systems, tended to have a poor outcome, but any differences between them were not statistically significant. Multivariate analysis showed that only the presence of residual tumor after initial surgery was an independent prognostic factor for overall survival. These results suggest that the 2 tested grading systems have limited value for the prognostication of patients with clear cell adenocarcinoma, and that a more effective grading system for this tumor may be required.

Introduction: Ovarian clear cell carcinoma (CCC) is regarded as grade 3 tumor, and the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines recommend adjuvant chemotherapy for the tumor even at stage IA. However, CCC often showed chemo-resistant phenotype, and the effect of adjuvant chemotherapy still remained uncertain., Methods: Clear cell carcinoma cases treated at collaborating institutions during the period 1992-2005 were retrospectively identified. After a central pathological review, survival analysis was estimated by the Kaplan-Meier method, and prognostic factors were evaluated using a Cox regression model., Results: Among 219 patients with stage I CCC, 195 patients received adjuvant chemotherapy (C+) and 24 patients (C-) did not. The C+ group had 77 pT1a and 118 pT1c cases, and the C- group included 18 pT1a and 6 pT1c tumors (P < 0.001). The median age was 52 years in the C+ group and 57 years in C- group (P = 0.04). During the median follow-up period of 48 months (range, 7-160 years), relapse was observed in one patient (4%) in the C- group and in 35 patients (18%) in the C+ group. There were no statistical differences of progression-free survival and overall survival between the C+ and the C- groups. Multivariate analysis revealed that peritoneal cytology status (P = 0.02) and pT status (P = 0.04) were independent prognostic factors for progression-free survival; however, adjuvant chemotherapy was not a prognostic factor (P = 0.80)., Conclusions: Although the present study was a limited retrospective investigation, it suggested that adjuvant chemotherapy had little impact on the survival of stage I CCC patients. Further strategy, such as a molecular targeting agent, is needed to improve survival of CCC, especially in cases with positive peritoneal washing.

A total synthesis of (±)-chamobtusin A has been accomplished on the basis of our presumed biosynthetic pathway: the imine formation of keto aldehyde followed by intramolecular aza-Michael addition.