First-line nivolumab plus ipilimumab versus chemotherapy in patients with unresectable malignant pleural mesothelioma: 3-year outcomes from CheckMate 743.

BACKGROUND: In the phase III CheckMate 743 study (NCT02899299), first-line nivolumab plus ipilimumab significantly improved overall survival (OS) versus chemotherapy in patients with unresectable malignant pleural mesothelioma (MPM). We report updated data with 3-year minimum follow-up. PATIENTS AND METHODS: Adults with previously untreated, histologically confirmed, unresectable MPM and Eastern Cooperative Oncology Group performance status of ≤1 were randomized 1 : 1 to nivolumab (3 mg/kg every 2 weeks) plus ipilimumab (1 mg/kg every 6 weeks) for up to 2 years, or six cycles of platinum plus pemetrexed chemotherapy. This report includes updated efficacy and safety outcomes, exploratory biomarker analyses including four-gene inflammatory expression signature score, and a post hoc efficacy analysis in patients who discontinued treatment due to treatment-related adverse events (TRAEs). RESULTS: With a median follow-up of 43.1 months, nivolumab plus ipilimumab continued to prolong OS versus chemotherapy. Median OS was 18.1 versus 14.1 months [hazard ratio (95% confidence interval), 0.73 (0.61-0.87)], and 3-year OS rates were 23% versus 15%, respectively. Three-year progression-free survival rates were 14% versus 1%, and objective response rates were 40% versus 44%. At 3 years, 28% versus 0% of responders had an ongoing response. Improved survival benefit with nivolumab plus ipilimumab versus chemotherapy was observed across subgroups, including histology. A high score of the four-gene inflammatory signature appeared to correlate with improved survival benefit with nivolumab plus ipilimumab. No new safety signals were observed with nivolumab plus ipilimumab, despite patients being off therapy for 1 year. In patients who discontinued nivolumab plus ipilimumab due to TRAEs, median OS was 25.4 months, and 34% of responders maintained their responses for ≥3 years after discontinuation. CONCLUSIONS: With 3 years' minimum follow-up, nivolumab plus ipilimumab continued to provide long-term survival benefit over chemotherapy and a manageable safety profile, supporting the regimen as standard-of-care treatment for unresectable MPM, regardless of histology.

Gene polymorphisms in antioxidant enzymes correlate with the efficacy of androgen-deprivation therapy for prostate cancer with implications of oxidative stress.

Background: Oxidative stress mitigated by antioxidant enzymes is thought to be involved in the progression to castration-resistant prostate cancer (CRPC) during androgen-deprivation therapy (ADT). This study investigated the association between genetic variations in antioxidant enzymes and the efficacy of ADT as well as its biological background. Patients and methods: The non-synonymous or promoter-locating polymorphisms of antioxidant enzymes were examined as well as the time to CRPC progression and overall survival in 104 and 92 patients treated with ADT for metastatic and non-metastatic prostate cancer, respectively. In addition, intracellular reactive oxygen species and expression levels of antioxidant enzymes were examined in castration-resistant and enzalutamide-resistant cells. Results: In metastatic prostate cancer, the AG/GG allele in GSTM3 rs7483 and CT/TT allele in CAT rs564250 were associated with a significantly lower risk of progression to CRPC and all-cause death compared with homozygotes of the major AA allele (hazard ratio [HR]; [95% confidence interval (CI)], 0.55 [0.34-0.86], P = 0.0086) and CC allele (HR; [95% CI], 0.48 [0.24-0.88], P = 0.016), respectively. On multivariate analyses, only GSTM3 rs7483 was associated with significant progression risk (AG/GG versus AA; HR; [95% CI], 0.45 [0.25-0.79], P = 0.0047) even after Bonferroni adjustment. In non-metastatic prostate cancer, the AG/GG allele in GSTM3 rs7483 was associated with a significantly lower risk of progression to CRPC (HR; [95% CI], 0.35 [0.10-0.93], P = 0.034) and all-cause death (HR; [95% CI], 0.26 [0.041-0.96], P = 0.043) compared with the AA allele. Intracellular reactive oxygen species levels were increased, accompanied with augmented GSTM3 expression in both castration-resistant and enzalutamide-resistant cells. Conclusions: Differential activity of antioxidant enzymes caused by the polymorphism in GSTM3 may contribute to resistance to hormonal therapy through oxidative stress. The GSTM3 rs7483 polymorphism may be a promising biomarker for prostate cancer patients treated with ADT.

Decreased level of interleukin-10-producing B cells in patients with pemphigus but not in patients with pemphigoid.

