Small non-functioning pancreatic neuroendocrine tumors (pNETs) measuring under 10 mm are considered eligible for observation and follow-up, although a minority of small NETs may exhibit show an aggressive behavior. We report a case of small G2-NET that was surgically removed and later developed metastatic recurrence in multiple organs. The patient, a woman in her sixties with a pancreatic body cyst, had been under follow-up for more than a decade. Several years later, a hypoechoic area appeared in the pancreatic body. Endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) was performed twice; however, a definitive diagnosis was not obtained. Subsequent EUS revealed extension of the lesion into the main pancreatic duct, which was diagnosed as a pancreatic body tumor with intraductal extension. Distal pancreatectomy was performed, and histology revealed a small G2-NET, measuring 8 × 7 mm in diameter. Multiple metastatic tumors were detected 4.5 years after surgery, and the patient is currently undergoing treatment with everolimus and lanreotide. This case supports the viewpoint that small G2-NETs, even those measuring less than 10 mm, may have a risk of metastasis, highlighting the need for careful follow-up and appropriate therapeutic interventions.

Neoadjuvant gemcitabine plus S-1 (GS) followed by surgery and adjuvant S-1 is the standard of care for resectable pancreatic cancer. Since ~73% of newly diagnosed pancreatic cancer patients are aged ≥70, effective treatments are strongly needed in this geriatric population. In unresectable pancreatic cancer, gemcitabine plus nab-paclitaxel (GnP) is widely used, even among geriatric patients. To evaluate the survival advantage of neoadjuvant GnP over GS for geriatric patients with resectable pancreatic cancer, an open-label randomized phase III trial (JCOG2101C) has been initiated since October 2022. A total of 400 patients will be enrolled from 28 institutions within 3 years. The primary endpoint is overall survival. This trial was registered at the Japan Registry of Clinical Trials as jRCTs031220351 [https://jrct.mhlw.go.jp/latest-detail/jRCTs031220351].

Although Helicobacter pylori (H. pylori) infection, a well-established risk factor for gastric cancer, has been implicated as causative in biliary tract cancer (BTC) and pancreatic cancer (PC), the evidence remains inconclusive. Moreover, while germline pathogenic variants may modify the association between H. pylori infection and gastric cancer risk, their roles in BTC and PC are unclear. We examined these associations while accounting for genetic susceptibility and lifestyle factors. Two case-control studies were conducted, including 116 BTC cases, 417 PC cases, and 3086 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression adjusted for age, sex, study version, carrier status of pathogenic variants, smoking, and alcohol consumption. H. pylori infection was defined by antibody seropositivity, pepsinogen-based atrophic gastritis (AG), and their combination. Subsite-specific analyses were also performed. No significant association was observed between H. pylori infection and BTC risk. However, higher H. pylori antibody titers (per 10 U/mL increase) were positively associated with overall PC risk (OR 1.04, 95% CI: 1.01-1.07). In subsite analyses, AG without detectable antibodies was positively associated with pancreatic head cancer risk (OR 3.04, 95% CI: 1.23-7.54), whereas H. pylori seropositivity was positively associated with pancreatic body cancer risk (OR 1.75, 95% CI: 1.10-2.77). No interaction between H. pylori infection and pathogenic variants, smoking, or alcohol consumption was observed for either cancer. These findings suggest that H. pylori infection may be associated with pancreatic cancer risk in specific anatomical regions, with limited evidence for modification by genetic or lifestyle factors.

OBJECTIVES:The Clinical Practice Guidelines for Pancreatic Cancer were first published in 2006 by the Japan Pancreas Society and have been revised in 2009, 2013, 2016, 2019, and 2022. In July 2025, a newly revised version was released in Japanese. METHODS:This latest revision was developed in accordance with the Minds Manual for Guideline Development 2020, which incorporates the principles of GRADE (Grading of Recommendations Assessment, Development, and Evaluation) to improve clarity, transparency, and reliability of the recommendations. Patients and citizens were actively involved in both the development and implementation processes. RESULTS:The guideline provides updated algorithms for the diagnosis, treatment, drug therapy, and precision medicine of pancreatic cancer, comprising 8 domains: diagnosis, surgical therapy, adjuvant therapy, radiation therapy, drug therapy, stent therapy, supportive and palliative care, and patient and citizen involvement. It includes 63 clinical questions and 99 corresponding statements, each accompanied by an evidence level, strength of recommendation, and consensus rate. CONCLUSIONS:These guidelines represent the most comprehensive and standardized resource currently available in Japan for the clinical management of pancreatic cancer. This English synopsis aims to disseminate the 2025 edition of the Japanese Clinical Practice Guidelines for Pancreatic Cancer to a global audience and highlight the Japanese approach to pancreatic cancer care.

