Prophylactic effect of compression stockings for elevated D-dimer levels following endoscopic submucosal dissection.

Objectives: A relationship between endoscopic submucosal dissection (ESD) and deep vein thrombosis has been recognized. We previously reported that a high corrected midazolam dose (total midazolam dose/initial dose of midazolam used to induce sedation) is related to elevated D-dimer levels after ESD. In this study, the effect of compression stockings (CSs) in preventing thrombosis following ESD under sedation was evaluated by measuring D-dimer levels before and after ESD. Methods: The participants were patients who underwent ESD for upper gastrointestinal tumors during the period between April 2018 and October 2022. Patients with pre-ESD D-dimer levels ≥1.6 µg/m and patients with corrected midazolam doses ≤3.0 were excluded. A retrospective investigation of the relationship between CS use and high post-ESD D-dimer levels (difference in D-dimer levels ≥1.0 µg/mL between before and after ESD) was conducted. Results: There were 27 patients in the non-CS group (NCS) and 33 patients in the CS group. The number of patients with high post-ESD D-dimer levels was 13 (48.2%) in the non-CS group and six (18.2%) in the CS group; the number in the CS group was significantly lower (p = 0.024). On logistic regression analysis, a relationship was seen between the wearing of CSs and a lower number of patients with high post-ESD D-dimer levels (odds ratio 0.24, 95% confidence interval 0.08-0.79, p = 0.019). Conclusion: Wearing CSs was related to a lower risk of high post-ESD D-dimer levels. This result suggests that thrombus formation is a cause of elevated D-dimer levels after ESD.

A first report of right-hemicolectomy for ascending colon cancer in Japan with the da Vinci SP surgical robot system.

BACKGROUND: The da Vinci SP robotic surgical system received regulatory approval for use in colorectal cancer surgery in Japan in April 2023. Given the advantages of the precision of a robot and the postoperative cosmesis of single-site surgery, the system is expected to be further utilized for minimally invasive surgeries, in addition to the curative and safety-assured laparoscopic technique. CASE PRESENTATION: A 73-year-old man presented at our hospital with positive fecal occult blood. He was diagnosed with cT2N0M0 (Stage I) ascending colon cancer and underwent a right hemicolectomy, which was performed with the da Vinci SP system. The operation was performed safely, and the patient was discharged without complications. Pathology findings showed that complete mesocolic excision was achieved. CONCLUSIONS: Herein, we report the first colorectal cancer surgery performed using the da Vinci SP system in Japan. The use of this robotic surgical system with access forms for right hemicolectomy is safe and oncologically appropriate.

Cylindrical abdominoperineal resection for rectal cancer using the Hugo RAS system: The first ever case report for rectal cancer.

In May 2023, the Hugo RAS system obtained pharmaceutical approval for use in gastroenterological surgery in Japan. It is expected to be particularly effective in rectal cancer surgery, which require the manipulation of the deep pelvic cavity and communication with surgeons operating from the intraperitoneal and anal approaches. A 68-year-old woman presented to our hospital with bloody stools and was diagnosed with cStage I (cT2N0M0) rectal cancer and underwent abdominoperineal resection employing the Hugo RAS system. Two arm carts were placed on the left and right lateral sides with an interleg space, and trocars were placed in a straight line between the right superior iliac spine and umbilicus. Herein, we report the first abdominoperineal resection for rectal cancer using the Hugo RAS system.

CD8-positive T Cell Infiltration With Human Leukocyte Antigen Class 1 Expression Predicts Patients With Stage IV Colorectal Cancer Survival.

