Artificial intelligence (AI) has emerged as a transformative tool in gastrointestinal (GI) endoscopy, addressing challenges in detection, diagnosis, and decision-making. In upper GI endoscopy, AI supports blind spot monitoring, Helicobacter pylori diagnosis, and the identification of premalignant and malignant lesions, with high accuracy and reduced miss rates. In lower GI endoscopy, computer-aided detection improves adenoma detection, whereas computer-aided diagnosis supports "resect-and-discard" and "diagnose-and-leave" strategies. However, real-world benefits remain modest, with concerns regarding overdetection and variable performance across lesion types and colon segments. In inflammatory bowel disease, AI standardizes endoscopic and histologic scoring, reduces interobserver variability, and accelerates capsule endoscopy interpretation, including high diagnostic accuracy for Crohn's disease. Pancreatobiliary applications, including endoscopic ultrasound, endoscopic retrograde cholangiopancreatography, and cholangioscopy, demonstrate strong performance in differentiating pancreatic masses and biliary strictures and in predicting postprocedural complications. Despite expert-level performance across multiple domains, most studies remain single-center or retrospective, and explainability, workflow integration, medicolegal responsibility, and cost-effectiveness continue to limit adoption. Emerging solutions, including explainable AI and AI-generated common data model-compatible reports, may bridge these gaps. With rigorous multicenter validation and real-world implementation, AI can evolve from an experimental adjunct into a core component of routine endoscopic practice.

PURPOSE:Endoscopically identifying eosinophilic esophagitis (EoE) is difficult due to its rare incidence and subtle morphology. We aimed to develop a robust and accurate convolutional neural network (CNN) model for EoE identification and classification in endoscopic images. MATERIALS AND METHODS:We collected 548 endoscopic images from 81 patients with EoE and 297 images from 37 normal patients. These datasets were labeled according to the four eosinophilic esophagitis endoscopic reference score (EREFS) features: edema, rings, exudates, and furrows. A multi-task U-Net with an auxiliary classifier on various levels of skip connections (scaU-Net) was proposed. Then, scaU-Net was compared with VGG19, ResNet50, EfficientNet-B3, and a typical multi-task U-Net CNN. The performances of each model were evaluated quantitatively and qualitatively based on accuracy (ACC), area under the receiver operating characteristics (AUROC), and gradient-weighted class activation map (Grad-CAM), and were also compared with those of 25 human endoscopists. RESULTS:Our sca4U-Net with 4th-level skip connection showed the best performances in ACC (86.9%), AUROC (0.93), and outstanding Grad-CAM results compared to other models, reflecting the importance of utilizing the deepest skip connection. Moreover, the sca4U-Net showed generally better performance when compared with endoscopists with various levels of experience. CONCLUSION:Our method showed robust performance compared to expert endoscopists and could assist endoscopists of all experience levels in the early detection of EoE-a rare but clinically important condition.

Background/Aims Balloon dilatation under endoscopic or fluoroscopic guidance is regarded as the gold standard for treating benign esophageal strictures. However, no prior studies have compared endoscopic balloon dilatation (EBD) with fluoroscopic balloon dilatation (FBD). We aimed to compare the efficacy and safety of the two methods. Methods Subjects who underwent balloon dilatation under endoscopic or fluoroscopic guidance for benign esophageal strictures between 2001 and 2018 were eligible. Their medical records were retrospectively reviewed, and clinical characteristics were investigated. Results From 201 patients, 60 patients underwent EBD, and the remaining 141 underwent FBD. The mean age was higher in the FBD group than in the EBD group (69.77 vs. 58.63 yr, p < 0.001). The most frequent etiology of the strictures was surgery in both groups. Longer procedure times, cervical esophageal location, and short stricture length were significantly associated with the FBD group. Multivariable analysis showed that old age (HR 1.028), higher dysphagia grade (HR 1.561 for grade II and HR 3.518 for grade III), and long stricture length (HR 1.943) were significantly associated with the short dilatation-free period. There were no significant differences in dilatation-free periods or adverse events between the groups. Conclusions Both EBD and FBD are safe and effective primary treatment modalities for treating benign esophageal strictures. Choosing an appropriate method depending on the location and length of the stricture and the institution’s capacity and resources would produce more effective results.

