Niigata University Medical and Dental Hospital

Intravesical Bacillus Calmette-Guérin (BCG) therapy is an established treatment for non-muscle-invasive bladder cancer, involving direct instillation of a solution containing attenuated Mycobacterium bovis into the bladder. Although generally well-tolerated, rare vascular complications, including mycotic aneurysms and aortoenteric fistulas, have been reported. We report the case of a 76-year-old Japanese man who developed an aortoesophageal fistula three years after completing intravesical BCG therapy for superficial bladder carcinoma. The patient initially presented with bilateral lower limb pain following thoracic endovascular aortic repair. During hospitalization for lumbar pyogenic spondylitis, M. bovis was isolated from both sputum and spine biopsy cultures and confirmed using single-nucleotide polymorphism analysis. Despite the initiation of antimycobacterial therapy with rifampicin, isoniazid, ethambutol, and levofloxacin, he developed hematemesis and upper abdominal pain. Computed tomography findings were highly suggestive of an aortoesophageal fistula. The patient underwent successful surgical repair followed by a prolonged course of antimycobacterial therapy for at least ten months. To our knowledge, this is the first documented case of an aortoesophageal fistula caused by M. bovis following intravesical BCG therapy. Clinicians should maintain a high index of suspicion for this life-threatening complication in patients presenting with vascular abnormalities, hematemesis, or abdominal pain following BCG therapy, regardless of the time interval since treatment. Early recognition and aggressive management are essential for improving the outcomes of this rare but life-threatening condition.

Although programmed cell death-1 (PD-1) inhibitors have shown promising and durable responses in patients with several types of cancer, many patients show resistance to PD-1 inhibitors. Recent evidence has demonstrated that immunosuppressive cells are induced in tumor microenvironment and inhibit the anti-tumor effects of anti-PD-1 monoclonal antibody (αPD-1 mAb). To investigate whether nintedanib-a multi-tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor-suppresses immunosuppressive cells and enhances the anti-tumor effects of αPD-1 mAb in preclinical models, flowcytometry, immunohistochemistry, and RNA sequencing of tumor-tissue, tumor-draining lymph nodes, spleens were conducted. RNA sequencing of murine tumor tissues revealed that nintedanib decreased the gene signatures related to myeloid-derived suppressor cells (MDSCs) and cancer-associated fibroblasts (CAFs). Flow cytometry showed that nintedanib significantly decreased the MDSC and CAF percentage in tumor-bearing hosts and increased IFN-ϒ+CD4+ and CD8+ T cells infiltrating into tumors. Immunohistochemical analysis demonstrated that nintedanib treatment significantly increased the number of CD8+ T cells in the internal area of the tumor. Adding nintedanib to anti-PD-1 mAb therapy significantly inhibited in vivo tumor progression. These results indicate that nintedanib suppresses MDSCs and CAFs by inhibiting VEGFR-, PDGFR-, and FGFR-mediated signaling, thereby increasing effector T-cell infiltration into tumors and enhancing the anti-tumor effects of αPD-1 mAb therapy.

Megaprosthetic reconstruction has become the standard method for resecting bone and soft tissue tumors. However, the long-term functional outcomes and complications have not yet been sufficiently investigated. This study aimed to address a gap in the literature by analyzing patients who underwent tumor prosthesis of the hip or knee and were followed up for over 30years. We retrospectively analyzed 10 patients who underwent megaprosthetic reconstruction of the hip or knee between 1986 and 1995 at two institutions in Japan, with a minimum follow-up of 30years. Patient characteristics, complications, reoperation, and Musculoskeletal Tumor Society (MSTS) scores were reviewed. The long-term risks of reoperation, major revision, and deep infection were assessed. This study included seven distal femoral, two proximal femoral, and one proximal tibial reconstructions (median age at surgery, 22years). Histologically, the tumors were predominantly osteosarcomas (n=7). Eight of the 10 patients (80%) developed complications, with a median of 1.5 reoperations (range, 1-5). Major revisions occurred in five patients, including four with stem fractures and two with deep infections. The median overall reoperation-free survival was 16.2years (95% confidence interval, 2.4-24.2). At the final follow-up, all patients remained ambulatory, and the median MSTS score was 75.0% (range, 53.3-96.7). Despite the occurrence of frequent late complications, considerably long-term survivors following tumor endoprosthetic reconstruction in this small cohort were able to preserve ambulatory function for more than three decades, suggesting the effectiveness of this method while underscoring its lifelong risks and the necessity of long-term follow-up.

Chemotherapy-induced nausea and vomiting (CINV) remain major challenges during concurrent chemoradiotherapy (CCRT) for cervical cancer. Mannitol and furosemide are agents widely used to prevent cisplatin-induced nephrotoxicity; however, the differences in their effect on CINV have not been characterized. This study aimed to evaluate the impact of concomitant diuretic administration (mannitol versus furosemide) on the incidence and timing of vomiting in patients with cervical cancer undergoing CCRT. This multicenter, retrospective study evaluated the impact of concomitant diuretic administration on CINV in 485 patients receiving weekly, cisplatin-based CCRT between 2016 and 2024, including 206 who received mannitol and 279 who received furosemide. Vomiting occurred more frequently in the mannitol group than in the furosemide group (18.4% vs. 10.4%). Time-to-event analysis found that vomiting occurred earlier with mannitol during the entire CCRT course. These findings may reflect mannitol's osmotic properties and the increased, intestinal permeability associated with CCRT-related mucosal injury. To the best of our knowledge, this study is the largest investigation to date comparing diuretic agents in this setting. The results suggested that furosemide may be a more appropriate option for patients with a high risk of CINV.