The clinical utility of tumor markers such as neuron-specific enolase (NSE) and progastrin-releasing peptide (ProGRP) in digestive neuroendocrine carcinoma (NEC) remains unclear. This exploratory analysis aimed to evaluate whether pretreatment and changes of tumor marker levels can predict treatment efficacy. In 137 of the 170 patients enrolled in JCOG1213 with digestive NECs (WHO 2010), we evaluated the association between treatment response and pretreatment NSE and ProGRP levels as well as the changes of these tumor markers from baseline to 6 weeks after chemotherapy. Pretreatment NSE and ProGRP were elevated in 127 and 74 patients. The objective response rate was 58.3%/55.6% in patients with high/normal NSE, and 60.8%/56.7% in patients with high/normal ProGRP. Any decline in tumor markers at 6 weeks tended to be associated with response, particularly for NSE than for ProGRP. The odds ratios for response in decreased NSE and ProGRP at 6 weeks of chemotherapy were 3.231 (P = 0.0198) and 1.652 (P = 0.2247) in multivariable analysis. Pretreatment NSE and ProGRP levels were not associated with tumor response. NSE and ProGRP have potential roles in treatment monitoring, especially changes in NSE were more relevant to tumor response than changes in ProGRP.

Artificial intelligence (AI) is rapidly being applied to medical imaging; however, the evidence base for endoscopic ultrasonography-based AI (EUS-AI) remains limited. We conducted a structured literature search (PubMed, Embase, and the Cochrane Library) for studies on AI for the diagnosis of pancreatic diseases using EUS images. Overall, 1 detection and 17 classifications of pancreatic tumors, 4 classifications of cystic lesions, and 4 focused on parenchymal or station recognition were reported in recent peer-reviewed publications. Deep learning architectures, such as ResNet, EfficientNet, VGG, UNet++, YOLO, and custom convolutional networks, were utilized. Multimodal models combine imaging with clinical or cytological data. Reported accuracy ranged from 0.84 to 0.94; however, only a small number of studies performed external validation with enough data to confidently support their findings. Only one model has been approved in Japan with unpublished technical details. Significant challenges include limited data from single institutions, inconsistent case labeling, varying diagnostic criteria, and internal validation, which may overestimate the actual performance of the AI models. Future directions include establishing nationwide systems for collecting and sharing EUS images, applying large language models to assist in reporting and patient explanation, and exploring the use of AI to support or partially automate EUS procedures through integration with robotics. With the first commercial systems now appearing, continued innovation and rigorous validation are expected to accelerate the clinical usage of EUS-AI.

PURPOSE:This study aimed to investigate the clinicomolecular profiles and the efficacy of human epidermal growth factor receptor 2 (HER2)-targeted therapy in HER2-amplified biliary tract cancer (BTC). METHODS:This study was an international collaboration that used combined data from the prospective SCRUM-Japan GOZILA and MONSTAR-SCREEN in Japan and retrospective reviews in the United States; patients with advanced BTC who had received systemic therapy were included. The clinicomolecular profiles were evaluated in an exploratory cohort, whereas the efficacy of HER2-targeted therapy was assessed in a biomarker-selected cohort. RESULTS:Of the 439 patients in the exploratory cohort, 43 (10%) had HER2 amplification. The frequencies of coalterations were higher in patients with HER2 amplification versus patients without HER2 amplification including HER2 mutations (26% v 5%, P < .001), TP53 mutations (84% v 61%, P = .003), and BRAF amplification (9% v 2%, P = .030). There were no KRAS mutations identified in patients with HER2-amplified BTC. No significant difference in overall survival (OS) was observed between patients with and without HER2 amplification (median, 17.7 v 16.9 months; hazard ratio [HR], 0.95 [95% CI, 0.65 to 1.40]). Of the 60 patients with HER2-amplified BTC in the biomarker-selected cohort (43 from Japan and 17 from the United States), the OS was significantly longer in 29 patients who received HER2-targeted therapy than in those who did not receive HER2-targeted therapy (median, 24.3 v 12.1 months; HR, 0.39 [95% CI, 0.23 to 0.82]). Multivariate analysis identified HER2-targeted therapy as an independent prognostic factor for OS (HR, 0.29 [95% CI, 0.14 to 0.58]; P < .001). CONCLUSION:HER2 amplification was found in 10% of advanced BTC and was not identified as an independent prognostic factor for OS. Patients with HER2-amplified BTC derive significant benefit from HER2-targeted therapy.