BACKGROUND: While the frequency of interleukin (IL)-10-producing B (B10) cells is reported to have an inverse correlation with disease activity in some human autoimmune diseases, the association between B10 cells and autoimmune blistering diseases (AIBD) has not been well evaluated. Although several phenotypes of human regulatory B cells have been proposed, the most appropriate one in AIBD has not been established. OBJECTIVE: To evaluate B10 cells in AIBD including their phenotypes. METHODS: Peripheral blood mononuclear cells were isolated from 39 patients with AIBD, including 14 with pemphigus and 25 with pemphigoid, and 10 healthy controls. We investigated the frequencies of B10 cells and CD19+ CD24hi CD38hi B cells using flow cytometry. RESULTS: The frequencies of B10 cells and CD19+ CD24hi CD38hi B cells were significantly lower and higher, respectively, in patients with pemphigus compared with healthy controls. Comparing patients with pemphigoid and healthy controls, no significant difference in the frequencies of B10 cells and CD19+ CD24hi CD38hi B cells was observed. B10-cell level in pemphigus was not associated with disease severity but inversely correlated with the required dose of steroid for treatment. While no significant difference in the frequency of IL-10-producing cells among CD19+ CD24hi CD38hi B cells was observed, in CD9+ and CD27- B-cell subsets it was significantly decreased in patients with pemphigus compared with healthy controls. CONCLUSIONS: Our results suggest the association of B10 cells with pemphigus but not with pemphigoid. The decrease in B10-cell level in pemphigus is partly caused by the lower production of IL-10 in CD9+ and CD27- B-cell subsets.

EFFECTS OF EXPOSURE TO RADIOACTIVE 56MnO2 POWDER ON HYALURONAN SYNTHASE 2 IN THE LUNGS OF RATS.

Manganese-56 (56Mn) is among the predominant radioisotopes produced in soil by neutrons from atomic bombs. Previously, we examined the effects of the internal exposure of this radioisotope in Wistar rats and reported significant pathological changes in the lung and small intestine. In the present study, we focused on its effects on hyaluronan synthase 2 (Has2) gene expression that may related to pathological changes in the lung. Ten-week-old male Wistar rats were exposed to neutron-activated 56MnO2 powder, non-radioactive MnO2 powder or external 60Co γ-rays (2 Gy, whole body). Animals were examined on days 3, 14, and 60 post-exposure. Absorbed doses in the lung of rats exposed to 56Mn were 55-110 mGy. Quantitative reverse transcription polymerase chain reaction analysis revealed that 56Mn exposure significantly reduced the expression of Has2 gene in the lung, while γ-rays did not change it. Our findings suggest that internal exposure to 56Mn, even at low doses, has a significant biological impact on the lung compared with external radiation.

Deposition of elafin in the involved vascular wall of neutrophil-mediated cutaneous vasculitis.

BACKGROUND: Neutrophil elastase plays an important role in skin inflammation induced by neutrophil infiltration. Elafin is an inducible elastase inhibitor expressed by keratinocytes, and is known to be involved in pathogenesis of neutrophilic skin disorders such as psoriasis. METHODS: Immunohistochemical studies of elafin expression in the cases of vasculitis were performed. Induction of elafin expression in cultured vascular cells and its effect on neutrophil migration were studied in vitro. RESULTS: A positive immunoreactivity was detected in polyarteritis nodosa, giant cell arteritis and Schönlein-Henoch purpura, but no immunoreactivity was found in Churg-Strauss syndrome. Elafin expression in cultured venous endothelial cells and arterial smooth muscle cells was undetectable, but induced by interleukin-1ß (IL-1ß) and IL-8. Elafin inhibited the elastin peptide-induced neutrophil chemotaxis at the concentration of 10(-8) -10(-5) mol/L. CONCLUSION: Elafin deposition induced by cytokines (IL-1ß or IL-8) will be an important regulator for the progress of leucocytoclastic vasculitis by functioning as an inhibitor for neutrophil chemotaxis as well as for vascular elastin degradation.

Cardiovascular response to exercise training in the systemic right ventricle of adults with transposition of the great arteries.

