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Siberia, which experienced disastrous heat waves in 2010 and 2012, is one of the regions in which extreme climate events have occurred recently. To compare the long-term trends of extreme climate events in the southern part of Siberia with those of surrounding regions, we calculated 11 extreme climate indexes from observational data for 1950–2019 and analyzed the trends in Siberia and other parts of Russia using statistical techniques, i.e., Welch’s t-test, the Mann–Kendall test, Sen’s slope estimator, and a cluster analysis. We clarified that high-temperature events in March are more frequent in Siberia than in the surrounding areas. However, the increasing trends of high temperatures in Siberia were lower than those in northwestern China and Central Asia. The intensity of heavy precipitation is increasing in Siberia, as it is in the surrounding areas. Compared to the surrounding areas analyzed in previous studies, the trend of heavy precipitation in Siberia has not increased much. In particular, Siberia shows a more remarkable decreasing trend in heavy precipitation during the summer than other regions. The dry trends in the summer, however, do not occur in Siberia as a whole, and the opposite trend of summer precipitation was observed in some areas of Siberia.

The usefulness of angiogenesis inhibitors as second-line treatment after the progression of anti-epidermal growth factor receptor antibody drug-containing regimens for RAS wild-type metastatic colorectal cancer (mCRC) has not been fully investigated. Therefore, we conducted a phase II study to verify the efficacy and safety of the combination of S-1 and irinotecan plus bevacizumab (SIRB regimen) as second-line treatment for patients with oxaliplatin and cetuximab-refractory KRAS wild-type mCRC.Patients with mCRC who had previously received oxaliplatin and cetuximab-containing regimen were eligible for this study. Patients were infused with bevacizumab 7.5 mg/kg and irinotecan 150 mg/mIn total, 17 patients were enrolled in this study. The 6-month PFS rate was 64.7% [95% confidence interval (CI)=41.99-87.43], median PFS was 10.1 months (95%CI=4.11-17.28), and median overall survival was 21.8 months (95%CI=9.79-37.91). The response rate was 23.5% (95%CI=6.81-49.90%). Grade ≥3 adverse events were observed in 10% of patients, and included leukopenia [3 (17.6%)], neutropenia [5 (29.4%)], anorexia [2 (11.8%)], diarrhea [2 (11.8%)], and hypertension [3 (17.6%)]. No treatment-related deaths or febrile neutropenia were observed.The SIRB regimen might be a promising second-line treatment option for patients with oxaliplatin and cetuximab-refractory KRAS wild-type mCRC in terms of efficacy and safety.

We evaluated the role of raw-material features for machine-learning prediction of the flux crystal growth of Al2O3 in MoO3 based on 185 types of growth trials.

Background: Regorafenib is a standard salvage line therapy used for advanced colorectal cancer (CRC). Recently, FTD/TPI plus bevacizumab also showed promising efficacy as a salvage line therapy for advanced CRC. However, the efficacy and safety of regorafenib for patients with advanced CRC who have previously received trifluridine/tipiracil (TFTD) plus bevacizumab is unclear.Results: We retrospectively collected clinicopathologic data from patients with advanced CRC who received regorafenib after TFTD plus bevacizumab in multiple institutions between April 2017 and June 2020.Thirty-four advanced CRC patients who received regorafenib were analyzed. The median age was 66.5 (range 43−81 years), 11 patients were male, and all had an ECOG performance status(PS) of 0 or 1. Twenty-two patients had left-sided tumors, 18 patients had RAS mutants, and 1 patient had a BRAF V600E mutation. The response rate was 0%, and the disease control rate was 31%. The median progression-free survival was 70 days (95% CI: 56−91), and the overall survival was 233 days (95% CI: 188−324). Treatment was discontinued in 32 patients, and 28 (82%) discontinued treatment due to progressive disease. The major grade 3 and4 toxicities were proteinurea (29%), hypertension (26%), hand-foot syndrome(15%), and platelet decrease (6%).Conclusion: Regorafenib after TFTD plus bevacizumab showed efficacy similar to that of the previous study, and no new adverse events were observed.

