Published papers

Biliary tract carcinoma (BTC) is a malignancy with poor prognosis. Current molecular targeted therapies benefit only a limited subset of patients, underscoring the need for novel approaches, such as combining DNA-damaging chemoradiotherapy with an immune checkpoint inhibitor. Although cellular responses following chemoradiotherapy-induced DNA damage are essential, they remain poorly understood in the context of three-dimensional tumor structures. This study aimed to investigate the effects of ionizing radiation, a DNA-damaging cancer therapy, on patient-derived BTC organoids. DNA repair and gene expression regulation was integrally examined by immunofluorescence and RNA-Seq analysis following 10 Gy of X-rays. X-ray irradiation caused significant morphological changes. In addition, X-ray irradiation upregulated extracellular matrix-related gene expression as revealed by RNA sequencing. DNA damage response analysis indicated that non-homologous end joining was the primary repair pathway in patient-derived BTC organoids. Moreover, X-ray irradiation activated immune-related pathways, such as cGAS/STING, RIG-I/MDA-5, and JAK/STAT, suggesting potential immune activation following radiotherapy. Our study revealed that DNA damage response altered the tumor structure and modulated the expression of multiple genes, including extracellular matrix- and immune-related genes. Studies using in vitro organoid models can be useful for investigating three-dimensional cellular responses after DNA-damaging cancer therapies, such as chemoradiotherapy.

Background/Objectives: Although vonoprazan-based triple therapy has improved the first- and second-line Helicobacter pylori eradication rates, a subset of patients still require third-line or later treatments. The present study aimed to evaluate the efficacy and safety of susceptibility-guided eradication strategies from third-line or later treatments in a multicenter setting. Methods: This retrospective multicenter study (2019–2024) enrolled 94 patients who had failed second-line eradication therapy and underwent H. pylori isolation and susceptibility testing. Based on sitafloxacin sensitivity, patients received vonoprazan, amoxicillin, and sitafloxacin (VAS) if sensitive, or vonoprazan, amoxicillin, and rifabutin (VAR) if resistant. Altogether, 75 patients received treatment according to this protocol. Results: Among the 75 patients, 61.3% were sitafloxacin-sensitive (VAS group), and 38.7% were resistant (VAR group). All strains were rifabutin-sensitive. The overall eradication rates were 92.0% and 95.8% in the intention-to-treat and per-protocol analyses, respectively. Adverse events occurred in 17.3% of cases. One patient in the VAR group discontinued therapy due to dizziness, whereas all other adverse events were mild and did not require treatment cessation. Subgroup analysis showed eradication rates of 93.5% (43/46) and 89.7% (26/29) for the VAS and VAR groups, respectively. The eradication rate for third-line therapy was 96.2% (50/52), whereas that for fourth-line therapy was 85.7% (18/21). Fifth-line therapy showed an eradication rate of 50.0% (1/2). Conclusions: Susceptibility-guided vonoprazan-based regimens from the third-line treatment onward achieved high eradication and tolerability in a multicenter cohort. This approach may offer a valuable treatment option for patients with refractory H. pylori infections.

Upper gastrointestinal stenosis, which can be congenital or acquired, can lead to dysphagia. The association between trisomy 17p syndrome, a rare chromosomal abnormality, and upper gastrointestinal stenosis is unclear. A 20-year-old man diagnosed with trisomy 17p syndrome was referred to our department due to recurrent vomiting. Esophagogastroduodenoscopy revealed stenotic areas in the esophagus, stomach, and duodenum. The congenital gastrointestinal stenosis present in both the duodenum and esophagus suggested that the stasis and reflux of digestive fluids exacerbated stenosis in the stomach and esophagus. Gastric acid suppression therapy and endoscopic dilation of the esophagus and duodenum effectively resolved the patient's vomiting symptoms.

