CheckMate 274 (NCT02632409), a phase 3 trial of adjuvant nivolumab (NIVO) vs placebo (PBO) in high-risk muscle-invasive urothelial carcinoma (MIUC) after radical resection, demonstrated improved disease-free survival (DFS) with adjuvant NIVO vs PBO in the intent-to-treat (ITT) and tumor PD-L1 expression ≥ 1% populations. We report exploratory analyses (minimum follow-up, 11.0 months) of associations between pre-treatment tumor and immune features and DFS to identify patients (pts) who may potentially benefit most from adjuvant NIVO. Pts were randomized 1:1 to NIVO 240 mg IV every 2 weeks or PBO for ≤ 1 year of adjuvant treatment. Pre-treatment tumor tissue from the most recently resected site or the transurethral resection yielding MIUC diagnosis was provided for biomarker analyses. Tumor mutation burden (TMB; mutations/MB) was measured by whole exome sequencing. CD8+ immune cell infiltration was measured with digital immunohistochemistry (IHC). Gene signature scores were computed from RNA-seq data. Cox proportional hazards models were used to assess association between DFS and biomarkers (continuous scale) and estimate treatment-effect hazard ratios (HRs; NIVO vs PBO) for biomarker tertile subgroups. Of 709 randomized pts, 458, 445, and 323 were evaluable for TMB, CD8 IHC, and RNA-seq. TMB, and CD8 T cell infiltration and IFN-γ signature scores (Table) were positively associated with DFS in the NIVO arm. The associations appeared more pronounced in pts with PD-L1 ≥ 1%. Of these 3 biomarkers, evidence that association with DFS differed between arms was strongest for the IFN-γ signature. Biomarkers associated with preexisting antitumor immunity were associated with improved DFS with NIVO vs PBO, reinforcing the mechanism for benefit with immunotherapy and extending prior findings in metastatic UC to the adjuvant setting. Multivariable modeling is ongoing. Further validation of these exploratory analyses is warranted.Table: 1737MOPopulationDFS HR (95% CI)ITT; n = 7090.70 (0.57–0.85)BiomarkerTertile lowTertile mediumTertile highCD8 IHCOverall; n = 445a0.86 (0.58–1.29)0.78 (0.51–1.21)0.55 (0.33–0.90)PD-L1 ≥ 1%; n = 1790.60 (0.28–1.25)0.44 (0.21–0.92)0.36 (0.17–0.78)PD-L1 < 1%; n = 2641.01 (0.62–1.65)1.12 (0.64–1.95)0.81 (0.41–1.59)IFN-γ gene signatureOverall; n = 323a1.05 (0.64–1.72)0.71 (0.42–1.20)0.28 (0.14–0.54)PD-L1 ≥ 1%; n = 1280.54 (0.20–1.46)0.57 (0.23–1.41)0.12 (0.04–0.41)PD-L1 < 1%; n = 1931.36 (0.76–2.43)0.78 (0.40–1.51)0.57 (0.24–1.33)aTwo patients were not evaluable for PD-L1.CI, confidence interval; IFN-γ, interferon gamma. Open table in a new tab

Tracheal and main bronchial tumors are relatively rare diseases. Primary or metastatic malignant tumors and benign tumors are also found. Even benign tumors can obstruct the airways and may require urgent treatment. We report three cases of endoscopic snare resection.

The treatment of lung cancer has advanced in recent years, and the postoperative survival period has been extended. As a result, the incidence of multiple lung cancer tends to increase. At the time of second surgery, it is necessary to examine the extent of resection in more detail.

10 to 15% of cases of myasthenia gravis have thymoma. In cases with thymoma, extended thymectomy is performed, and surgery is expected to improve symptoms of myasthenia gravis. However, it often takes a long time to improve symptoms after surgery, and there are many unclear points about the cases leading to the improvement of symptoms. In addition, there are cases in which crisis occurs due to surgical stress, and it is necessary to examine the effectiveness of surgery.

ABSTRACTWe examined whether dynamic light across a scheduled 16-h waking day influences cognitive performance, visual comfort, melatonin secretion, sleepiness and sleep under strictly controlled laboratory conditions of 49-h duration.Participants spent the first 5-h in the evening under standard lighting, followed by an 8-h nocturnal sleep episode at habitual bedtimes. Thereafter volunteers either woke up with static daylight LED (100 lux and 4000 Kelvin) or with a dynamic daylight LED that changed color (2700 – 5000 Kelvin) and intensity (0 - 100 lux) across the scheduled 16-h waking day. This was followed by an 8-h nocturnal treatment sleep episode at habitual bedtimes. Thereafter, volunteers spent another 12-h either under static or dynamic light during scheduled wakefulness.Under dynamic light, evening melatonin levels were less suppressed 1.5hours prior to usual bedtime, and participants felt less vigilant in the evening compared to static light. Sleep latency was significantly shorter in both the baseline and treatment night compared to the static light condition while sleep structure, sleep quality, cognitive performance and visual comfort did not significantly change. Our results support the recommendation of using blue-depleted light and low illuminances in the late evening, which can be achieved by a dynamically changing daylight LED solution.

