Original Article Genetic profile of thymic epithelial tumors in the Japanese population: an exploratory study examining potential therapeutic targets Midori Shimada, Hirokazu Taniguchi, Hiroyuki Yamaguchi, Hiroshi Gyotoku, Daisuke Sasaki, Norihito Kaku, Chikako Senju, Hiroaki Senju, Erika Imamura, Shinnosuke Takemoto, Kazuko Yamamoto, Noriho Sakamoto, Yasushi Obase, Tomoshi Tsuchiya, Minoru Fukuda, Hiroshi Soda, Kazuto Ashizawa, Junya Fukuoka, Takeshi Nagayasu, Katsunori Yanagihara, Hiroshi Mukae

Background: Thymic epithelial tumors (TETs) are rare, posing challenges for conducting large-scale clinical trials and leading to slower therapeutic advancements compared with other cancers. Although carboplatin plus paclitaxel therapy is the preferred standard treatment, its clinical use presents challenges, including the frequent occurrence of peripheral neuropathy. In a phase III study, carboplatin plus nab-paclitaxel therapy demonstrated superior efficacy over carboplatin plus paclitaxel therapy in advanced or recurrent non-small cell lung cancer, with reduced adverse events such as peripheral neuropathy, neutropenia, and myalgia. Carboplatin plus nab-paclitaxel therapy has the potential to offer similar efficacy with reduced toxicity in TETs. Therefore, we plan to conduct a phase II clinical trial to clarify the efficacy and safety of carboplatin plus nab-paclitaxel in patients with TETs. Methods: This study plans to enroll 44 patients with advanced or recurrent TETs, with a performance status of 0 or 1, and adequate organ function. Carboplatin (area under the blood concentration-time curve of 5 or 6) will be administered on day 1, while nab-paclitaxel (100 mg/m²) will be administered on days 1, 8, and 15 intravenously every 3 weeks for four cycles. The primary endpoint is overall response rate, and the secondary endpoints are overall survival, progression-free survival, incidence rate of adverse events, and quality of life. Discussion: Carboplatin plus nab-paclitaxel therapy may serve as a promising first-line regimen with a relatively mild side-effect profile and expected efficacy in rare TETs. We aim to determine whether this therapy is a better treatment option with lower toxicity. Trial Registration: This clinical trial was registered in the Japan Registry of Clinical Trials (No. jRCTs071240019) on June 6^th, 2024.

Radiotherapy (RT) has traditionally been considered a local treatment modality; however, accumulating evidence suggests that it can induce systemic antitumor responses outside the irradiated field. The classical abscopal effect, defined as the regression of non-irradiated tumor lesions following localized RT, has gained renewed attention in the era of immune checkpoint inhibitors (ICIs). Preclinical and clinical studies have demonstrated that RT can promote immunogenic cell death, antigen presentation, cytokine release, and adaptive immune activation, processes that may contribute to systemic antitumor immunity, particularly when combined with ICIs. Clinically apparent abscopal responses remain rare and heterogeneous, and the biological mechanisms underlying these phenomena are not completely understood. Systemic tumor regression has occasionally been observed in clinical settings that do not involve checkpoint blockade, including RT alone, chemotherapy-containing regimens, and central nervous system-directed therapies. These findings suggest that radiation-associated systemic antitumor responses may arise through overlapping immunologic mechanisms involving both innate and adaptive immunity, tumor microenvironment remodeling, and treatment-associated cellular stress. This review summarizes the current clinical evidence and biological mechanisms underlying radiation-associated systemic antitumor responses and discusses emerging concepts extending beyond the conventional RT–immunotherapy paradigm. We further examined unresolved challenges, including treatment heterogeneity, biomarker limitations, pseudoprogression, and difficulties in mechanistic confirmation. Finally, we propose that the broader “beyond-abscopal” framework may serve as a hypothesis-generating conceptual model for investigating systemic tumor responses across diverse treatment contexts while emphasizing the need for cautious interpretation and prospective translational validation.

