National Institute of Technology, Tomakomai College

Clazosentan (CLZ) therapy prevents delayed ischemia following aneurysmal subarachnoid hemorrhage (aSAH), but non-ischemic adverse events necessitate optimized protocols. This study presents outcomes of contemporary CLZ therapy under a unified protocol and identifies factors influencing delayed ischemic and non-ischemic adverse events following aSAH. This multicenter prospective registry analyzed data from 80 aSAH patients receiving CLZ therapy (April 2023 - October 2024). Primary endpoints were delayed ischemic events and non-ischemic adverse events; secondary endpoint was favorable outcome (modified Rankin Scale 0-2) at discharge or six weeks post-onset. Delayed ischemic events occurred in 19 patients (23.8%), including delayed ischemic neurological deterioration (8.8%), moderate-to-severe cerebral vasospasm (20.0%), and symptomatic delayed cerebral infarction (7.5%). Non-ischemic adverse events were observed in 22 patients (27.5%). Favorable outcomes were achieved in 52 patients (65.0%). Delayed ischemic events were associated with female sex, poor severity grades, higher Fischer scale scores, and elevated neutrophil-to-lymphocyte ratios. Non-ischemic adverse events were associated with older age, anemia, hypoproteinemia, and elevated cardiothoracic ratios. Multivariate analysis identified non-ischemic adverse events as significant for unfavorable outcomes (FDR p <.001), whereas delayed ischemic events were not (FDR p =.705). Among non-ischemic adverse events, pulmonary edema was the strongest factor associated with unfavorable outcomes. In conclusion, CLZ therapy with appropriate candidate selection and management protocol appears promising as a treatment option to prevent delayed ischemia after aSAH, though potential confounders warrant careful consideration. Addressing clinical risk factors for non-ischemic adverse events may further enhance treatment outcomes. Clinical trial number Not applicable.

Abstract Many animals reap significant benefits from migration, yet they face high mortality rates during the journey. As the mortality during migration typically operates more strongly on smaller migratory individuals (migrants), small pre‐migrants among migratory animals tend to grow better than larger ones prior to migration, enabling them to attain a larger body size. A common growth strategy for smaller pre‐migrants is extending their growth period compared to larger ones. Although this tactic has been documented in previous studies, the landscape‐scale habitat utilization that allowed smaller pre‐migrants to stay longer prior to migration remains largely unknown. Here, we focused on two distinct riverscape habitats (nursery habitat and transitional habitat) and investigated where smaller pre‐migrants of masu salmon (Oncorhynchus masou) stayed longer than larger ones prior to oceanic migration. We conducted an individual monitoring survey on their habitat utilization in two distinct migration years. We found that in 1 year, smaller pre‐migrants stayed longer in the transitional habitat compared to the nursery habitat, whereas in the other year, they stayed longer in the nursery habitat compared to the transitional habitat. This suggests that smaller pre‐migrants can adjust their duration of stay in each riverscape habitat. Our findings highlight the importance of conserving the entire pre‐migration habitat to enhance the resilience of migratory animals in the face of rapid environmental changes.

Seasonal changes in the environment often strongly influence biological communities. In environmental transition zones, or ecotones, the environment fluctuates over time between two different types of environments and the seasonal change is more pronounced. Although emphasis has been placed on the spatial variation of biota along environmental gradients, seasonal change has not been well studied despite the seasonal nature of many ecotones. In this study, we investigated seasonal shifts in aquatic community structures of floodplain waterbodies characterised as transitions between lotic and lentic environments, and further investigated the biological processes behind the shift. We observed a clear seasonal shift of community structure in floodplain waterbodies. From the spring snowmelt season to the summer low flow season, the aquatic community structure was largely driven by the hydrological connectivity to the river, represented as the timing of the lotic-lentic transition during the seasonal flood recession. In contrast, after a few months of summer low flow period, the effect weakened over time, and the communities were structured based more on the basis of the local environment. The seasonal shift was largely explained by the change in amphibian and aquatic insect larvae, the main members of the floodplain aquatic assemblage, which metamorphose and emerge from the water during the summer period and then redistribute in different ways more strongly influenced by local environmental factors such as water body size, temperature and dissolved oxygen levels. Given that biota in ecotones occupy the habitat for a limited time due to the severe environmental fluctuations, such seasonal changes as we observed in this study may be widespread in ecotones. Landscape and local environmental conditions could alternately shape community structures in different seasons. Further attention to the temporal aspects of community structure is needed for community studies and for conservation.

