Ryo Takemura’s research while affiliated with Keio University Hospital and other places

2084 Background: The majority of meningiomas, which are the most common central nervous system (CNS) tumors, are benign and often cured by surgical resection alone. However, 20%–30% of meningiomas can be malignant tumors of CNS WHO grade II or III that are refractory to repetitive resection and radiotherapy. Moreover, a proportion of grade I meningiomas is associated with an aggressive clinical course reminiscent of grade II tumors. Reports of effective medical therapy for those tumors are extremely rare. Methods: A single-arm, open-label, phase 2 study was conducted to evaluate the efficacy and safety of nivolumab for meningiomas refractory to surgery and radiotherapy. Nivolumab (480 mg) was administered intravenously every 4 weeks and continued until tumor progression or unacceptable toxicity for up to 365 days. The primary endpoint was the objective response rate (ORR) determined by a central independent review committee. With a one-sided significance level of 5%, a power of 80%, a threshold response rate of 5%, and an expected response rate of 20%, the required sample size was calculated to be 27 patients using the exact binomial test. Considering a 10% attrition rate, the target sample size was set at 29. To avoid premature discontinuation of potentially effective immunotherapy, response was evaluated based on the iRANO (meningioma) criteria, which is based on the RANO (meningioma) criteria (Neuro Oncol 21(1):26-36, 2019) with the integration of the immune-related response criteria outlined previously (Lancet Oncol 16(15):e534-e542, 2015). Archival tumor specimens from all 29 cases were obtained for biomarker analyses. Results: A total of 29 patients started the study therapy. Response assessment by the central review committee was performed for 28 patients: grade I meningioma in 5, grade II in 19, and grade III in 4 by definition of the 2016 WHO criteria. The best overall response was PR in 1, SD in 13, and uPD/cPD in 14. The ORR was 3.6% and progression-free survival at 6 months was 23.9%. Biallelic inactivation of the NF2 gene was detected in 20/27 cases (74%), whereas biallelic inactivation of the CDKN2A gene was identified in 7/27 cases (26%). One patient who had multiple grade I meningiomas with biopsy-proven lung metastases showed near CR following initial radiological progression. The TMB of the tumor was 8.1/MB. Next-generation sequencing found that none of the tumors had mutations of the DNA mismatch repair genes. Nivolumab was well tolerated. Conclusions: Although nivolumab monotherapy failed to meet the prespecified primary endpoint, our study demonstrated that a subset of patients could benefit from the therapy and that immune-related response criteria are necessary to evaluate immunotherapy for meningiomas. Clinical trial information: jRCT2031190074 .

We investigate the completeness of intuitionistic logic with respect to Prawitz's proof-theoretic validity. As an intuitionistic natural deduction system, we apply atomic second-order intuitionistic propositional logic. By developing phase semantics with proof-terms introduced by Okada & Takemura (2007), we construct a special phase model whose domain consists of closed terms. We then discuss how our phase semantics can be regarded as proof-theoretic semantics, and we prove completeness with respect to proof-theoretic semantics via our phase semantics.

418 Background: Based on the JCOG1109 trial, neoadjuvant docetaxel, cisplatin, and fluorouracil (DCF) followed by surgery has become the standard of care for resectable locally advanced esophageal squamous cell carcinoma (ESCC). Although the combination of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) demonstrated benefits for esophageal adenocarcinoma as a perioperative therapy, its safety and efficacy for locally advanced ESCC have not been evaluated. Methods: We conducted a multicenter phase II study of neoadjuvant FLOT therapy for ESCC. Patients with cT1N1-3M0-1 or cT2-3N0-3M0-1 (only supraclavicular lymph node (SCLN) metastasis is included as M1) based on the 8th edition of the UICC TNM staging system were eligible. Neoadjuvant chemotherapy consisted of oxaliplatin (85 mg/m ² ), docetaxel (50 mg/m ² ), and l-leucovorin (200 mg/m ² ) on day 1, and continuous infusion of fluorouracil (2600 mg/m ² /day) for 24 hours. This regimen was repeated every 2 weeks with a maximum of four cycles. The prophylactic antibody and G-SCF were not used mandatory. After completion of neoadjuvant chemotherapy, esophagectomy with extended lymphadenectomy was performed. Adjuvant treatment was prohibited for all patients. The primary endpoint was the pathological response rate (pRR), defined as the Grade 2 (more than two-thirds of the tumor is necrotic or fibrotic) or 3 (no viable tumor cells), based on the Japanese Classification of Esophageal Cancer. The sample size was determined based on an expected pRR of 38%, aiming for the lower bound of the 95% confidence interval to exceed the predetermined threshold of 20%. The expected number of patients to be enrolled was 60, with enrollment to be stopped when 45 patients with negative SCLN were enrolled. Results: Fifty-four patients were enrolled between September 2020 and January 2024. Patients with cStage I/II/III/IVB were 3/16/27/8. Of 54 patients, 45 patients were M0 without SCLN metastasis. Excluding 1 patient who did not receive any treatment after enrollment, 53 patients were included in the full analysis set. During chemotherapy, the most common grade 3 or 4 toxicities were neutropenia (73.6%), and leukopenia (22.6%). Febrile neutropenia was observed in 1 patient (1.9%). Finally, 46 patients underwent surgery. No treatment-related deaths were observed and the incidence of operative morbidity was tolerable. The pRR was 43.4% (23/53) (95% CI 29.8-57.7, p=00002). This study met the primary endpoint. The radical resection rate was 83.0% (44/53). The pathological complete response rate was 13.2% (7/53). Conclusions: Neoadjuvant FLOT therapy showed a promising pathological response with acceptable toxicities. It was noteworthy that the incidence of febrile neutropenia was relatively lower with compared to neoadjuvant DCF therapy. This regimen might be a treatment option for locally advanced ESCC. Clinical trial information: jRCTs031200094.