BackgroundMajor hepatectomy (MH) can increase the risk of adverse events (AEs) owing to impaired drug metabolism due to decreased liver volume and surgical injury. Thus, we performed this subgroup analysis using data from JCOG1113, a phase III trial comparing gemcitabine plus S-1 (GS) and gemcitabine plus cisplatin (GC) in patients with advanced and recurrent biliary tract cancer (BTC), to evaluate the effect of MH on the safety and efficacy of GC and GS regimens in patients with recurrent BTC.MethodsOf the 354 patients with advanced BTC enrolled in JCOG1113, 76 patients with postoperative recurrence (30 in the MH group and 46 in the non-MH group) were analyzed.ResultsGrade >= 3 platelet count decreased in both arms was more frequent in the MH group than in non-MH group (GC, 0.0 vs. 17.6%; GS, 3.9 vs. 15.4%). However, in the MH group, the white blood cell decreased (GC, 55.0 vs. 38.5%; GS, 23.1 vs. 7.7%) and anemia (GC, 15.0 vs. 11.8%; GS, 23.1 vs. 7.7%) were less common than in the non-MH group. The MH and non-MH groups showed no significant difference in overall survival (OS) in both GC [median OS, 23.0 in MH vs. 16.9 months in non-MH (hazard ratio, 0.857; 95% CI 0.387-1.899)], and GS [median OS, 21.5 vs. 14.9 months (hazard ratio, 0.670; 95% CI 0.310-1.447)] arms.ConclusionsThe safety and efficacy of gemcitabine-based chemotherapy were comparable between patients who underwent MH and those who underwent other surgeries.

652 Background: There is limited evidence regarding the benefit of adding somatostatin analogs to molecular targeted agents for well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). This phase III trial was conducted to compare everolimus plus lanreotide (EVE/LAN) with everolimus monotherapy (EVE) in patients with unresectable or recurrent GEP-NETs in the first-line setting. Methods: Patients with grade 1 or grade 2, nonfunctioning GEP-NETs with poor prognostic factors (Ki-67 labeling index (LI) 5-20% or diffuse liver metastases) were randomly assigned (1:1) to EVE (10 mg/day) or EVE/LAN (EVE + LAN 120 mg every 28 days). The primary endpoint was progression-free survival (PFS). The key secondary endpoint was overall survival (OS), and other secondary endpoints were objective response rate (ORR), disease control rate (DCR), and safety. The study was based on the hypothesis of an assumed median PFS of 11.0 months for EVE, expecting a 4-month improvement by EVE/LAN (HR: 0.73). The planned sample size was 250, requiring 195 events overall with a one-sided alpha level of 5%, a power of 70%, an accrual period of 5 years, and a follow-up period of 1.5 years. Results: Between April 2020 and June 2024, a total of 178 patients were enrolled, and the planned interim analysis was conducted in 145 patients (72 in the EVE and 73 in the EVE/LAN) in June 2024 with a data cut-off date of Nov 2023. The median PFS was 11.5 months in the EVE arm and 29.7 months in the EVE/LAN arm (HR 0.38 [99.91% CI 0.15–0.96], P = 0.00017 < the prespecified significance level of 0.00046, by the stratified log-rank test). The HR for OS was 0.97 (95% CI: 0.24-3.90). The ORR and DCR were 8.7% (6/69) and 87.0% (60/69) in the EVE arm and 26.8% (19/71) and 91.5% (65/71) in the EVE/LAN arm, respectively. Both hematologic and non-hematologic toxicities tended to be more frequent in the EVE/LAN arm than in the EVE arm. No treatment-related deaths were observed in either arm. Based on the efficacy results, the Data and Safety Monitoring Committee recommended early termination of the study. Conclusions: The EVE/LAN provides statistically significant prolongation of PFS compared with EVE monotherapy, and the safety profile of EVE/LAN was manageable. The EVE/LAN might be a new standard treatment in the first-line setting for well-differentiated grade 1/2 GEP-NETs with poor prognostic factors. Clinical trial information: jRCT1031200023.

