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Objectives: To assess the clinical benefit of pembrolizumab as second-line therapy for advanced urothelial carcinoma. Methods: We retrospectively compared the effects of pembrolizumab with those of conventional chemotherapy on the prognosis of patients with advanced urothelial carcinoma at six hospitals between January 2004 and August 2020. We compared the oncological outcomes between the patients treated with pembrolizumab and those treated with conventional chemotherapy using Kaplan-Meier curve analysis and multivariate Cox regression analysis with the inverse probability of treatment weighting method. Results: The numbers of patients in the pembrolizumab and chemotherapy groups were 121 and 67, respectively. Patients in the pembrolizumab group were significantly older (median 72 vs 66 years, P = 0.001), and had poor Eastern Cooperative Oncology Group performance status (median 1 vs 0, P = 0.001). The unadjusted Kaplan-Meier curve analysis showed no significant differences in the median overall survival from the first-line chemotherapy (24.7 months vs 16.3 months, P = 0.159). Inverse probability of treatment weighting-adjusted multivariate Cox proportional hazards analyses showed a significant difference between the pembrolizumab and chemotherapy groups in overall survival (P = 0.003, hazard ratio 0.63). Conclusions: Despite the non-negligible age difference between the trial and our clinical practice, our study supports the benefit of second-line pembrolizumab over chemotherapy in real-world practice.

We examined the effects of intracerebroventricular (i.c.v.) administration of colchicine on the expression of the arginine vasopressin (AVP)-enhanced green fluorescent protein (eGFP) fusion gene in rats. In rats administered i.c.v. vehicle (control), eGFP fluorescence was observed in the supraoptic nucleus (SON), the magnocellular division of the paraventricular nucleus (PVN), the suprachiasmatic nucleus (SCN), the median eminence (ME) and the posterior pituitary. Two days after i.c.v. administration of colchicine, eGFP fluorescence was markedly increased in the SON, the magnocellular and parvocellular divisions of the PVN, the SCN, the ME and the locus coeruleus (LC). Immunohistochemical staining for eGFP confirmed the distribution of fluorescence in both groups. In the colchicines-administered groups, immunohistochemistry for tyrosine hydroxylase (TH) revealed that the eGFP fluorescence was co-localised with TH-immunoreactivity in the LC. Similarly, in situ hybridization histochemistry for eGFP mRNA revealed a significant increase in gene expression in the LC, the SON and the PVN 12-48 h after administration of colchicine. Our results indicate that the synthesis of AVP-eGFP is upregulated in noradrenergic neurones in the LC after colchicine administration. This implies that AVP and noradrenaline, originating from LC neurones, might play a role in response to chronic stress.

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Objectives To assess the impact of histological variants on survival and response to treatment with pembrolizumab in patients with chemo‐resistant urothelial carcinoma (UC). Patients and Methods The medical records of 755 patients with advanced UC who received pembrolizumab were reviewed retrospectively. Patients were classified into pure UC (PUC) and each variant. Best overall response (BOR) and overall survival (OS) were compared between the groups using a propensity score matching (PSM). Results Overall, 147 (19.5%) patients harboured any histological variant UC (VUC). After PSM, there were no significant differences in the objective response rate (ORR, 24.5% vs 17.3%, P = 0.098) or disease control rate (DCR, 36.7% vs 30.2%, P = 0.195) when comparing patients with any VUC and PUC. Furthermore, any VUC, as compared with PUC, was associated with a similar risk of death (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.68–1.20; P = 0.482). Squamous VUC, which was the most frequent variant in the cohort, had a comparable ORR, DCR and OS as compared with PUC or non‐squamous VUC. The patients with sarcomatoid VUC (n = 19) had significantly better ORR (36.8%, P = 0.031), DCR (52.6%, P = 0.032), and OS (HR 0.37, 95% CI 0.15–0.90; P = 0.023) compared to patients with PUC. Conclusions The presence of variant histology did not seem to affect BOR or OS after pembrolizumab administration in patients with chemo‐resistant UC. The patients with sarcomatoid VUC achieved favourable responses and survival rates compared to PUC.