120 Background: Triplet regimen, FOLFOXIRI, plus bevacizumab is considered as one of standard first-line treatments in metastatic colorectal cancer (mCRC). On the contrary, FOLFOXIRI plus anti-EGFR antibody has been shown to be a promising regimen with greater depth of response (DpR) in patients with RAS wild-type mCRC from the VOLFI and MACBETH trials (J Clin Oncol 2019, JAMA Oncol 2018). We therefore performed a randomized phase II study, DEEPER trial (JACCRO CC-13) [NCT02515734], to investigate the efficacy and safety of cetuximab (cet) vs. bevacizumab (bev) in combination with modified (m)-FOLFOXIRI in previously untreated mCRC patients with RAS wild-type tumors. We have reported a significantly better DpR of m-FOLFOXIRI plus cet compared to bev as the primary endpoint (Tsuji A, et al. ASCO 2021). Methods: This trial was a randomized phase II trial to evaluate modified (m)-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, 5-FU 2400 mg/m2) plus cet vs. bev as initial treatment in terms of DpR during the entire course as the primary endpoint in 360 patients with RAS wild-type mCRC. The aim of the trial was to show that median DpR of cet arm was more than 12.5% higher than bev arm, with a power of 85% at a significance level of 0.05, in per protocol set (PPS) consisted of patients evaluable for the DpR. Secondary endpoints included progression-free survival, overall survival, overall response rate, early tumor shrinkage rate, secondary resection rate, and toxicity. A total of 359 patients were enrolled between July 2015 and June 2019. For the PPS (median age 65y, 64% male, PS0/1: 91%/9%, left/right primary: 84%/16%), 159 and 162 patients were randomly assigned to the cet and bev arms, respectively. Clinical outcomes will be analyzed according to primary tumor sidedness which is included in the stratification factor. Additionally, we will collect data of BRAF status, and analyze the clinical outcomes in mCRC patients with RAS/ BRAF wild-type tumors and/or left-sided tumors. Pre-planned survival analysis will be performed to compare the two treatment arms at the time of 3 years after last patients’ enrollment using a log-rank test. All statistical tests are two-sided, and P values ≤ 0.05 are deemed significant. Statistical analyses will be performed using SAS version 9.4. Clinical trial information: NCT02515734 .

The objective of this study is to clarify the regional difference in hydrometeorological parameters in Western Siberia (WS), an area which suffered from severe drought in the summer of 2012. The drought was especially apparent in middle WS. Regional differences in the hydrometeorological parameters have not been fully investigated so far; therefore, we investigated them based on the temporal variation in the hydrometeorological data. All of WS experienced an extremely hot summer in 2012, particularly in June and July. In middle WS, the snow water equivalent in March 2012 was the third lowest recorded from 1985 to 2019. The runoff during April–September 2012 was smaller than the long-term mean. Precipitation during April–August 2012 was also continuously lower. All this resulted in a severe drought in the summer. In particular, precipitation in July 2012 in middle WS was among the lowest recorded for the period of 1966–2019. These characteristics were unique to middle WS in July 2012. North and south WS did not suffer from a severe drought in 2012 because substantial precipitation was observed in summer. The findings of this study will contribute to the prediction of future hydrometeorological events, as extreme phenomena are more likely to occur in accordance with the progress of global warming.