Neoadjuvant immunotherapy may improve long-term outcomes by activating antitumor immunity before surgery. We evaluated danburstotug (IMC-001), an anti-PD-L1 antibody, in resectable gastric cancer (GC), esophageal squamous cell carcinoma (ESCC), and hepatocellular carcinoma (HCC). In this phase II trial, patients received two cycles of danburstotug (20 mg/kg every 2 weeks) before surgery. The primary endpoint was major pathologic response (MPR, <10% viable tumor). Key secondary endpoints included safety, radiologic/metabolic response, survival outcomes, and translational immune profiling. Forty-eight patients were evaluable (16 per cohort). The study did not meet its pre-specified primary endpoint, with MPR achieved in 2/48 patients (4.2%)-one ESCC and one HCC (6.3% per cohort). However, pathologic tumor regression to ≤50% viable tumor was observed in 11/48 patients (22.9%; GC 25.0%, ESCC 31.3%, HCC 12.5%). Among evaluable patients, partial responses were observed radiographically in 17.6% and metabolically in 23.3%. Treatment was well tolerated, with grade ≥3 treatment-related adverse events in 6.0% and no grade 4-5 events; two surgical delays were observed, of which one was treatment-related. All patients underwent surgery with R0 resection. Immune profiling revealed cancer type-specific immune-remodeling. Neoadjuvant danburstotug was safe, did not compromise surgical outcomes, and provided exploratory insights into treatment-induced immune microenvironment remodeling. ClinicalTrials.gov ID: NCT04196465, date of registration: August 28, 2019.

N-butyl cyanoacrylate (NBCA) glue embolization is a minimally invasive technique widely used in interventional radiology to achieve vascular occlusion. It is a liquid embolic agent that rapidly polymerizes on contact with ionic substances such as blood or saline, allowing immediate solidification and formation of a durable embolus. This property makes it especially effective in controlling arterial bleeding from small-caliber or tortuous vessels that cannot be accessed by using microcatheters or in cases requiring urgent hemostasis due to severe hemorrhage. The embolization process involves mixing NBCA glue with an oil-based contrast agent to adjust the viscosity and regulate the polymerization rate. Under fluoroscopic guidance, the mixture is injected through a microcatheter by using pressure- or flow-dependent techniques. Modified approaches have also been developed and include flow-controlled injection with use of a balloon catheter or the addition of ethanol to reduce adhesiveness. Clinical applications include embolization for gastrointestinal bleeding and arteriovenous, portal vein, and lymphatic anomalies; preoperative devascularization of hypervascular tumors; and balloon-occluded retrograde transvenous obliteration. Despite the effectiveness of NBCA glue embolization, the risk of nontarget embolization remains a significant concern, potentially resulting in tissue necrosis or ischemia. Therefore, a comprehensive understanding of the vascular anatomy and hemodynamics is essential to minimize complications. NBCA glue embolization is a powerful and versatile tool for vascular occlusion. Successful outcomes rely on meticulous patient selection, adherence to procedural protocols, and the experience of the operator. ©RSNA, 2026 Supplemental material is available for this article.

Background: Esophageal epiphrenic diverticulum (ED) is a pulsion diverticulum of the distal esophagus that arises from elevated lower esophageal sphincter pressure. Conventional treatment has traditionally involved complex thoracic surgical approaches that are associated with substantial morbidity and mortality. This study aimed to compare outcomes between two minimally invasive variations of diverticular per-oral endoscopic myotomy (D-POEM): full-thickness septotomy with transverse closure (POEM + FTS) and traditional submucosal tunneling followed by septotomy (POEM + S). Methods: This international, multicenter retrospective cohort study included six centers between January 2020 and October 2024. Patients with symptomatic ED who underwent D-POEM were included. The primary outcome was clinical success, defined as an Eckardt score (ES) <= 3 or a 1-point reduction in ES for patients with a baseline ES < 3, without the need for repeat intervention during follow-up. Results: A total of 35 patients (mean age, 64.4 years; 51.4% female) underwent D-POEM for ED. POEM + FTS (n = 6) and POEM + S (n = 29) both demonstrated a technical success rate of 100%. An associated esophageal motility disorder was identified in 17 patients (48.6%), including achalasia in 9 patients (52.9%) and esophagogastric junction outflow obstruction in 4 patients (23.5%). Procedural duration was comparable between groups, with a median of 52 minutes in the POEM + FTS group versus 62 minutes in the POEM + S group (P = 0.59). There was no statistically significant difference in adverse event rates between the two groups (0% vs 6.8%; P > 0.999). The median length of hospital stay was significantly longer after POEM + S than after POEM + FTS (4 days [interquartile range (IQR), 2-4 days] vs 1 day [IQR, 1-1 day]; P = 0.01). Clinical success rates were equivalent between groups (100% vs 96.6%, not significant) at a median follow-up of 10 months (IQR, 9-11 months) and 11 months (IQR, 9-12 months), respectively. Conclusion: D-POEM, whether performed as POEM + S or POEM + FTS in expert centers, is feasible, safe, and clinically effective for the treatment of ED. Prospective studies are warranted to further define comparative outcomes. (c) 2026, Society of Gastrointestinal Intervention.

