The registration committee for esophageal cancer in the Japan Esophageal Society (JES) has collected the characteristics, treatments, and outcomes of patients who underwent any treatment in 2016 in Japan. We analyzed data on patients who had visited the participating hospitals in 2016. We collected the data using the National Clinical Database with a web-based data collection system. We used the Japanese Classification of Esophageal Cancer 11th edition by JES and the TNM Classification 8th edition by the Union of International Cancer Control (UICC) for cancer staging. Two committee members (A. O. and M. T.), endorsed by the Japan Esophageal Society and certified by the NCD, analyzed the data. A total of 9,593 cases were registered from 347 institutions in Japan. Squamous cell carcinoma (SCC) and adenocarcinoma accounted for 87.5% and 7.2%, respectively. The 5-year survival rates of patients treated by endoscopic resection, concurrent chemoradiotherapy, radiotherapy alone, and esophagectomy were 89%, 36%, 26%, and 59%, respectively. Esophagectomy was performed in 4,988 cases. Minimally invasive approaches were selected for 65.1%, and 57.7% underwent thoracoscopic esophagectomy. The 5-year survival rates of esophagectomy cases with pStage 0, I, II, III, IVa, and IVb in the JES system were 83%, 79%, 67%, 40%, 34%, and 27%, respectively. In the UICC system, the survival of surgically resected SCC cases with pStage IVB, mainly due to supraclavicular lymph-node metastasis, was better than that with pStage IVA. We hope that this report improves all aspects of diagnosing and treating esophageal cancer in Japan.

Treatment with bevacizumab, ramucirumab, and aflibercept increases the risk of developing proteinuria; however, their association with the risk of renal impairment or failure remains unknown, warranting further investigation. Consequently, a systematic review and meta-analysis were conducted to quantify the exact risk and incidence of proteinuria, renal impairment, and renal failure associated with bevacizumab, ramucirumab, and aflibercept therapy. We searched the PubMed, Cochrane Library, and Web of Science databases for phase III randomized controlled trials (RCTs) of these therapies published before November 5, 2024. The meta-analysis included 29,165 patients from 47 RCTs, including 14,211 patients who received bevacizumab, ramucirumab, and aflibercept. The incidence of proteinuria was 24% (95% confidence interval [CI] 18-33) for all-grades and 3% (95% CI 2-4) for grades ≥ 3 proteinuria. Compared with controls, the addition of these medications was associated with an increased risk of developing all grades of proteinuria (odds ratio [OR]: 7.32; 95% CI 5.17-10.3), as well as grades ≥ 3 proteinuria (OR: 7.05; 95% CI 5.52-9.00). The risk of all-grade (OR: 1.54; 95% CI 1.21-1.96) and grade ≥ 3 (OR; 1.64, 95% CI 1.08-2.24) renal impairment significant increased with additional treatment with these drugs. However, no significant increase in risk was observed for renal failure at any grade (OR: 1.26; 95% CI 0.92-1.72). Bevacizumab, ramucirumab, and aflibercept significantly increased the risk of developing proteinuria and renal impairment, but not renal failure. Monitoring and managing renal function and proteinuria in patients treated with these drugs is crucial.

Several prospective studies have evaluated the benefit of primary tumour resection (PTR) in de novo Stage IV breast cancer (BC) patients, but it remains controversial. We aimed to investigate whether PTR improves the survival of de novo stage IV BC patients. De novo stage IV BC patients were enrolled in the first registration and received systemic therapies according to clinical subtypes. Patients without progression after primary systemic therapy for 3 months were randomly assigned 1:1 to systemic therapy alone (arm A) or PTR plus systemic therapy (arm B). The primary endpoint was overall survival (OS), and the secondary endpoints included local relapse-free survival (LRFS). Five hundred seventy patients were enrolled between May 5, 2011, and May 31, 2018. Of these, 407 were randomised to arm A (N = 205) or arm B (N = 202). The median follow-up time of all randomised patients was 60 months. The difference in OS was not statistically significant (HR 0.86 90% CI 0.69-1.07, one-sided p = 0.13). Median OS was 69 months (arm A) and 75 months (arm B). In the subgroup analysis, PTR was associated with improved OS in pre-menopausal patients, or those with single-organ metastasis. LRFS in arm B was significantly longer than that in arm A (median LRFS 20 vs. 63 months: HR 0.42, 95% CI 0.33-0.53, p < 0.0001). There were no treatment-related deaths. PTR did not prolong OS. However, it improved local control and might benefit a subset of patients, such as those with premenopausal status or with single-organ metastasis. It also improved local relapse-free survival (LRFS), which is a clinically meaningful outcome in trials of systemic therapy. UMIN Clinical Trials Registry (UMIN000005586); Japan Registry of Clinical Trials (jRCTs031180151).