KEY POINTS: Patients with transposition of the great arteries (TGA) and systemic right ventricles have premature congestive heart failure; there is also a growing concern that athletes who perform extraordinary endurance exercise may injure the right ventricle. Therefore we felt it essential to determine whether exercise training might injure a systemic right ventricle which is loaded with every heartbeat. Previous studies have shown that short term exercise training is feasible in TGA patients, but its effect on ventricular function is unclear. We demonstrate that systemic right ventricular function is preserved (and may be improved) in TGA patients with exercise training programmes that are typical of recreational and sports participation, with no evidence of injury on biomarker assessment. Stroke volume reserve during exercise correlates with exercise training response in our TGA patients, identifying this as a marker of a systemic right ventricle (SRV) that may most tolerate (and possibly even be improved by) exercise training. ABSTRACT: We aimed to assess the haemodynamic effects of exercise training in transposition of the great arteries (TGA) patients with systemic right ventricles (SRVs). TGA patients have limited exercise tolerance and early mortality due to systemic (right) ventricular failure. Whether exercise training enhances or injures the SRV is unclear. Fourteen asymptomatic patients (34 ± 10 years) with TGA and SRV were enrolled in a 12 week exercise training programme (moderate and high-intensity workouts). Controls were matched on age, gender, BMI and physical activity. Exercise testing pre- and post- training included: (a) submaximal and peak; (b) prolonged (60 min) submaximal endurance and (c) high-intensity intervals. Oxygen uptake (V̇O2; Douglas bag technique), cardiac output (Q̇c, foreign-gas rebreathing), ventricular function (echocardiography and cardiac MRI) and serum biomarkers were assessed. TGA patients had lower peak V̇O2, Q̇c, and stroke volume (SV), a blunted Q̇c/V̇O2 slope, and diminished SV response to exercise (SV increase from rest: TGA = 15.2%, controls = 68.9%, P < 0.001) compared with controls. After training, TGA patients increased peak V̇O2 by 6 ± 8.5%, similar to controls (interaction P = 0.24). The magnitude of SV reserve on initial testing correlated with Q̇c training response (r = 0.58, P = 0.047), though overall, no change in peak Q̇c was observed. High-sensitivity troponin T (hs-TnT) and N-terminal prohormone of brain naturetic peptide (NT pro-BNP) were low and did not change with acute exercise or after training. Our data show that TGA patients with SRVs in this study safely participated in exercise training and improved peak V̇O2. Neither prolonged submaximal exercise, nor high-intensity intervals, nor short-term exercise training seem to injure the systemic right ventricle.

Wells syndrome associated with Churg­Strauss syndrome.

Churg­Strauss syndrome (CSS) is a systemic vasculitis occurring in patients with a history of asthma. Wells' syndrome (WS) is a rare inflammatory dermatosis that clinically resembles cellulitis, and is histologically characterized by eosinophilic infiltration and flame figures. We report a case of WS associated with CSS. There have been three previous reports of WS associated with CSS; ours is the fourth. All cases had bullous lesions, and three cases were positive for antineutrophil cytoplasmic antibodies.

Anti-PD-1 antibody monotherapy versus anti-PD-1 plus anti-CTLA-4 combination therapy as first-line immunotherapy in unresectable or metastatic mucosal melanoma: a retrospective, multicenter study of 329 Japanese cases (JMAC study).

BACKGROUND: Anti-programmed cell death protein 1 (PD-1) antibody monotherapy (PD1) has led to favorable responses in advanced non-acral cutaneous melanoma among Caucasian populations; however, recent studies suggest that this therapy has limited efficacy in mucosal melanoma (MCM). Thus, advanced MCM patients are candidates for PD1 plus anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) combination therapy (PD1 + CTLA4). Data on the efficacy of immunotherapy in MCM, however, are limited. We aimed to compare the efficacies of PD1 and PD1 + CTLA4 in Japanese advanced MCM patients. PATIENTS AND METHODS: We retrospectively assessed advanced MCM patients treated with PD1 or PD1 + CTLA4 at 24 Japanese institutions. Patient baseline characteristics, clinical responses (RECIST), progression-free survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier analysis, and toxicity was assessed to estimate the efficacy and safety of PD1 and PD1 + CTLA4. RESULTS: Altogether, 329 patients with advanced MCM were included in this study. PD1 and PD1 + CTLA4 were used in 263 and 66 patients, respectively. Baseline characteristics were similar between both treatment groups, except for age (median age 71 versus 65 years; P < 0.001). No significant differences were observed between the PD1 and PD1 + CTLA4 groups with respect to objective response rate (26% versus 29%; P = 0.26) or PFS and OS (median PFS 5.9 months versus 6.8 months; P = 0.55, median OS 20.4 months versus 20.1 months; P = 0.55). Cox multivariate survival analysis revealed that PD1 + CTLA4 did not prolong PFS and OS (PFS: hazard ratio 0.83, 95% confidence interval 0.58-1.19, P = 0.30; OS: HR 0.89, 95% confidence interval 0.57-1.38, P = 0.59). The rate of ≥grade 3 immune-related adverse events was higher in the PD1 + CTLA4 group than in the PD1 group (53% versus 17%; P < 0.001). CONCLUSIONS: First-line PD1 + CTLA4 demonstrated comparable clinical efficacy to PD1 in Japanese MCM patients, but with a higher rate of immune-related adverse events.

