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Background: Regorafenib improves overall survival (OS) of patients with advanced progressive gastrointestinal stromal tumors (GISTs) after standard chemotherapy in phase III trials in the 3rd-line setting. This large-scale, prospective observational study evaluated the safety and effectiveness of regorafenib in Japanese patients with GIST in a real-world clinical setting., Methods: Patients with GIST received oral regorafenib at a maximum daily dose of 160 mg for weeks 1-3 of each 4-week cycle (dose could be modified at investigator's discretion). The primary objective was to assess safety, particularly significant adverse drug reactions (ADRs), as well as the frequency of occurrence of ADRs, hand and foot syndrome (HFS), discontinuation of treatment due to disease progression and adverse events. A Cox proportional hazards model was used to evaluate associations between OS or time to treatment failure (TTF) and baseline characteristics or HFS., Results: Between August 2013 and March 2021, 143 evaluable patients were enrolled. ADRs occurred in 90.2% of patients and led to treatment discontinuation in 28.3%. The most frequent ADRs were HFS, hypertension, and liver injury. The overall response rate was 11.3% and disease control rate 56.5% (RECIST) based on investigators' assessments. Median OS was 17.4 months (95% CI 14.24-23.68). Median TTF was 5.3 (95% CI 4.0-6.5) months. Improved OS and TTF responses occurred in patients with an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1., Conclusion: The outcomes in this real-world study were consistent with those seen in clinical trials. No new safety concerns were identified., Clinical Trial Registration: https://clinicaltrials.gov, identifier NCT01933958., Competing Interests: YK has received scholarship fundings and research fundings from Ono Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., scholarship fundings from Shionogi & Co., Ltd., Nippon Zoki Pharmaceutical Co., Ltd., Asahi Kasei Pharma Corporation, Nippon Kayaku Co.Ltd., research fundings from Daiichi Sankyo company, limited, IQVIA Services Japan K.K., MSD, Astellas Pharma Inc., National Cancer Center Japan, Syneos Health Clinical K.K., ShiftZero K.K. PAREXEL International Inc., Japan Clinical Cancer Research Organization, EPS Holdings, Inc., SYSMEX corporation, Public Health Research Foundation, Aichi Cancer Center, Kyushu Study group of Clinical Cancer, honoraria and manuscript writings from Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo company, limited, Eli Lilly and Company, manuscript writing from Alfresa Pharma Corporation, and honoraria from Astellas Pharma Inc., EA Pharma Co.,Ltd., Nippon Kayaku Co.Ltd., Pfizer, Nippon Zoki Pharmaceutical Co., Ltd., Sanofi K.K., NIPRO, MOROO, Boehringer Ingelheim, Hakodate National Hospital, Asahi Kasei Pharma Corporation, MSD, Zeria Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd., Yakult Honsha Co.,Ltd., Sumitomo Dainippon Pharma Co., Ltd., Incyte Corporation, Merck Biopharma Co., Ltd, The Japanese Gastroenterological Association, Sapporo Minami Tokushukai Hospital, Pancan Japan. KM has received honoraria from Ono, Bristol-Myers Squibb, Eli Lilly, Takeda, Taiho, MSD, and Daiichi Sankyo, research fundings from Eli Lilly, Pizer, and Ono, research fundings as representative of organization for clinical study from Astellas, PRA Health Sciences Inc., Parexel International Inc., Taiho, Amgen, Sanofi, MSD, Chugai, and Novartis. TN has received honoraria from Pfizer, Otsuka, and consulting/advisory relationship from Taiho Pharmaceutical. MC, KHi, TS, KA, and KHa have the employment of Bayer Yakuhin Ltd. The authors declare that this study received funding from Bayer Yakuhin Ltd. Bayer collaborated with the authors to design the study. Bayer worked with the investigators on the collection, analysis, and interpretation of the data, and on the preparation of this report. The authors made the final decision to submit the article for publication., (Copyright © 2024 Komatsu, Muro, Chosa, Hirano, Sunaya, Ayukawa, Hattori and Nishida.)

Background/aims: Although urokinase-type plasminogen activator (u-PA) is suggested to initiate various factors in liver regeneration after hepatectomy, no corroborative evidence has been reported. In the present study, we investigated the effect of u-PA on liver regeneration after hepatectomy., Methods: Mice were placed into either a control group or a u-PA-inhibited group that received an in vivo u-PA inhibitor, p-aminobenzamidine. After we had removed two-thirds of the liver, we examined the expressions of c-jun mRNA and activated transforming growth factor beta 1 (TGF-beta 1), matrix metalloproteinase-2 (MMP-2) activity, and the level of hepatocyte and non-parenchymal cell proliferation in the two groups., Results: In the u-PA-inhibited group, the delays in c-jun mRNA expression, hepatocyte proliferation, activated TGF-1 expression, and expression of MMP-2 activity, were 2h, 1, 2, and 1 day, respectively, and the sinusoid architecture was not restored by 10 days after hepatectomy., Conclusions: u-PA inhibition delays the expression of c-jun mRNA, hepatocyte proliferation, and restoration of the sinusoid architecture, suggesting that u-PA plays important roles in liver regeneration after hepatectomy through control of a transcription factor, c-jun expression.