Cisplatin, gemcitabine, and durvalumab (CGD) combination is a standard first-line treatment for advanced biliary tract cancer (BTC). This study aimed to assess the impact of genetic alterations on outcomes in patients with advanced BTC treated with CGD in real-world clinical practice. Patients with unresectable, locally advanced, or metastatic BTC treated with CGD across 39 centers in 11 countries (Europe, United States, and Asia) were included in this analysis. The cohort included 513 patients with advanced BTC. The five most frequently altered genes were TP53 (22.1%), KRAS (13.7%), CDKN2A/B (13.6%), ARID1A (12.2%), and IDH1 (9.2%). In multivariate analysis, SMAD4 mutations were associated with improved progression-free survival (PFS) (HR 0.49, p = .018) and overall survival (OS) (HR 0.11, p = .023), while TP53 mutations were linked to worse PFS (HR 1.62, p = .0047) and TERT mutations to worse OS (HR 8.92, p = .0012). No other genomic alterations were significantly associated with outcomes.Subgroup analysis showed that TP53 mutations negatively impacted PFS and OS in intrahepatic cholangiocarcinoma (iCCA), while KRAS mutations were associated with poorer PFS in extrahepatic cholangiocarcinoma (eCCA). No gene alterations were linked to outcomes in gallbladder cancer. This large-scale analysis, with comprehensive molecular profiling, supports the positive prognostic impact of SMAD4 mutations for PFS and OS and highlights the negative prognostic roles of TP53 (PFS) and TERT (OS) mutations, providing valuable insights for personalized treatment strategies in BTC.

To evaluate the safety and efficacy of multimodality treatment with vincristine, actinomycin D, and cyclophosphamide (VAC) therapy, surgery, and radiotherapy according to the US Intergroup Rhabdomyosarcoma Study IV (IRS-IV), and to establish a central review system and standard treatment for intermediate-risk pediatric rhabdomyosarcoma in Japan. The Japan Rhabdomyosarcoma Study-I (JRS-I) was a single-arm, phase II trial for intermediate-risk rhabdomyosarcoma treatment with open enrollment from June 2004 to March 2009. Patients received 12 cycles of VAC every 3 weeks for 42 weeks, with local therapy beginning after Week 12. The endpoints were progression-free survival (PFS), overall survival (OS), and incidence of hepatic veno-occlusive disease (VOD). Thirty-one eligible patients were enrolled, and at a median follow-up of 5.2 years, the 3-year PFS and OS for patients were 74.2%±7.9% (95% confidence interval [CI] 55.0%-86.2%) and 90.3%±5.3% (95% CI 72.9%-96.8%), respectively. VOD occurred in 3 (8%) of the 40 evaluable patients, but all recovered, and there were no deaths. The VAC regimen for intermediate-risk rhabdomyosarcoma with the first central review system in Japan is safe and feasible, and these findings can be positioned as basic data for improving treatment outcomes in Japan.

Automated surgical skill assessment using artificial intelligence (AI) in laparoscopic cholecystectomy (Lap-C) can be a valuable method for improving the effectiveness of surgical education and enhancing the surgical outcomes of Lap-C. This study aimed to assess the applicability of automated surgical skill assessment using a developed AI-based surgical phase recognition model in Lap-C. We collected Lap-C videos and categorized them into training and test datasets. The training dataset was used to develop a surgical phase recognition model that classified the Lap-C procedure into 10 phases. The test dataset was categorized into three surgical skill levels (expert, intermediate, and novice groups) based on predefined criteria. We evaluated the applicability of our model to automatically categorize the three surgical skill levels using parameters derived from the model, including time spent in each phase and the confidence level for phase recognition (AI confidence score [AICS]). The overall accuracy of the surgical phase recognition model was 82.3%. Manual analysis showed that the time for dissection in the gallbladder neck in the novice group was significantly longer than in the expert group (P < 0.01), and a similar trend was observed in the model-based analysis. The time for clipping and cutting the cystic duct and artery in the novice group was significantly longer than in the expert group in both manual and model-based analyses. AICS was higher in the expert group than in the intermediate group (P = 0.02). We developed an automated surgical phase recognition model in Lap-C with AI, which was applicable for surgical skill assessment by measuring the time required for dissection of the gallbladder neck, clipping and cutting the cystic duct and artery, and calculating the AICS. Our model is expected to contribute to the efficiency of surgical education.