Introduction and importance:Hypopharyngeal carcinoma (HC) is a relatively rare malignancy, with an incidence of approximately 0.7 per 100 000 individuals. The early detection rate of hypopharyngeal carcinoma is low, ranging from 4% to 13%. Synchronous early detection of esophageal cancer (EC) and hypopharyngeal carcinoma occurs in approximately 15% of cases. Gastrointestinal endoscopy with image-enhanced endoscopy (IEE) using narrow-band imaging (NBI) is a valuable tool for synchronous early detection of hypopharyngeal carcinoma. Endoscopic submucosal dissection (ESD) is a minimally invasive, safe, and effective method for endoscopic resection. Presentation of case:We reported the case of a 46-year-old Vietnamese male diagnosed with synchronous early-stage left pyriform sinus cancer and EC diagnosed using gastrointestinal endoscopy with image-enhanced endoscopy with narrow-band imaging (IEE-NBI). Both lesions were successfully resected en bloc using ESD. After 24 months of follow-up, there were no new lesions or metastases from the tumor. Clinical discussion:This case highlights the application of NBI classification according to intrapapillary capillary loops morphology under IEE-NBI endoscopy for the diagnosis of synchronous early HC and EC and the prediction of the invasion depth based on microvessel morphology. Conclusion:Gastroenterologists should be vigilant in observing the pharynx with IEE-NBI for patients with EC to facilitate early detection of HC, and vice versa.

Objective: We aimed to investigate the effectiveness of buspirone as an adjunctive therapy for alleviating anxiety symptoms in patients with depressive disorders who are already taking antidepressants. Methods: This was an open-label prospective multicenter non-interventional observational study conducted over 12 weeks. We enrolled 180 patients diagnosed with depressive disorders according to DSM-5 criteria and Hamilton Anxiety Rating Scale (HAMA) scores >= 18. Participants were already taking selective serotonin reuptake inhibitors or serotoninnorepinephrine reuptake inhibitors and were prescribed adjunctive buspirone. Efficacy was assessed using HAMA, Hamilton Depression Rating Scale (HAMD), Clinical Global Impression Scale-Improvement, Clinical Global Impression Scale-Severity, Sheehan Disability Scale (SDS), and WHO-5 Well-Being Index. Results: The efficacy analysis included 161 patients. HAMA scores decreased significantly from 25.2 +/- 6.7 at baseline to 15.4 +/- 8.6 at 12 weeks (p < 0.001), whereas HAMD scores decreased from 19.4 +/- 4.6 to 12.7 +/- 5.7 (p < 0.001). WHO-5 and SDS scores showed significant improvements. The HAMA response rate was 39.1% and the remission rate was 13.7% at 12 weeks. Adverse drug reactions were reported in 3.7% of participants. Subgroup analyses showed no significant differences in treatment response based on buspirone dosage, baseline anxiety/depression severity, or benzodiazepine use. Conclusion: Adjunctive buspirone therapy effectively improved anxiety symptoms in depressed patients taking antidepressants, regardless of baseline symptom severity or buspirone dosage. The treatment was well-tolerated with few adverse events. Future studies using a control group are needed.

