Real-world treatment patterns and outcomes of patients with unresectable or metastatic urothelial carcinoma receiving systemic therapy in Japan.

BACKGROUND: Cisplatin-based chemotherapy has traditionally been the standard treatment for unresectable or metastatic urothelial carcinoma (mUC). Recently, the longstanding paradigm has changed with the emergence of immune checkpoint inhibitors and antibody-drug conjugates, such as pembrolizumab and enfortumab vedotin (EV). This longitudinal descriptive study aimed to identify real-world treatment patterns and assess the outcomes of patients with mUC between 2010 and 2023. METHODS: Patients with mUC who received first-line systemic therapy were identified from a Japanese electronic medical records database. A Sankey diagram was used to present the proportion of patients who transitioned to second- and third-line therapies. Kaplan-Meier survival analysis was used to estimate the time to next treatment (TTNT) and overall survival (OS). RESULTS: A total of 794 patients were included in this study. The median age of the patients was 73.0 years, and 72.9% were male. The most common primary tumor site was the bladder (59.7%). First-line therapy comprised cisplatin-based regimens in 52.0% of the patients (11.8% at standard doses, 32.4% at reduced doses, and 7.8% at unknown doses), carboplatin-based regimens in 32.1%, and other regimens in 15.9%. Among the patients enrolled after 2017, following the approval of pembrolizumab for mUC progressing after chemotherapy in Japan, 58.2% received pembrolizumab as second-line therapy, and 19.1% received EV monotherapy as third-line therapy. The median OS for the total population was 24.1 months, with patients enrolled between 2010 and 2016 having a shorter OS (21.1 months) than those enrolled between 2017 and 2022 (24.9 months). For patients with eGFRs of ≥60 and <60 mL/min/1.73 m2, the median OS was 24.1 and 23.8 months, respectively. CONCLUSION: Platinum-based regimens, including reduced-dose cisplatin and carboplatin, remain the predominant first-line systemic therapies. Since 2017, pembrolizumab and EV have become widespread choices for second-line and subsequent treatments, gradually surpassing the previously prevalent platinum-based regimens. The introduction of these novel therapies might have prolonged the OS of patients with mUC. A plain language summary is available in this article.

Glucocorticoid treatment and clinical outcomes in patients with polymyalgia rheumatica: A cohort study using routinely collected health data.

OBJECTIVE: We aimed to describe the following in patients with polymyalgia rheumatica (PMR): (1) real-world glucocorticoid (GC) therapy, (2) improvement in inflammatory parameters associated with disease activity (C-reactive protein [CRP] level and erythrocyte sedimentation rate [ESR]), and (3) incidence of GC-related adverse events (AEs). METHODS: A cohort study was conducted using a Japanese electronic medical records database. We included newly diagnosed PMR patients aged≥50years with baseline CRP levels≥10mg/L and/or ESR>30mm/h and an initial GC dose of≥5mg/day. The outcomes were GC dose, inflammatory parameters, and GC-related AEs. RESULTS: A total of 373 PMR patients (mean age, 77.3 years) were analyzed. The median initial GC dose was 15.0mg/day, which gradually decreased to 3.5mg/day by week 52. The median cumulative GC dose at week 52 was 2455.0mg. The median CRP level on day 0 was 64.3mg/L, which decreased during weeks 4-52 (1.4-3.2mg/L). At week 52, 39.0% of patients had a CRP level>3.0mg/L. The cumulative incidence of GC-related AEs at week 52 was 49.0% for osteoporosis, 30.2% for diabetes, 14.9% for hypertension, 12.2% for peptic ulcer, 11.3% for dyslipidemia, 2.9% for glaucoma, and 4.3% for serious infection. The incidence of osteoporosis and diabetes increased with the GC dose. CONCLUSION: The incidence of GC-related AEs was associated with the GC dose in PMR patients. Further research is required to identify treatment strategies that can effectively control PMR disease activity while minimizing GC use.

Phototropin-dependent weak and strong light responses in the determination of branch position in the moss Physcomitrella patens.

Branch position in the moss Physcomitrella patens is regulated by blue light. In this study, fluence rate dependency of branch position determination was investigated by partial cell irradiation with a microbeam. With a 30 Wm(-2) or lower fluence rate, branches formed at the microbeam area, but formed outside the microbeam when the fluence rate was raised to > or = 200 Wm(-2). Thus, both weak and strong light responses influence the determination of branch position. Further, light sensitivity of both responses was reduced in phototropin knock-out lines, revealing an involvement of phototropin as the blue light receptor.

Functional analyses of the Physcomitrella patens phytochromes in regulating chloroplast avoidance movement.

Red light-induced chloroplast movement in Physcomitrella patens (Pp) is mediated by dichroic phytochrome in the cytoplasm. To analyze the molecular function of the photoreceptor in the cytoplasm, we developed a protoplast system in which chloroplast photomovement was exclusively dependent on the expression of phytochrome cDNA constructs introduced by polyethylene glycol (PEG) transformation. YFP was fused to the phytochrome constructs and their expression was detected by fluorescence. The chloroplast avoidance response was induced in the protoplasts expressing a YFP fusion of PHY1-PHY3, but not of PHY4 or YFP alone. Phy::yfp fluorescence was detected in the cytoplasm. No change in the location of phy1::yfp or phy2::yfp was revealed before and after photomovement. When phy1::yfp and phy2::yfp were targeted to the nucleus by fusing a nuclear localization signal to the constructs, red light avoidance was not induced. To determine the domains of PHY2 essential for avoidance response, various partially-deleted PHY2::YFP constructs were tested. The N-terminal extension domain (NTE) was found to be necessary but the C-terminal histidine kinase-related domain (HKRD) was dispensable. An avoidance response was not induced under expression of phytochrome N-terminal half domain [deleting both the PAS (Per, Arnt, Sim)-related domain (PRD) and HKRD]. GUS fusion of this N-terminal half domain, reported to be fully functional in Arabidopsis for several phyA- and phyB-regulated responses was not effective in chloroplast avoidance movement. Domain requirement and GUS fusion effect were also confirmed in PHY1. These results indicate that Pp phy1-Pp phy3 in the cytoplasm mediate chloroplast avoidance movement, and that NTE and PRD, but not HKRD, are required for their function.

Four distinct photoreceptors contribute to light-induced side branch formation in the moss Physcomitrella patens.

Side branch formation in the moss, Physcomitrella patens, has been shown to be light dependent with cryptochrome 1a and 1b (Ppcry1a and Ppcry1b), being the blue light receptors for this response (Imaizumi et al. in Plant Cell 14:373, 2002). In this study, detailed photobiological analyses were performed, which revealed that this response involves multiple photoreceptors including cryptochromes. For light induction of branches, blue light of a fluence rate higher than 6 micromol m(-2) s(-1) for period longer than 3 h is required. The number of branches increased with the increase in fluence rate and in the irradiation period. The number of branches also increased when red light was applied together with the blue light, although red light alone had a very few effect. By partially irradiating a cell, both receptive sites for blue and red light were found to be located around the nucleus. Further, both red and blue light determine the positions of branches being dependent upon the vibration plane of polarized light. Red light control of branch position was nullified by simultaneous far-red light irradiation. A blue light effect on branch position was not found in lines with disrupted phototropin genes. Thus, dichroic phytochrome and phototropin, possibly on the plasma membrane, regulate branch position. These results indicate that at least four distinct photoreceptor systems, namely, cryptochromes and red light receptor around or in the nucleus, dichroic phytochrome and phototropin around the cell periphery, are involved in the light induction of side branches in the moss Physcomitrella patens.