This study aimed to analyze the efficacy and safety of a prospective, multicenter registry study of proton beam therapy (PBT) for extrahepatic cholangiocarcinoma (EHC) in Japan. Patients who underwent PBT for EHC between May 2016 and June 2021 were registered in the Particle Beam Therapy Committee and Subcommittee of the Japanese Society for Radiation Oncology. We updated the overall survival (OS), progression-free survival (PFS), local control rate (LC), and toxicity. Among 201 registered cases, 124 cases including elder population (median age 76 years old, range; 44–91) with initial definitive PBT were evaluated. The follow-up period for survivors was 18.3 months, the median OS time was 20.0 months (95% CI: 17.3–22.8 months), and the 2-year OS rate was 36.9% (27.3–46.4%). The 2-year LC and PFS were 65.2% and 23.0%. The OS was significantly higher for tumor size < 3 cm vs. ≥ 3 cm (p = 0.015); liver function Child–Pugh score normal/A vs. B/C (p < 0.001); and distance of the tumor from the gastrointestinal tract > 2 cm vs. ≤ 2 cm (p = 0.008) in multivariate analysis. Elderly patients age > 75 years underwent less chemotherapy and showed a 2-year OS of 41.3%, whereas young patients with age ≤ 75 years showed a 2-year OS of 32.0%. A higher prescribed dose (biologically effective dose: BED) > 89 Gy10 was associated with better LC and PFS but not OS. PBT-related grade 3 acute and late adverse events occurred in 4.0 and 12.1% of the patients, respectively. These updated multicenter prospective registry data demonstrate that PBT is an effective treatment for unresectable EHC, including in elderly patients.

Effective clinical management of patients with cancer requires highly accurate diagnosis, precise therapy selection, and highly sensitive monitoring of disease burden. Caris Assure is a multifunctional blood-based assay that couples whole exome and whole transcriptome sequencing on plasma and leukocytes with advanced machine learning techniques to satisfy all three clinical testing needs on one platform. Caris Assure for therapy selection was CLIA validated using 1,910 samples. 376,197 tissue profiles along with 7,061 paired blood and tissue profiles were used to engineer features for three machine learning models. The MCED model was trained on 1,013 patients and validated on an independent set of 2,675 patients. The tissue of origin for MCED model was trained on 1,166 samples and validated using 5-fold cross validation. The MRD & Monitoring model was trained on 3,439 patients and validated on two independent sets of 86 patients for MRD and 101 patients for monitoring. For early detection, sensitivities for stages I-IV cancers (n = 284, 129, 90, 23 respectively) were 83.1%, 86.0%, 84.4%, and 95.7%, all at 99.6% specificity (n = 2149). The diagnostic first-line procedure for tissue of origin was determined for 8 categories with a top-3 accuracy of 85% for stage I and II cancers. Detection of driver mutations for therapy selection from blood collected within 30 days of matched tumor tissue, demonstrated high concordance (PPA of 93.8%, PPV of 96.8%) using CHIP subtraction. For MRD and recurrence monitoring, the disease-free survival of patients whose cancers were predicted to have an event was significantly shorter than those predicted not to have an event using a tumor naïve approach (HR = 33.4, p < 0.005, HR = 4.39, p = 0.008, respectively). The data presented here demonstrate a unified liquid biopsy platform that uses blood-based whole-exome and transcriptome sequencing coupled with artificial intelligence to address the important clinical needs in multi-cancer early detection, monitoring of MRD and recurrent cancers, and precision selection of molecularly targeted therapies.