Description of International Caenorhabditis elegans Experiment first flight (ICE-FIRST).

Traveling, living and working in space is now a reality. The number of people and length of time in space is increasing. With new horizons for exploration it becomes more important to fully understand and provide countermeasures to the effects of the space environment on the human body. In addition, space provides a unique laboratory to study how life and physiologic functions adapt from the cellular level to that of the entire organism. Caenorhabditis elegans is a genetic model organism used to study physiology on Earth. Here we provide a description of the rationale, design, methods, and space culture validation of the ICE-FIRST payload, which engaged C. elegans researchers from four nations. Here we also show C. elegans growth and development proceeds essentially normally in a chemically defined liquid medium on board the International Space Station (10.9 day round trip). By setting flight constraints first and bringing together established C. elegans researchers second, we were able to use minimal stowage space to successfully return a total of 53 independent samples, each containing more than a hundred individual animals, to investigators within one year of experiment concept. We believe that in the future, bringing together individuals with knowledge of flight experiment operations, flight hardware, space biology, and genetic model organisms should yield similarly successful payloads.

Monitoring of hemostatic abnormalities in major orthopedic surgery patients treated with edoxaban by APTT waveform.

INTRODUCTION: An analysis of the activated partial thromboplastin time (APTT) in major orthopedic surgery patients receiving edoxaban for the prevention of venous thromboembolism (VTE) was carried out. METHODS: The APTT waveform was analyzed in the above patients to monitor edoxaban administration. RESULTS: Of these 99 patients, 12 exhibited deep vein thrombosis, and 25 had massive bleeding. An increased biphasic pattern of the APTT waveform was observed after the administration of edoxaban, but there were no significant differences between the patients with and without complications. The peak times of acceleration, velocity, and 1/2 fibrin formation were significantly prolonged after the administration of edoxaban, especially in patients with massive bleeding, and were moderately correlated with the anti-Xa activity. While the heights of velocity and acceleration peak 2 were lower in patients receiving warfarin treatment than in those receiving edoxaban, the widths of these parameters were significantly longer. The height of 1/2 fibrin formation and the width of acceleration peaks 1 and 2 and the velocity were significantly increased after the administration of edoxaban. CONCLUSION: The peak time of the APTT waveform was significantly prolonged after the administration of edoxaban. The analysis of the APTT waveform may therefore be useful for the prediction of the risk of massive bleeding.

Culture substrates made of elastomeric micro-tripod arrays for long-term expansion of human pluripotent stem cells.

Culturing and expansion of human pluripotent stem cells (hPSCs) depend on the chemical and physical properties of the substrates. Gel-coated substrates providing low stiffness are commonly used for long-term pluripotency maintenance of hPSCs. We previously reported that gelatin nanofibrous substrates also allow long-term culturing of hPSCs, suggesting the importance of three-dimensional (3D) organization of extracellular matrix proteins. To further evaluate the significance of 3D features and material stiffness, we fabricated elastomeric micro-tripod arrays (MTAs) and maintained hPSC propagation over 10 passages without observing the pluripotency loss or the development of chromosomal abnormality. We also found that the hPSC colonies on MTAs were more rounded than those on gel-coated flat substrates. Theoretical analyses suggested that the effective stiffness of elastomeric MTAs is comparable to that of gel-coated substrates and that the effect of structural anisotropy is negligible. Cells on MTAs benefit from enhanced diffusion underneath the hPSC colonies as well as enzyme-free detachment from the substrate during passage.

Expression of Neuropeptide Y gene in mouse testes during testicular development.

AIM: To elucidate the distribution and regulation of Neuropeptide Y (NPY) gene expression in testes under physiological and pathophysiological conditions, such as testicular development, fasting and experimental cryptorchidism. METHODS: In the first experiment, C57BL/6J male mice at the ages of 3 days as well as 2, 3, 5 and 8 weeks were used. In the second and third experiments, adult C57BL/6J male mice were subjected to fasting for 48 h and experimental cryptorchidism for 72 h. The NPY transcripts were detected by isotopic in situ hybridization histochemistry. RESULTS: The NPY transcripts were exclusively expressed in the interstitial cells regardless of the age groups and experimental conditions. The NPY mRNA levels were found to increase significantly with age (from the neonatal to prepubertal period [P<0.01] and from the prepubetal to postpubertal period [P<0.01]). Food deprivation for 48 h resulted in a significant increase in the NPY mRNA levels in the arcuate nucleus of the hypothalamus (P<0.01), but not in the testes. Experimental cryptorchidism for 72 h failed to regulate the NPY gene expression in the testes. CONCLUSION: NPY gene expression is distributed in Leydig cells and increases in line with testicular development. The regulation of testicular NPY is different from that of hypothalamic NPY.