WJOG15221M is Japan's first fully remote, investigator-initiated oncology trial, successfully enrolling 28 patients-36% remotely-by integrating trial access into the national CGP program and leveraging existing healthcare infrastructure without new digital tools. Targeting rare ALK fusion-positive tumors, the trial demonstrated that decentralized models can improve equity, efficiency, and continuity of care, offering a scalable path for future precision oncology trials.

Pancreatic cancer (PC) remains a highly lethal disease with few reliable biomarkers to guide chemotherapy choices. New biomarkers for selecting anticancer drugs are needed to enhance the effectiveness of current multimodal treatment approaches. This study aimed to find a new biomarker by using clinical data and specimens collected for a Japanese randomized controlled trial (RCT). Gene expression array analysis was performed using PC tissues collected for the ancillary research of JASPAC01, a nationwide phase 3 RCT of adjuvant chemotherapy for patients with PC in Japan. A candidate gene was validated using tissue and blood samples from a second PC patient cohort undergoing radical surgery at the authors’ institution. Additionally, experiments were performed with cancer cell lines to investigate the functions of the candidate gene. Expression of E2F7 mRNA was the most influential prognostic factor of postoperative overall survival outcomes in the primary tissue-available cases in the JASPAC01 cohort (hazard ratio [HR], 1.386; 95

The phase III randomized trial, JCOG1113 has demonstrated the non-inferiority of gemcitabine and S-1 (GS) therapy to gemcitabine and cisplatin (GC) therapy for advanced biliary tract cancer (BTC). However, biomarkers for favorable therapy or to predict patient prognosis remain lacking. In this study, we evaluated five candidate biomarkers potentially involved in the efficacy of cisplatin or S-1 by immunostaining tumor specimens obtained from JCOG1113 participants. The participants were randomly divided into training or test sets and classified into high- or low-expression groups based on the cutoff value calculated from the immunostaining results for each biomarker in the training set. Associations between the expression of each biomarker and the outcomes in JCOG1113 were analyzed. Among the 148 eligible participants, no interaction was observed between the treatment arms of GC or GS for any factor or biomarker. However, high excision repair cross-complementing gene 1 (ERCC1) was associated with poor overall survival (HR, 2.226; 95% CI, 1.160-4.272) and progression-free survival (HR, 1.793; 95% CI, 0.945-3.402) compared with low ERCC1 in the training set. Similar trends were observed for the test set. Our results indicate that in advanced BTC, high ERCC1 expression is a poor prognostic factor.

BACKGROUND:The JCOG1113, a multicenter, randomized phase III trial in patients with advanced/recurrent biliary tract cancer showed the non-inferiority of gemcitabine plus S-1 to gemcitabine plus cisplatin. Although liver cirrhosis (LC) is a known risk factor for intrahepatic cholangiocarcinoma (ICC), few reports focus on the efficacy and safety of chemotherapy in ICC patients with LC. METHODS:We performed a subgroup analysis of ICC patients enrolled in the JCOG1113. The presence or absence of LC was evaluated based on clinical factors such as radiographic findings, medical history, laboratory data, and physical examination at enrollment. We evaluated differences in the safety and efficacy of chemotherapy according to the presence or absence of clinically diagnosed LC. RESULTS:Of the 94 eligible patients with ICC, 10 were clinically diagnosed with LC. In the non-LC/clinically diagnosed LC group, grade 3 or 4 neutropenia, anemia, decreased platelet count, and non-hematological adverse events were observed in 51.2%/60%, 15.5%/0%, 11.9%/40%, and 38.1%/30% patients. The median overall survival was 13.7 months in the non-LC group and 19.0 months in the clinically diagnosed LC group (hazard ratio [HR]: 0.969, 95% confidence interval [CI]: 0.482-1.948). The median progression-free survival was 5.9 months in the non-LC group and 7.1 months in the clinically diagnosed LC group (HR, 0.995; 95% CI, 0.513-1.929). CONCLUSION:The results of this study indicated that eligible ICC patients with clinically diagnosed LC, as determined by clinical and CT imaging findings, did not exhibit any apparent safety or efficacy disadvantage compared to those without LC.