Localized photodynamic therapy (PDT) using a photoactive stent-based catheter involves the direct delivery of reactive oxygen species to the mucosa in esophageal carcinoma; however, the damaged mucosa recovers within 2 to 4 weeks, which considerably limits the clinical application of PDT. Here, we used aluminum(III) phthalocyanine chloride tetrasulfonic acid (AlPcS4) as a photosensitizer due to its excellent photochemical durability, low photobleaching, and high quantum yield and investigated whether repeated and periodic PDT via an AlPcS4-embedded stent-based catheter can provide sustained therapeutic efficacy. AlPcS4 was uniformly embedded in silicone membranes via coordination bonding to form a photoactive stent-based catheter. The membrane demonstrated excellent photostability and consistent singlet oxygen generation under near-infrared irradiation, as evidenced by a 67.2% decrease in 9,10-dimethylanthracene fluorescence intensity, even after 90 J cm-2 irradiation, markedly superior to methylene blue (15.3%) and chlorin e6 (30.9%). Repeated PDT effectively enhanced cell death rates in KYSE-70 cells. In the xenograft model, MRI-based volumetric analysis showed that the tumor volume change in the thrice-PDT group (57.40% ± 9.26%) was significantly lower than those in the control (212.07% ± 38.44%, P < 0.001) and once-PDT groups (130.77% ± 11.25%, P = 0.018), accompanied by apoptotic and necrotic tumor destruction. Repeated PDT at 1-week intervals was technically successful in the porcine esophagus, leading to progressive mucosal injury, luminal narrowing, and apoptosis, while demonstrating sustained therapeutic efficacy. Thus, the minimally invasive repeatable photoactive stent-based catheter may be an effective and safe approach for treating esophageal carcinoma.

Objective:: Several studies have reported the therapeutic effects of phytoncides on various mental disorders. However, little is known about the therapeutic effects of phytoncides on mild cognitive impairment (MCI), a prodromal stage of dementia. In this pilot study, we aimed to clarify the effect of inhaled phytoncides on the cognitive function of patients clinically diagnosed with MCI. Methods:: In total, 21 patients with MCI were randomly assigned to either a saline (no-odor) or phytoncide group and subsequently inhaled saline or phytoncide for 30 minutes indoors, respectively. To evaluate changes in cognitive function, we implemented functional near-infrared spectroscopy along with the Stroop task and compared task performance and hemodynamic responses in the dorsolateral/ventrolateral part of the prefrontal cortex (DLPFC/VLPFC) before and after inhalation. Results:: While the saline group showed no significant difference in either task performance (Wilcoxon W = 18.50, p = 0.385) or hemodynamic response, a significant increase in Stroop task performance (Wilcoxon W = 1.50, p = 0.009) and hemodynamic attenuation in the left VLPFC (Wilcoxon W = 56.00, p = 0.042) were found in the phytoncide group after inhalation. Conclusion:: Since compensatory task-related prefrontal hyperactivation represents one of the neural indicators of cognitive dysfunction in MCI, our findings shed light on the beneficial effects of phytoncide on cognitive function in MCI.

Photodynamic therapy (PDT) using photosensitizer (PS)-integrated covered self-expandable metallic stents (SEMS) is proposed a new therapeutic approach for the treatment of palliative malignancies; however, the currently hydrophobic PS reduces the photoreactive effect, which leads to aggregation with low water solubility. In here, an aluminum (III)-phthalocyanine chloride tetrasulfonic acid (Al-PcS4)-integrated silicone-covered self-expanding catheter was successfully fabricated to perform localized PDT. The ratio of MeOH and Al-PcS4 concentrations was optimized to achieve PS coating uniformity. The photodynamic activity of the Al-PcS4-integrated silicone membrane was evaluated through laser exposure on membrane-layered tumor cell lines, tumor xenograft-bearing mice. PDT with the Al-PcS4-integrated membrane successfully generated sufficient cytotoxic singlet oxygen, inducing cell death in the esophageal cancer cell lines. PDT-treated tumor xenograft-bearing mice undergo apoptotic cell death and showed significant tumor regression. Localized PDT using an Al-PcS4-integrated silicone-covered self-expanding catheter was technically successful in the rabbit esophagus without severe complications. Based on the endoscopy, esophagography, histology, and immunohistochemistry, our study verified that localized PDT using the Al-PcS4-integrated silicone-covered self-expanding catheter was effective and safe to evenly induce tissue damage. Al-PcS4-integrated silicone-covered self-expanding catheter has substantial potential for the minimally invasive local therapy in malignant esophageal cancer.