BACKGROUND/AIM: The immune microenvironment in cancer correlates with cancer progression and patient prognosis. Cancer immune microenvironment evaluation, based on CD3+ and CD8+ T cell infiltration at the center and invasive margin of the tumor, is defined as the immunoscore. An international multicenter analysis revealed that the immunoscore can accurately predict the prognosis of patients with colorectal cancer (CRC) (stage I, II, and III). However, no markers are currently available to predict the prognosis in patients with stage IV CRC. We thus aimed to analyze the immune microenvironment in patients with stage IV CRC in this study. PATIENTS AND METHODS: We analyzed the immune microenvironment of patients with stage IV CRC using immunohistochemical (IHC) staining. We evaluated the expressions of CD8 and the cases were divided into CD8 high (CD8Hi) and CD8 low (CD8Low) groups according to median CD8 expression. HLA class 1 (HLA1) expression was also evaluated using IHC staining and the cases were divided into HLA1Hi group and HLA1Low group according to 50% of HLA1 expression rate. CD8×HLA1 score was defined by the combination of CD8 and HLA1 expressions. RESULTS: CD8Hi and HLA1Hi cases were associated with better prognosis compared with CD8Low and HLA1Low cases according to a log-rank test, respectively. We defined a novel biomarker by combining CD8+ T-cell infiltration and HLA1 expression, referred to as the CD8×HLA1 score. We found that CD8×HLA1Hi cases predicted patient prognosis better than CD8×HLA1Int and CD8×HLA1Low according to a log-rank test. CONCLUSION: The combination of CD8+ T cell infiltration and HLA1 expression is crucial for cancer immune microenvironment evaluation in CRCs.

Tele-proctoring for minimally invasive surgery across Japan: An initial step toward a new approach to improving the disparity of surgical care and supporting surgical education.

Aim: The aim of this study was to verify the clinical feasibility of tele-proctoring using our ultra-low latency communication system with shared internet access. Methods: Connections between two multiple remote locations at various distances were established through the TELEPRO® tele-proctoring system. The server records the latency between the two locations for tele-proctoring using the annotations. Questionnaires were administered to the surgeons, assistants, and medical staff. Respondents rated the quickness and quality of communication in terms of latency and disturbances in the audio, video, and usefulness of the live telestrations with annotation. Results: Seven hospitals tele-proctored with Sapporo Medical University between January 2021 and September 2022. The median latency of annotation between the two locations ranged from 24.5 to 48.5 ms. No major technological problems occurred, such as streaming interruption, loss of video or audio, poor resolution. The video encoding time was 10 ms, and its decoding time was 0.8 ms. The total latency positively correlated with the distance between two locations (R = 0.55, p < 0.01). The quality of communication regarding latency, disturbance, and surgical education with intraoperative annotative instructions showed similar trends, with perfectly fine being the most common response. No significant differences in surgical quality, educational effect, or social impact were observed between the latency ≥30 and <30 ms groups for whether the size of latency affects surgical education. Conclusion: The feasibility of the tele-proctoring system is expected to be a sustainable approach to help education for young surgeons and surgical supports in rural areas, thereby reducing disparities in health care.

Safety and effectiveness of SARS-CoV-2 vaccines for patients with intractable hepatobiliary diseases: A multicenter, questionnaire-based, cross-sectional study.

AIM: There are few data regarding the safety and effectiveness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients with intractable hepatobiliary diseases. We conducted a multicenter, questionnaire-based, cross-sectional study to determine the safety and effectiveness of the SARS-CoV-2 vaccines in Japanese patients with intractable hepatobiliary disease. METHODS: Patients aged ≥18 years with autoimmune hepatitis (AIH), primary biliary cholangitis, primary sclerosing cholangitis, Budd-Chiari syndrome, idiopathic portal hypertension, and extrahepatic portal vein obstruction at each center were consecutively invited to join the study. Participants were asked to complete a questionnaire regarding their characteristics, vaccination status, post-vaccination adverse effects, and SARS-CoV-2 infection. Additionally, liver disease status, treatment regimens, and liver function test values pre- and post-vaccination were collected. RESULTS: The survey was conducted from September 2021 to May 2022, and 528 patients (220 AIH, 251 primary biliary cholangitis, 6 AIH- primary biliary cholangitis/primary sclerosing cholangitis overlap, 39 primary sclerosing cholangitis, 4 Budd-Chiari syndrome, 5 idiopathic portal hypertension, and 3 extrahepatic portal vein obstruction) participated in the study. Post-vaccination adverse effects were comparable to those observed in the general population. Post-vaccination liver injuries classified as grade 1 or higher were observed in 83 cases (16%), whereas grades 2 and 3 were observed in only six cases (1.1%); AIH-like liver injury requiring treatment was not observed. Overall, 12 patients (2.3%) were infected with SARS-CoV-2, and only one patient was infected 6 months after the second vaccination. CONCLUSION: SARS-CoV-2 vaccines demonstrated satisfactory safety and effectiveness in Japanese patients with intractable hepatobiliary diseases.