PURPOSE:Modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) and nab-paclitaxel + gemcitabine are recommended as first-line treatments for metastatic pancreatic cancer. S-1, irinotecan, and oxaliplatin (S-IROX) demonstrated activity in a phase Ib trial in this population. Therefore, these three regimens were directly compared. METHODS:This randomized phase II/III trial was performed at 45 centers in Japan. Eligible patients age 20-75 years with an Eastern Cooperative Oncology Group performance status of 0 or 1 and pathologically confirmed metastatic or recurrent pancreatic cancer were randomly assigned (1:1:1) to receive mFOLFIRINOX (oxaliplatin 85 mg/m2 over 2 hours, irinotecan 150 mg/m2 over 90 minutes, l-leucovorin 200 mg/m2 over 2 hours, each once daily on day 1, and fluorouracil 2,400 mg/m2 over 46 hours on days 1-3, every 2 weeks), S-IROX (oxaliplatin 85 mg/m2 over 2 hours, irinotecan 150 mg/m2 over 90 minutes on day 1, and S-1 80 mg/m2/day administered orally twice daily on days 1-7, every 2 weeks), or nab-paclitaxel (125 mg/m2) + gemcitabine (1,000 mg/m2) on days 1, 8, and 15 every 4 weeks. The primary end point was overall survival (OS). RESULTS:A total of 527 patients were enrolled, with 426 included in the planned interim analysis. The median OS was 14.0 months (hazard ratio [HR], 1.31 [95% CI, 0.97 to 1.77]) and 13.6 months (HR, 1.35 [95% CI, 1.00 to 1.82]) in the mFOLFIRINOX and S-IROX groups, respectively, as compared with 17.1 months in the nab-paclitaxel + gemcitabine group. The predictive probability of achieving superiority in the final analysis was <1% in both groups. Thus, the trial was terminated owing to its futility. Grade 3 to 4 anorexia was more frequent in the mFOLFIRINOX (23.3%) and S-IROX (27.5%) groups than in the nab-paclitaxel + gemcitabine group (5.0%). CONCLUSION:Neither mFOLFIRINOX nor S-IROX appeared to be superior compared with nab-paclitaxel + gemcitabine as the first-line treatment for metastatic or recurrent pancreatic cancer.

548 Background: Biliary tract cancers (BTCs) include gallbladder cancer (GBC), intrahepatic cholangiocarcinoma (IHCC), extrahepatic cholangiocarcinoma (EHCC), and ampulla of Vater cancer (AV). Although it was previously reported that there were differences in clinical features individually, the reported data were limited to data from some subgroup analyses of recent randomized controlled trials. JCOG1113 (UMIN000010667) showed the non-inferiority of gemcitabine plus S-1 to gemcitabine plus cisplatin in terms of overall survival (OS) in patients (pts) with advanced BTCs. We aimed to compare clinical features among the primary sites of BTCs using JCOG1113 data. Methods: Among the 354 pts enrolled in JCOG1113, 352 pts were included in this analysis except for 2 pts without BTCs. We compared the patient characteristics and treatment outcomes, such as OS, progression-free survival (PFS), and objective response rate (ORR), among the four primary sites. Results: Of the 352 pts, 137 pts (38.9%), 94 pts (26.7%), 108 pts (30.7%) and 13 pts (3.7%) had GBC, IHCC, EHCC, and AV, respectively. GBC was more common in females (58.4%) than males, in contrast to the other primary sites. The percentage of pts with metastatic disease for GBC was the highest (78.1%) and involved multiple metastatic organs (41.6%), in contrast with the other primary sites. The median OS for GBC, IHCC, EHCC and AV were 12.6 months (reference), 15.7 months (hazard ratio [HR]; 0.749, 95% confidence interval [CI], 0.559-1.005), 16.3 months (0.704, 0.532-0.934) and 11.5 months (1.148, 0.633-2.080), respectively. The median PFS for GBC, IHCC, EHCC and AV were 5.7 months (reference), 6.2 months (0.843, 0.644-1.104), 8.7 months (0.636, 0.489-0.826) and 4.1 months (1.506, 0.851-2.665), respectively. The ORRs for GBC, IHCC, EHCC and AV were 34.4%, 28.9%, 34.4%, and 0.0%, respectively. Conclusions: Except for AV which included a few patients in this trial, GBC showed a poorer prognosis compared with the other primary sites. Furthermore, it was more likely to include metastatic disease and multiple metastases, and this is likely one of the causes of the poorer prognosis. [Table: see text]