Purpose: Esophageal cancer is a predominantly male disease. However, the sex differences associated with esophageal cancer have not been thoroughly investigated. This study aimed to evaluate the differences between esophageal cancer in males and females in the Korean population. Materials and Methods: We assessed patients diagnosed with esophageal cancer between 2005 and 2015 at a tertiary referral center. The clinical features of patients, histopathologic characteristics of tumors, and treatment and survival outcomes were compared between male and female patients. Results: We enrolled 2,068 patients, comprising 1,924 (93.0%) males and 144 (7.0%) females. The median age at diagnosis was younger for females than males (65 vs. 63 years, p=0.004). Squamous cell carcinoma was the predominant pathological type (99.0% in males and 93.1% in females); however, the proportion of adenocarcinoma cases was higher in females than males (0.8% vs. 5.6%, p<0.001). Multivariate analysis indicated favorable overall survival for female patients (hazard ratio [HR], 0.685; 95% confidence interval [CI], 0.548-0.857) and patients with high body mass index (>= 25 kg/m 2 , HR, 0.432; 95% CI, 0.355-0.526), and in early tumor stage (Stage 4, HR, 12.684; 95% CI, 7.451-21.591). The 5-year overall survival (44.8% vs. 53.5%, p=0.016) and recurrence-free survival rates (74.0% vs. 84.3%, p=0.036) were higher in females than in males. Conclusions: We found significant sex differences in esophageal cancer among the Korean population, with female patients demonstrating distinct clinical characteristics and more favorable survival outcomes compared to male patients. These findings underscore the importance of considering sex-specific factors in the management and prognosis of esophageal cancer.

Migration of implanted self-expandable metallic stent (SEMS) in the malignant or benign esophageal stricture is a common complication but not yet resolved. Herein, this research develops a hydrogel-impregnated robust interlocking nano connector (HiRINC) to ensure adhesion and reduce the mechanical mismatch between SEMSs and esophageal tissues. Featuring a network-like porous layer, HiRINC significantly enhances adhesion and energy dissipation during esophageal peristalsis by utilizing mechanical interlocking and increasing hydrogen bonding sites, thereby securing SEMS to tissues. The anti-swelling property of HiRINC prevents excessive hydrogel expansion, avoiding esophageal blockage. Ex vivo and in vivo adhesion tests confirm that the HiRINC outperforms flat surfaces without RINC structures and effectively prevents stent migration. HiRINC-coated SEMS maintains its position and luminal patency, minimizing stent-induced tissue hyperplasia and inflammatory responses in rat and porcine esophageal models during the 4-week follow-up. This novel HiRINC-SEMS can ensure anti-migration and prolonged stent patency in the rat and porcine esophagus and seems to be expanded to other nonvascular luminal organs and various implantable metallic devices.

Background/Objectives: This study aimed to investigate the predictive power of integrated longitudinal amyloid positron emission tomography (PET) and brain magnetic resonance imaging (MRI) data for determining the likelihood of conversion to Alzheimer’s disease (AD) in patients with mild cognitive impairment (MCI). Methods: We included 180 patients with MCI from the Alzheimer’s Disease Neuroimaging Initiative, with baseline and 2-year follow-up scans obtained using F-18 florbetapir PET and MRI. Patients were categorized as converters (progressing to AD) or nonconverters based on a 6-year follow-up. Quantitative analyses included the calculation of amyloid burden using the standardized uptake value ratio (SUVR), brain amyloid smoothing scores (BASSs), brain atrophy indices (BAIs), and their integration into shape features. Longitudinal changes and receiver operating characteristic analyses assessed the predictive power of these biomarkers. Results: Among 180 patients with MCI, 76 (42.2%) were converters, who exhibited significantly higher baseline and 2-year follow-up values for SUVR, BASS, BAI, and shape features than nonconverters (p < 0.001). Shape features demonstrated the highest predictive accuracy for conversion, with areas under the curve of 0.891 at baseline and 0.898 at 2 years. Percent change analyses revealed significant increases in brain atrophy; amyloid deposition changes showed a paradoxical decrease in converters. Additionally, strong associations were observed between longitudinal changes in shape features and neuropsychological test results. Conclusions: The integration of amyloid PET and MRI biomarkers enhances the prediction of AD progression in patients with MCI. These findings support the potential of combined imaging approaches for early diagnosis and targeted interventions in AD.

