Yuji Matsumoto

Purpose: Nivolumab plus ipilimumab is a standard first-line therapy for unresectable malignant pleural mesothelioma (MPM), yet biomarkers predicting immune checkpoint inhibitor (ICI) efficacy remain undefined. We aimed to identify genomic and tumor immune microenvironmental features associated with ICI response in MPM. Experimental Design: We analyzed two independent MPM cohorts. The discovery cohort included patients at the National Cancer Center Hospital (2012–2022) with frozen tumor tissues available for whole-genome sequencing (WGS) and RNA sequencing. Genomic alterations, transcriptomic profiles, immune cell composition, and T-cell receptor repertoire were analyzed, and key findings were validated in a nationwide Center for Cancer Genomics and Advanced Therapeutics (C-CAT) cohort. Results: The WGS cohort comprised 52 patients. Among ICI-treated patients, overall response rates were 30% in the WGS cohort and 29.4% in the C-CAT cohort. Genomic analyses identified frequent alterations in BAP1 and NF2, across both cohorts. ICI responders showed higher T-cell receptor diversity, increased CD8⁺ T-cell infiltration, and enrichment of M1 macrophages compared with non-responders. MTAP loss was associated with higher CD8⁺ T-cell infiltration and T-cell receptor diversity, and was linked to a higher ICI response rate in the C-CAT cohort. In contrast, BAP1 and NF2 alterations showed no consistent association with immune features or ICI efficacy. Conclusions: An immune-active tumor microenvironment characterized by high T-cell receptor diversity, CD8⁺ T-cell infiltration, and M1 macrophage enrichment was associated with favorable ICI responses in MPM. MTAP loss was linked to immune-related features and a higher ICI response, supporting further investigation of MTAP loss as a candidate biomarker.

Diagnostic yield of bronchoscopy for peripheral pulmonary lesions (PPLs) remains suboptimal, particularly when probe–lesion alignment is imperfect. Cryobiopsy using thin cryoprobes may improve tissue acquisition; however, randomised evidence comparing cryobiopsy alone with conventional bronchoscopic sampling is limited. We conducted an international, multicentre, randomised, open-label trial involving adults with a PPL ≤30 mm. After radial endobronchial ultrasound (R-EBUS) assessment, patients with within/concentric or adjacent-to/eccentric findings (i.e., non-invisible lesions) were randomised (1:1) to standalone cryobiopsy or conventional sampling. The primary endpoint was histology-based diagnostic yield, tested hierarchically in the prespecified adjacent-to/eccentric cohort followed by the overall cohort. Adverse events were systematically assessed. Among 660 enrolled patients, 627 underwent randomisation (314 to cryobiopsy and 313 to conventional sampling). In the adjacent-to/eccentric cohort (167 patients per group), histology-based diagnostic yield was higher with cryobiopsy than with conventional sampling (76.7% vs. 64.7%; estimated difference, 12.4 percentage points; 95% CI 2.8–22.0). In the overall cohort, yields were 83.4% and 74.9%, respectively (estimated difference, 8.9 percentage points; 95% CI 2.8–15.0). Moderate bleeding occurred more frequently with cryobiopsy (38.2% vs. 19.2%), whereas severe bleeding was uncommon (0.6% vs. 1.0%). Serious adverse events were infrequent in both groups. In patients undergoing R-EBUS–guided bronchoscopy for PPLs, standalone cryobiopsy achieved a higher histology-based diagnostic yield than conventional sampling. The benefit was most pronounced in lesions with adjacent-to/eccentric probe–lesion relationships.