Human epidermal growth factor receptor 2 (HER2, also known as ERBB2) signaling promotes cell growth and differentiation, and is overexpressed in several tumor types, including breast, gastric and colorectal cancer. HER2-targeted therapies have shown clinical activity against these tumor types, resulting in regulatory approvals. However, the efficacy of HER2 therapies in tumors with HER2 mutations has not been widely investigated. SGNTUC-019 is an open-label, phase 2 basket study evaluating tucatinib, a HER2-targeted tyrosine kinase inhibitor, in combination with trastuzumab in patients with HER2-altered solid tumors. The study included a cohort of 31 heavily pretreated female patients with HER2-mutated metastatic breast cancer who were also HER2 negative per local testing. Hormone receptor (HR)-positive patients also received fulvestrant. The overall response rate (primary endpoint) was 41.9% (90% confidence interval (CI): 26.9-58.2). Secondary endpoints of duration of response and progression-free survival were 12.6 months (90% CI: 4.7 to not estimable) and 9.5 months (90% CI: 5.4-13.8), respectively. No new safety signals were detected. Responses were observed across various HER2 mutations, including mutations in the tyrosine kinase and extracellular domains. The chemotherapy-free regimen of tucatinib and trastuzumab showed clinically meaningful antitumor activity with durable responses and favorable tolerability in heavily pretreated patients with HER2 mutations. These data support further investigation of HER2-targeted therapies in this patient population. ClinicalTrials.gov registration: NCT04579380.