Background Recent studies have demonstrated that uric acid (UA) enhances arginase activity, resulting in decreased NO in endothelial cells. However, the role of lung UA in pulmonary arterial hypertension (PAH) remains uncertain. We hypothesized that increased lung UA level contributes to the progression of PAH. Methods and Results In cultured human pulmonary arterial endothelial cells, voltage‐driven urate transporter 1 (URATv1) gene expression was detected, and treatment with UA increased arginase activity. In perfused lung preparations of VEGF receptor blocker (SU5416)/hypoxia/normoxia‐induced PAH model rats, addition of UA induced a greater pressure response than that seen in the control and decreased lung cGMP level. UA‐induced pressor responses were abolished by benzbromarone, a UA transporter inhibitor, or L‐norvaline, an arginase inhibitor. In PAH model rats, induction of hyperuricemia by administering 2% oxonic acid significantly increased lung UA level and induced greater elevation of right ventricular systolic pressure with exacerbation of occlusive neointimal lesions in small pulmonary arteries, compared with nonhyperuricemic PAH rats. Administration of benzbromarone to hyperuricemic PAH rats significantly reduced lung UA levels without changing XOR (xanthine oxidoreductase) activity, and attenuated right ventricular systolic pressure increase and occlusive lesion development. Topiroxostat, a XOR inhibitor, significantly reduced lung XOR activity in PAH rats, with no effects on increase in right ventricular systolic pressure, arterial elastance, and occlusive lesions. XOR‐knockout had no effects on right ventricular systolic pressure increase and arteriolar muscularization in hypoxia‐exposed mice. Conclusions Increased lung UA per se deteriorated PAH, whereas XOR had little impact. The mechanism of increased lung UA may be a novel therapeutic target for PAH complicated with hyperuricemia.

112 Background: Ramucirumab (RAM) plus FOLFIRI has been considered as the standard care of second-line treatment in metastatic colorectal cancer (mCRC). However, there have been few data which prospectively evaluated the efficacy and safety of RAM or other anti-VEGF drugs plus FOLFIRI after anti-EGFR antibody therapy in RAS wild-type mCRC. We therefore investigated the efficacy and safety of RAM plus FOLFIRI as second-line treatment in patients with RAS wild-type mCRC previously treated with oxaliplatin-containing chemotherapy with anti-EGFR antibody. Methods: The JACCRO CC-16 was a multicenter, phase 2 trial to evaluate the efficacy and safety of RAM (8 mg/kg) plus FOLFIRI (irinotecan 150 mg/m2, bolus 5-FU 400 mg/m2, infusional 5-FU 2400 mg/m2) in mCRC patients with RAS wild-type tumors and ECOG PS 0 or 1, after first-line doublet or triplet plus anti-EGFR antibody therapy. The primary endpoint was 6-month progression-free survival (PFS) rate. The secondary endpoints included PFS, overall survival, objective response rate (ORR), early tumor shrinkage (ETS), and safety. We hypothesized a threshold 6-month PFS rate of 30% and an expected 6-month PFS rate of 45% for the protocol treatment. A sample size of 74 patients was required (one-sided α, 0.05; β, 0.2). Results: A total of 92 patients were enrolled between October 2018 and December 2020. Ninety-one patients, excluding one ineligible patient, were analyzed as the full analysis set: median age 66.0-y (range, 29–84), 46% female, 81% ECOG PS 0, 40% with primary tumor, 95% left-sided (rectum, sigmoid or descending colon) primary tumors, 70%/42% with liver/lung metastases. In prior first-line treatment, 19 (21%) patients were treated with triplet plus anti-EGFR antibody. The median number of treatment cycles was 10 (range, 1–56). Primary endpoint was met; at data cut-off, with 76 events, 6-month PFS rate was 58.2% (95% CI; 47.4-67.6). The median PFS was 7.0 months. The ORR, disease control rate, and ETS were 10.7%, 86.9%, and 16.9%, respectively. In the safety population of 92 patients, any grade adverse events (AEs) were neutropenia (75%), hypertension (59%), proteinuria (34%), and diarrhea (33%). Grade 3-4 AEs were neutropenia (48%), hypertension (27%), proteinuria (4%), diarrhea (3%), and febrile neutropenia (3%). No treatment-related death was observed. Conclusions: This is the first prospective study to demonstrate that RAM plus FOLFIRI as second-line treatment has favorable PFS rate and tolerability after anti-EGFR antibody containing chemotherapy in RAS wild-type mCRC patients. Clinical trial information: jRCTs061180002.