Background: Histopathological evaluation of lung biopsy specimens is inherently destructive and reduces the three-dimensional tissue architecture to limited two-dimensional sections. For small bronchoscopic specimens, this may compromise the optimal tissue utilization for diagnosis and molecular testing. We investigated whether synchrotron-based phase-contrast X-ray computed tomography (CT) could be used to non-destructively visualize the three-dimensional architecture of clinically obtained transbronchial cryobiopsy specimens. Methods: In this exploratory imaging study, we prospectively enrolled patients with peripheral pulmonary lesions who underwent bronchoscopy. An additional single cryobiopsy specimen was obtained and imaged using synchrotron-based phase-contrast CT. The structural features were evaluated by three blinded observers using predefined ordinal scores. Interobserver agreement was assessed using the weighted kappa and intraclass correlation coefficients. Representative cases underwent serial histological sectioning, and exploratory slow-freezing micro-CT imaging was performed on a subset. Results: Fifteen patients were included. Phase-contrast CT revealed major structural features including alveolar-like airspaces, tissue density, glandular lumina, solid nest-like structures, thickened bronchial wall structures, and calcified foci. The imaging findings generally corresponded to the histological findings. Interobserver agreement was moderate to substantial for airspace preservation and tissue density, whereas agreement was poor for glandular and solid nest-like structures. Exploratory micro-CT showed partial visualization of finer structures but was limited by image blurring and distortion. Conclusions: Synchrotron-based phase-contrast CT enabled non-destructive three-dimensional structural visualization of clinically obtained transbronchial cryobiopsy specimens. Although the current resolution remains insufficient for detailed histological classification, this study represents a proof-of-concept for the feasibility of this imaging technique rather than a clinical workflow utility.

Pulmonary vein stenosis—a complication of atrial fibrillation ablation unfamiliar to most pulmonologists—was identified in a 42‐year‐old man who presented with haemoptysis. Initial bronchoscopy at a previously visited hospital revealed a central airway lesion, but biopsy was declined because of its haemorrhagic nature. Repeat bronchoscopy at our hospital showed oedematous changes and vascular proliferation in the left main bronchus, suggesting adenoid cystic carcinoma. However, cryobiopsy excluded malignancy and suggested a vascular malformation with thickened, irregularly dilated muscular vessels. Contrast‐enhanced CT revealed occlusion of the left superior pulmonary vein, interpreted as a secondary change. The patient had a history of catheter ablation for atrial fibrillation. Based on these findings, the stenosis was determined to be a complication of catheter ablation, and surgical bypass was performed. Severe pulmonary vein stenosis was successfully diagnosed using cryobiopsy. This condition is unfamiliar to pulmonologists; however, differentiation from airway tumours is crucial for determining treatment.

Ground‐glass nodules (GGNs) pose a considerable diagnostic challenge. Recently, a balloon catheter to dilate peripheral bronchi has become commercially available, offering a potential solution to this limitation. This is a case of a 73‐year‐old female nonsmoker with rheumatoid arthritis on Tacrolimus. Chest CT scan showed a 13.9‐mm pure GGN at the right upper lobe. Annual chest CT scan noted stability in size for 7 years, but recently the size increased to 17.0 mm with a positive bronchus sign in the 12th generation. An ultrathin bronchoscope could be inserted up to the 9th generation. Balloon dilatation was done at this point to pass the subsequent tortuous bifurcation, advancing the bronchoscope further up to the 10th generation. Where radial endobronchial ultrasound showed a blizzard sign, cryobiopsy was performed, revealing lung adenocarcinoma. This case highlights the value of balloon dilatation and cryobiopsy for ultra‐peripheral GGNs.

Background: Invasive mucinous lung adenocarcinoma (IMA) is challenging to diagnose via bronchoscopy due to its distinct histopathological characteristics, including poorly atypical tumor cells with abundant mucins. Given that cryobiopsy facilitates high-quality and quantity tissue sampling, we hypothesized that it could improve diagnostic success. This retrospective study aimed to determine whether cryobiopsy is a valid diagnostic tool for IMA. Methods: We retrospectively reviewed consecutive patients who underwent surgical resection for lung cancer at our institution between March 2017 and July 2024. Among them, patients diagnosed with IMA were selected. Those who had undergone a diagnostic biopsy for peripheral pulmonary lesions (PPLs) were included in the study. These patients were divided into two groups: cryo and conventional, based on whether cryobiopsy was performed. The diagnostic yield and safety profiles of both groups were compared. Results: Of 5,053 surgeries for lung cancer, 201 (4.0%) were diagnosed with IMA. Among them, 106 patients who had undergone bronchoscopy for PPLs were included in the analyses: 46 in the cryo group and 60 in the conventional group. The diagnostic yield was significantly higher in the cryo group than in the conventional group (93.5% vs. 73.3%, P=0.01). Multivariable analysis showed cryobiopsy was significantly associated with higher yield [adjusted odds ratio (OR), 5.07; 95% confidence interval (CI): 1.33–19.40; P=0.02]. Although not fatal, complications like bleeding and pneumonia were more frequent in the cryo group. Conclusions: Cryobiopsy is a valid technique for making a diagnosis of IMA.