Treatment-associated regression of tumors outside the irradiated field has occasionally been reported, but the underlying mechanisms remain unclear, particularly in the context of central nervous system (CNS)–directed therapy. Glioblastoma (GBM) is commonly treated with radiotherapy and temozolomide, both of which may influence tumor biology and the systemic environment. We report a patient with synchronous primary GBM and early-stage lung adenocarcinoma who underwent craniotomy followed by intensity-modulated radiotherapy with concurrent temozolomide for GBM. During GBM-directed chemoradiotherapy, the untreated pulmonary lesion demonstrated progressive regression without any lung-specific therapy, temporally coinciding with CNS-targeted treatment. Although comprehensive immunophenotyping was not feasible, longitudinal changes in the proportion of peripheral blood lymphocytes were observed during therapy. These findings represent a clinical observation characterized by a temporal association between CNS-directed treatment and regression of a distant, non-irradiated tumor. However, the underlying mechanism remains uncertain, and a contribution from systemic temozolomide exposure cannot be excluded. While treatment-related systemic effects may be considered, no specific causal mechanism can be established based on this single case. This case highlights an unusual clinical observation that may warrant further investigation. Further studies are needed to clarify the relationship between CNS-directed therapies and systemic tumor behavior.

Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a rare inflammatory subtype of cerebral amyloid angiopathy that may present with leptomeningeal enhancement on magnetic resonance imaging (MRI), thereby mimicking leptomeningeal metastasis (LM) in patients with cancer. We report the case of an 82-year-old woman with a recently resected lung adenocarcinoma who underwent brain MRI following a fall. MRI revealed bilateral asymmetric white matter hyperintensities and multifocal leptomeningeal enhancement, which initially suggested LM. However, preserved neurological function, negative cerebrospinal fluid cytology, and the subsequent identification of numerous cortical and subcortical microbleeds on targeted reassessment with susceptibility-weighted MRI prompted diagnostic reassessment. Brain biopsy demonstrated vascular amyloid deposition with perivascular inflammatory infiltrates, confirming CAA-ri. Because the patient remained neurologically stable, she was managed conservatively, and spontaneous radiological improvement was observed during follow-up. This case highlights the fact that leptomeningeal abnormalities in patients with lung cancer do not invariably represent leptomeningeal metastasis. When clinicoradiological findings are discordant, prompt reassessment using appropriately selected MRI sequences should be integrated with cerebrospinal fluid analysis and multidisciplinary evaluation, with pathological confirmation considered when clinically consequential alternative diagnoses cannot be excluded. This approach may help avoid inappropriate LM-directed therapy.

Pleural mesothelioma (PM) is a rare and aggressive malignancy. The development of novel therapeutic strategies targeting PM remains an unmet clinical need. However, comprehensive genomic data from Asian populations, particularly from Japanese patients, are limited. This study aimed to elucidate the genomic landscape of PM in Japanese patients using the nationwide Center for Cancer Genomics and Advanced Therapeutics (C-CAT) genomic database. A total of 211 patients registered between June 2019 and March 2025 were analyzed. The most frequent genetic alterations were in BAP1, NF2, TP53, CDKN2A/B, and MTAP. The median tumor mutation burden (TMB) was 1.26, and no microsatellite instability–high patients were detected. The median overall survival (OS) after first-line treatment was 30.6 months. Patients treated with immune checkpoint inhibitors (ICIs) had a significantly better OS than those who did not receive ICIs. In univariate and multivariate analyses, TP53 alterations and high TMB (cutoff value of 1.6) were associated with poor prognosis. These results suggest that integrating clinical and genomic data can enhance prognostic stratification and contribute to the development of precision medicine for PM. This study provides the first large-scale genomic characterization of Japanese PM patients with C-CAT and highlights potential biomarkers for future therapeutic development.