BACKGROUND/AIMS:To overcome the technical limitations of classic endoscopic resection for gastric gastrointestinal stromal tumors (GISTs), various methods have been developed. In this study, we examined the role and feasibility of clip-and-cut procedures (clip-and-cut endoscopic full-thickness resection [cc-EFTR]) for gastric GISTs.METHODS:Medical records of 83 patients diagnosed with GISTs after endoscopic resection between 2005 and 2021 were retrospectively reviewed. Moreover, clinical characteristics and outcomes were analyzed.RESULTS:Endoscopic submucosal dissection (ESD) and cc-EFTR were performed in 51 and 32 patients, respectively. The GISTs were detected in the upper third of the stomach for ESD (52.9%) and cc-EFTR (90.6%). Within the cc-EFTR group, a majority of GISTs were located in the deep muscularis propria or serosal layer, accounting for 96.9%, as opposed to those in the ESD group (45.1%). The R0 resection rates were 51.0% and 84.4% in the ESD and cc-EFTR groups, respectively. Seven (8.4%) patients required surgical treatment (six patients underwent ESD and one underwent cc-EFTR,) due to residual tumor (n=5) and post-procedure adverse events (n=2). Patients undergoing R0 or R1 resection did not experience recurrence during a median 14-month follow-up period, except for one patient in the ESD group.CONCLUSIONS:cc-EFTR displayed a high R0 resection rate; therefore, it is a safe and effective therapeutic option for small gastric GISTs.

BACKGROUND:Previous studies have demonstrated that 50% of patients with normal high-resolution manometry (HRM) findings or ineffective esophageal motility (IEM) may have abnormal functional luminal imaging probe (FLIP) results. However, the specific HRM findings associated with abnormal FLIP results are unknown. Herein, we investigated the relationship between nonspecific manometry findings and abnormal FLIP results.METHODS:We retrospectively analyzed 684 patients who underwent HRM at a tertiary care center in Seoul, Korea, based on the Chicago Classification version 4.0 protocol.KEY RESULTS:Among the 684 patients, 398 had normal HRM findings or IEM. Of these 398 patients, eight showed esophageal wall thickening on endoscopic ultrasonography or computed tomography; however, no abnormalities were seen during esophagogastroduodenoscopy. Among these eight patients, seven showed repetitive simultaneous contractions (RSCs) in at least one of the two positions: 61% (±29%) in 10 swallows in the supine position and 51% (±30%) in five swallows in the upright position. Four patients who underwent FLIP had a significantly decreased esophagogastric junction distensibility index (1.0 ± 0.5 m m 2 mmHg - 1 at 60 mL). Two of these patients underwent per-oral endoscopic myotomy (POEM) due to a lack of response to medication. Esophageal muscle biopsy revealed hypertrophic muscle with marginal eosinophil infiltration.CONCLUSIONS & INFERENCES:A subset of patients (2%) with normal HRM findings or IEM and RSCs experienced dysphagia associated with poor distensibility of the thickened esophageal wall. FLIP assessment or combined HRM and impedance protocols may help better define these patients who may respond well to POEM.

The field of genetic counseling (GC) in the Republic of Korea has evolved from a single medical doctor's clinic to a multidisciplinary service with medical geneticists and non-medical professionals working as a team. Here, we assessed the current status of GC in the Republic of Korea based on professional surveys from the perspective of laboratory physicians. An electronic survey was designed and conducted, with the respondents being 50 certified laboratory physicians who were members of the Korean Society for Genetic Diagnostics. Among the 50 respondents, 12 (24%) operated GC clinics. The number of sessions and cases of GC have been on the rise over the last few years, and counseling for cancer genetics was the most common request. Most respondents considered a good understanding of the genetic test and the ability to interpret the test results as strengths of laboratory physicians as medical geneticists, while the lack of clinical experience was a weakness. Education programs regarding laboratory physicians' needs should be provided for high-quality counseling. Lastly, improving the efficiency of GC by strengthening the workforce through a multidisciplinary team is necessary.

Patients achieving pathological complete response (pCR) post-neoadjuvant chemoradiotherapy (nCRT) and surgery for locally advanced esophageal squamous cell carcinoma (ESCC) have a favorable prognosis. However, recurrence occurs in approximately 20–30 ≥ 60 years) [hazard ratio (HR) 3.228, 95