Fukuyama congenital muscular dystrophy (FCMD) is a second common, severe childhood muscular dystrophy with brain anomaly in Japan. All patients have ancestral insertion of a SINE-VNTR-Alu retrotransposal element (SVA) into a causative gene fukutin. We previously showed that aberrant mRNA splicing, induced by SVA exon-trapping caused FCMD. Introduction of three cocktailed antisense oligonucleotides (AONs) targeting around these splice sites prevented pathogenic splicing in FCMD patient cells and model mice, and normalized protein production and functions of Fukutin as well as O-glycosylation of α-dystroglycan. Here we show the results of an optimization of the best, single AON suitable for clinical trial. We re-designed AONs precisely around the splice sites and assessed the efficacy for exon trap inhibition of these AONs in FCMD patient cells and model mice. By testing on normal Fukutin production and functional analysis, we finally selected one best candidate AON termed AON-F. Then we also performed in silico analysis if AON-F has off-target or on-target effect on other sites in human genome. We also succeeded in improvement on production efficacy for AON-F. We show the promise of splicing modulation therapy as the first radical clinical treatment for FCMD in the near future.

LED *Shared senior authors. light sources have a discontinuous light spectrum with a prominent ‘blue’ peak between 450 and 470 nm that influences non-image forming responses in humans. We tested an LED lighting solution mimicking a daylight spectrum on visual comfort, circadian physiology, daytime alertness, mood, cognitive performance and sleep. Fifteen young males twice spent 49 hours in the laboratory under a conventional-LED and under a daylight-LED condition in a balanced cross over design flanked by a baseline and a post-light exposure night. Despite different light spectra, the photopic lux and the correlated colour temperature of the lighting were the same for both LEDs. The colour rendering index and the melanopic strength were 25.3% and 21%, respectively, higher for the daylight LED than the conventional LED. The volunteers had better visual comfort, felt more alert and happier in the morning and evening under daylight LED than conventional LED, while the diurnal melatonin profile, psychomotor vigilance and working memory performance were not significantly different. Delta EEG activity (0.75–4.5 Hz) was significantly higher after daylight-LED than conventional-LED exposure during the post-light exposure night. We have evidence that a daylight-LED solution has beneficial effects on visual comfort, daytime alertness, mood and sleep intensity in healthy volunteers.

We investigate the EQ-5D index in a randomized trial for human epidermal growth factor receptor type 2 (HER2) positive elderly breast cancer patients who receive trastuzumab with and without chemotherapy as postoperative adjuvant therapy. Women aged 70 to 80 years who underwent curative resection of HER2-positive primary breast cancer were randomly assigned to receive either trastuzumab (once at 8 mg/kg and then 6 mg/kg every 3 weeks for 1 year) plus chemotherapy (selected from prescribed regimens) or trastuzumab alone. The EQ-5D was assessed before randomization and at 2, 12, and 36 months after treatment initiation. Adjusted mean EQ-5D indices were estimated and compared between the two groups using linear mixed-effect models. Proportions of the deteriorated EQ-5D index based on the minimally important difference of 0.1 were also compared between the two groups. Of randomized 275 patients, 233 patients were included in the EQ-5D index analyses. Completion rates after treatment initiation ranged from 76 to 89%. At 2 months after treatment initiation, adjusted mean EQ-5D indices were 0.838 in the trastuzumab group and 0.771 in the trastuzumab plus chemotherapy group (difference, 0.067; 95% confidence interval [CI] 0.028–0.105). Adjusted mean EQ-5D index at 36 months was also higher in the trastuzumab group than in the trastuzumab plus chemotherapy group (0.834 and 0.785, respectively; difference, 0.049; 95% CI 0.003–0.094). In trastuzumab group, 12.1% of patients reported the deteriorated EQ-5D index at 2 months, whereas that proportion in the trastuzumab plus chemotherapy group was 29.7% (risk ratio, 0.41; 95% CI 0.22–0.75). The risk ratios for the deteriorated EQ-5D index at 12 and 36 months were 0.51 and 0.48, respectively. Trastuzumab without chemotherapy results in improved health status measured by the EQ-5D during adjuvant therapy and even thereafter.