447 Background: Ramucirumab (RAM) has shown efficacy in combination with paclitaxel (PTX) or irinotecan in the second-line treatment of advanced gastric cancer (AGC). However, the efficacy and safety regarding the combination therapy of RAM and docetaxel (DTX) have not been reported. We hypothesized that RAM plus DTX for patients with AGC could be as effective as RAM plus PTX and could reduce the incidence of neuropathy. Methods: HGCSG 1903 was a non-randomized, single arm, phase 2 trial carried out at 20 institutes in Japan. AGC patients with refractory or intolerance to primary chemotherapy were eligible. RAM (8 mg/kg on day1 and 15) plus DTX (60 mg/m 2 on day1) combination therapy administered in 28-day cycle were continued until disease progression or emergence of adverse events requiring discontinuation. The primary endpoint was response rate (RR) with threshold value of 10.7% and an expected value of 27.9%. A total of 35 cases are planned for registration. The secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety. This trial was registered with Japan Registry of Clinical Trials, number jRCTs011200010. Results: Between Nov 2020 and Dec 2023, 36 patients were enrolled. Median age was 70 (range, 36–82); female/male were 7/29; ECOG PS 0/1, 16/20, respectively. One patient did not initiate study treatment at the onset of bowel obstruction after enrollment. In the efficacy and safety analysis set of 35 patients, RR was 25.7% (95%C.I., 12.5–43.3%) and disease control rate was 74.3% (95%C.I., 56.7–87.5%). Median OS and PFS were 11.9 months (95%C.I., 3.0–20.7) and 3.1 months (95%C.I., 2.1–4.2), respectively. Grade 3 or higher adverse events that occurred in more than 5% of patients were neutropenia (68.6%), leucopenia (57.1%), febrile neutropenia (17.1%), hypertension (14.3%), anorexia (11.4%), anemia (8.6%), and fatigue (5.7%). Grade 4 neutropenia occurred in 60.0% of patients. The protocol was amended to allow primary G-CSF prophylaxis during study period. The number of patients who received primary G-CSF prophylaxis after the amendment was 7/13 (53.8%). Neuropathy occurred in 65.7% of all grades, with no incidence of grade 3 or higher. No death and new safety signals with a causal relation to study treatment were observed. Conclusions: The primary endpoint of response rate was met in HGCSG 1903. Although neutropenia and febrile neutropenia may be more frequent, they were manageable. RAM plus DTX might be considered as an option for second-line treatment of patients with AGC. Clinical trial information: jRCTs011200010.

Alien species can influence populations of native species through individual-level effects such as predation, competition, and poisoning. For alien species that possess strong defensive chemicals, poisoning is one of the most powerful mechanisms of individual-level effects on native biota. Although toxic alien species could potentially negatively affect survival (lethal effects) or life history traits (sub-lethal effects) of native predators via poisoning, previous studies have mainly focused on acute lethal effects. Thus, delayed effects on predator life history traits have been largely overlooked. To fill this knowledge gap, we conducted laboratory and field experiments to investigate whether toxic alien prey (hatchlings and tadpoles of an invasive toad, Bufo formosus) affect the survival and/or growth and development of a native predatory salamander (larvae of Hynobius retardatus) on Hokkaido, Japan. The laboratory experiment revealed that consumption of a single toad hatchling exerted non-lethal effects on salamanders, but suppressed both salamander growth and development of an ecological phenotype (broad-gape) normally induced by environmental conditions. Furthermore, the field experiment in a natural pond showed that the presence of toad hatchlings and tadpoles resulted in reduced salamander growth (smaller body size) and lower survival of salamanders in the later larval period. The results of the laboratory and field experiments are complementary evidence of the life history impacts of the toxic alien toad on native salamanders. Thus, the poisoning effects of toxic alien species can affect the life history of native predators even if they do not exert acute lethality.

Methane release is considered to be from human activities, Arctic Ocean, and the terrestrial regions such as wetland, lakes, geological seeps in the Arctic although glaciers have not been considered a source of methane emissions. A large amount of methane has been observed at the terminus of large glaciers and ice sheet, associated with methane-saturated meltwater runoff. We observed several glaciers in Alaska and found methane emissions from the runoff water of the small mountain glaciers.The observation periods, which was the beginning of the ablation season for the glacier, were June 12-14, 2022, and June 3-9, 2023. We measured methane and CO2 concentrations in ambient air over the water with a portable gas analyzer G4301 (Picarro, Inc.). Dissolved methane concentrations in runoff water were measured using the method of Morishita et al. (2015).The maximum methane concentration in the ambient air near the runoff water was higher than the background level, and the concentration decreased as the gas analyzer moved away from the tunnel. The dissolved methane concentration in runoff water was saturated. These results suggest that the high concentration methane observed in the ambient air near the glacier terminus was released from the runoff water saturated by methane underneath of the glaciers. This study was supported by ArCSII project (JPMXD1420318865).

While guidelines recommend immune checkpoint inhibitor (ICI) rechallenge as second-line therapy for unresectable hepatocellular carcinoma (HCC), data supporting this remain limited, particularly regarding a standard regimen for first- and second-line treatments. Tremelimumab/durvalumab was recently approved but data on ICI rechallenge are lacking. The purpose of this study was to evaluate the early efficacy and safety of tremelimumab/durvalumab for HCC as an ICI rechallenge following initial ICI therapy with atezolizumab/bevacizumab. This multicenter retrospective study included patients with HCC who underwent treatment with tremelimumab/durvalumab, with relevant available clinical information. We evaluated the safety and efficacy of tremelimumab/durvalumab as ICI rechallenge following initial treatment with atezolizumab/bevacizumab. We analyzed the outcomes in patients who underwent tremelimumab/durvalumab as an ICI rechallenge and those who received tremelimumab/durvalumab as their initial ICI therapy RESULT: A total of 45 patients treated with tremelimumab/durvalumab were included, with 55.6% (25/45) undergoing ICI rechallenge. The objective-response and disease-control rates in patients who underwent ICI rechallenge were 14.3% (3/21) and 47.6% (10/21), respectively, similar to those in patients initially treated with tremelimumab/durvalumab. All patients (n = 3) who experienced the best response to progressive disease (PD) with initial atezolizumab/bevacizumab experienced PD during ICI rechallenge. The incidence rates of adverse events were similar between patient groups treated with tremelimumab/durvalumab as ICI rechallenge and initial ICI. Among patients experiencing immune-related adverse events (irAEs) with atezolizumab/bevacizumab, 75% (3/4) encountered similar irAEs during ICI rechallenge. Early safety and efficacy profiles of durvalumab/tremelimumab as ICI rechallenge are satisfactory.