BACKGROUND:IgG4-related disease is a rare autoimmune disorder characterised by tissue infiltration of IgG4-positive plasma cells, storiform fibrosis, elevated serum IgG4 concentrations, and increased risk of tumour complications. Previous genetic studies have implicated FCGR2B and HLA loci in susceptibility to IgG4-related disease; however, most relied on microarray-based genotyping and imputation, which have limited resolution in highly polymorphic and structurally complex regions. This study aimed to investigate genetic susceptibility to IgG4-related disease using comprehensive genomic variant analysis, including low-frequency and structural variants not readily captured by microarrays. METHODS:We conducted a genome-wide association study using whole-genome sequencing data in a two-set, subtype-stratified case-control design in the Japanese population. Set 1 included samples (cases) from patients with IgG4-related disease from 50 hospitals across Japan participating in the Japanese IgG4-related disease Working Consortium (recruited between Oct 27, 2008, and March 3, 2016) and previously sequenced Japanese population control samples. Set 2 included samples (cases) from patients with IgG4-related disease from eight hospitals of the Consortium (recruited between Aug 12, 2021, and Dec 20, 2023) and previously sequenced healthy individuals residing in the Tokyo metropolitan area (controls). No specific inclusion or exclusion criteria were applied to either cases and controls. We used whole-genome sequencing at depths of 15× or 30× using HiSeqX and NovaSeq platforms (Illumina; San Diego, CA, USA) to enable the inclusion of previously uncaptured single nucleotide polymorphisms and direct analysis of HLA amino acid residues. We investigated complement component 4 copy number variations using short-read sequencing data and established read-depth-based typing methods. People with lived experience of IgG4-related disease were not involved in the study. FINDINGS:This whole-genome sequencing study comprised of 2 sets. Set 1 included 646 patient samples (172 [26·6%] were female, 474 [73·4%] were male, and the mean age was 64·4 years [SD 11·4]) and 2254 population controls (1348 [59·8%] were female and 906 [40·2%] were male). Set 2 included 223 patient samples (78 [35·0%] were female, 145 [65·0%] were male, and the mean age was 63·5 years [10·9]) and 405 population controls (65 [16·0%] were female and 340 [84·0%] were male). All individuals were of Hondo Japanese ancestry. The average IgG4 concentration at diagnosis was 653·1 mg/dL (SD 596·3) in Set 1 and 543·5 mg/dL (603·5) in Set 2. We validated the FCGR2B (p=9·8 × 10-11) region as the susceptibility locus for IgG4-related disease. PTCH1 (p=3·8 × 10-8) and long non-coding RNA LOC102724227 were found to be specific susceptibility loci for Mikulicz's disease. We also confirmed the association between the HLA amino acid residue DRB1-GB-7 (p=1·1 × 10-19) with IgG4-related disease and identified two additional residues, A-GA2-9 (p=4·1 × 10-6) and DQB1-GB-82 (p=4·7 × 10-9), that were significantly associated with IgG4-related disease. In the joint-association analysis of complement component 4 copy number variation, C4A showed a protective association with IgG4-related disease (β=-0·127, p=7·9 × 10-3), whereas C4B was associated with an increased risk (β=0·151, p=1·9 × 10-2). A low level of linkage disequilibrium (r2<0·15) was observed between the C4A and C4B alleles and the identified HLA amino acid residues in the main island Japanese population. INTERPRETATION:C4 copy number variation, in addition to HLA and FCGR2B, was found to be a distinct genetic factor associated with IgG4-related disease susceptibility, illustrating the complex polygenic nature of the disease. Furthermore, the identification of PTCH1 and the long non-coding RNA LOC102724227 as Mikulicz's disease-specific susceptibility loci suggests that genetic heterogeneity might underlie the clinical diversity of IgG4-related disease, particularly with respect to the affected organs. FUNDING:The Japanese Ministry of Health, Labour, and Welfare, the Japanese Agency of Medical Research and Development, the Kyoto University Grant for Top Global University Japan Project, and the Kyoto University Division of Graduate Studies SPRING Program.

Objectives Endoscopic ultrasound‐guided fine‐needle aspiration and fine‐needle biopsy (EUS‐FNA/FNB) is not fully established as a pathological sampling tool for gallbladder lesions due to limited evidence. We therefore aimed to clarify the effectiveness and safety of this procedure in a large‐population cohort. Methods This study retrospectively evaluated the diagnostic yield of EUS‐FNA/FNB for accurately differentiating between benign and malignant gallbladder lesions. Puncture targets included the gallbladder mass, lymph node, and liver mass. Adverse events and factors associated with diagnostic accuracy were analyzed as well. Results In 187 patients with gallbladder lesions undergoing EUS‐FNA/FNB, 18 benign lesions and 169 malignant lesions were identified. Overall sampling adequacy was 98% (184/187). The diagnostic accuracy of EUS‐FNA/FNB was 97% (182/187), sensitivity was 97% (164/169), and specificity was 100% (18/18). A single postprocedural complication (minor bleeding) was recorded in one patient. In the 169 cases of malignancy, 203 sites were punctured for pathological sampling of the primary mass ( n = 94), lymph node ( n = 79), and metastatic liver mass ( n = 30). No significant difference was found for diagnostic accuracy among the puncture sites ( P = 0.70). In cases having specimens obtained from the primary mass, the accuracy of those targeting liver invasion sites was significantly higher than that of other sites (98% vs. 83%, P < 0.01). Conclusion EUS‐FNA/FNB demonstrated clinical usefulness and safety for the pathological diagnosis of gallbladder lesions, with high diagnostic yield and a low incidence of adverse events. Targeting the site of liver infiltration may improve the diagnostic rate of EUS‐FNA/FNB in the primary mass.

"QIM24-188: Compliance With Recommendations and Clinical Practices Increased After Publication of the Japanese Clinical Practice Guidelines for Pancreatic Cancer 2022 Edition" published on 05 Apr 2024 by National Comprehensive Cancer Network.