Background: Rifabutin-based regimens are used as rescue therapy for refractory Helicobacter pylori infection; however, the duration for which treatment is required and side effects are concerning. This study assessed the efficacy and safety of 7-day rifabutin, amoxicillin, and vonoprazan triple therapy as third- or later-line treatment for H. pylori infection. Materials and Methods: Patients who did not respond to second-line therapy were enrolled. After H. pylori infection was confirmed with the culture method, the patients received rifabutin-containing triple therapy (20 mg vonoprazan b.i.d., 500 mg amoxicillin q.i.d., and 150 mg rifabutin q.d.) for 7 days. Twelve weeks after the eradication therapy, successful eradication was confirmed using a 13C urea breath test or the H. pylori stool antigen test. The results obtained from our previous study that reported a 10-day or 14-day esomeprazole based rifabutin-containing triple therapy as a third- or fourth-line rescue therapy treated patients were used as historical control. We determined the minimum inhibitory concentrations of amoxicillin and rifabutin. We also evaluated whether the patients were positive for the mutation of the rpoB gene. Results: Intention-to-treat and per-protocol analyses showed that our regimen resulted in a high eradication rate (91.2%, 95% CI: 84%–99% and 92.7%, 95% CI: 86%–100%, respectively). Adverse events occurred in 31.6% of the patients, and two patients discontinued the therapy. Conclusions: This is the first study to evaluate the efficacy and safety of a 7-day low-dose rifabutin-based triple therapy with vonoprazan and amoxicillin. Our results suggest that our regimen was effective and safe as a third- or later-line H. pylori eradication regimen. To clarify what component in this regimen are critical, subsequent studies using a factorial design (comparing vonoprazan-amoxicillin dual therapy vs. vonoprazan-rifabutin triple therapy) will be needed.

Background: Biliary tract cancer (BTC) remains a highly aggressive malignancy with limited treatment options and poor prognosis. To explore the association between KRAS variants and survival/therapeutic outcomes of patients with BTC, we analyzed genetic and clinical data obtained from BTC patients who underwent comprehensive genomic profiling (CGP) testing in Japan. Patients and methods: A total of 7773 patients with BTC who were registered in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) were included in this study. The main outcome was overall survival (OS) in months. For survival analysis, OS was measured from diagnosis to last follow-up or death, and for therapeutic outcomes, from treatment initiation to last follow-up or death. Results: The overall frequency of KRAS mutations in BTC was 23.4%. When classified according to tumor subtype, KRAS mutations were identified in 24.9% of patients with intrahepatic cholangiocarcinoma (IHC), in 32.2% of those with extrahepatic cholangiocarcinoma (EHC), and in 9.4% of those with gall-bladder cancer (GB). Among patients with KRAS mutations, G12D mutation was the most common in IHC (41.5%), EHC (35.9%), and GB (29.8%). In all BTC subtypes (IHC, EHC, and GB), patients with KRAS mutations had worse OS compared to those with wild-type KRAS. By KRAS variant, the G12D, G12V, and Q61H mutations were associated with poor OS in patients with IHC, while the G12D and G12V mutations were associated with poor OS in patients with EHC. Furthermore, in patients with unresectable BTC who received first-line treatment with regimens including gemcitabine, cisplatin, and durvalumab therapy, the G12D mutation was associated with poor OS across all regimens evaluated in this study. Conclusions: KRAS variants were significantly associated with poor prognosis and unfavorable therapeutic outcomes in BTC patients and may serve as potential prognostic and predictive factors.

Organoids are innovative three-dimensional and self-organizing cell cultures of various lineages that can be used to study diverse tissues and organs. Human organoids have dramatically increased our understanding of developmental and disease biology. They provide a patient-specific model to study known diseases, with advantages over animal models, and can also provide insights into emerging and future health threats related to climate change, zoonotic infections, environmental pollutants or even microgravity during space exploration. Furthermore, organoids show potential for regenerative cell therapies and organ transplantation. Still, several challenges for broad clinical application remain, including inefficiencies in initiation and expansion, increasing model complexity and difficulties with upscaling clinical-grade cultures and developing more organ-specific human tissue microenvironments. To achieve the full potential of organoid technology, interdisciplinary efforts are needed, integrating advances from biology, bioengineering, computational science, ethics and clinical research. In this Review, we showcase pivotal achievements in epithelial organoid research and technologies and provide an outlook for the future of organoids in advancing human health and medicine.