Clostridium paraputrificum Bacteremia in a Patient with Rectal Cancer after Receiving Antibiotic Therapy for Acute Pharyngolaryngitis.

Clostridium paraputrificum bacteremia is very rare, and its clinical importance is poorly understood. An 86-year-old man was receiving lascufloxacin therapy for acute pharyngolaryngitis before presenting to our emergency department with a recurrent fever. Two sets of blood cultures on admission revealed C. paraputrificum. A stool culture showed a reduced presence of intestinal commensal bacteria. After admission, the patient's fever resolved without antibiotics. Colonoscopy revealed a rectal tumor. Rectal tumor and microbial substitutions caused by antibiotics may have led to bacteremia. When treating C. paraputrificum bacteremia, physicians should be mindful of coexisting gastrointestinal disorders and a history of antibiotic administration.

World-first report of low anterior resection for rectal cancer with the hinotori™ Surgical Robot System: a case report.

BACKGROUND: The hinotori™ Surgical Robot System was approved for use in colorectal cancer surgery in Japan in 2022. This robot has advantages, such as an operation arm with eight axes, an adjustable arm base, and a flexible three-dimensional viewer, and is expected to be utilized in rectal cancer surgery. Herein, we report the world's first surgery for rectal cancer using the hinotori™ Surgical Robot System. CASE PRESENTATION: A 71-year-old woman presented to our hospital with bloody stools. A colonoscopy revealed type 2 advanced cancer in the rectum, and a histological examination exposed a well-differentiated adenocarcinoma. Abdominal enhanced computed tomography divulged rectal wall thickening without significant swelling of the lymph nodes or distant metastasis. Pelvic magnetic resonance imaging showed tumor invasion beyond the intrinsic rectal muscle layer. The patient was diagnosed with cStage IIa (cT3N0M0) rectal cancer and underwent low anterior resection using the hinotori™ Surgical Robot System. Based on an adequate simulation, surgery was safely performed with appropriate port placement and arm base-angle adjustment. The operating time was 262 min, with a cockpit time of 134 min. Subsequently, the patient was discharged 10 days postoperatively without complications. The pathological diagnosis was pStage IIA (cT3N0M0) and the circumferential resection margin was 6 mm. CONCLUSIONS: We report the first case of low anterior resection for rectal cancer using the hinotori™ Surgical Robot System, in which a safe and appropriate oncological surgery was performed.

Risk Factors for Elevated D-Dimer Levels in Patients with Gastrointestinal Tumors Treated with Endoscopic Submucosal Dissection.

Endoscopic submucosal dissection (ESD) is almost always performed with a sedative because of the longer procedure times involved. The risk of post-ESD deep vein thrombosis (DVT) has been reported as relatively high, and D-dimer levels are sometimes elevated after ESD. This retrospective study evaluated factors affecting changes in D-dimer levels from before to after ESD to identify causes of elevated D-dimer levels after ESD. This retrospective analysis included 117 patients with gastrointestinal tumors resected using ESD. After excluding eight patients with pre-ESD levels of D-dimer >1.5 µg/mL, factors correlating with changes in D-dimer from before to after ESD were analyzed using logistic regression analysis in 109 patients. Sedation was accomplished primarily using midazolam, but, because the sedative effect of midazolam shows marked inter-individual variability, a "corrected midazolam dose" was determined by dividing the total midazolam dose by the initial dose to correct for inter-individual differences in the sedative effect of midazolam. This value was used as one potential explanatory variable in the subgroup analysis of the 103 patients who received midazolam. In the subgroup analysis using the corrected midazolam dose as an explanatory variable, only the corrected midazolam dose correlated with a change in D-dimer ≥1.0 µg/mL in multivariate analysis (odds ratio (OR) = 1.5, 95% confidence interval (CI) 0.43-0.95; p = 0.030). The corrected midazolam dose correlated with increases in post-ESD D-dimer levels. This potential relationship indicates that patients undergoing ESD and requiring extended sedation may be at increased risk of DVT.

Determinants of the effectiveness of bezafibrate combined with ursodeoxycholic acid in patients with primary biliary cholangitis.

BACKGROUND AND AIMS: For patients with primary biliary cholangitis (PBC) exhibiting suboptimal responses to ursodeoxycholic acid (UDCA), obeticholic acid (OCA), and bezafibrate (BZF) are currently used and shown to improve long-term outcomes. Nevertheless, we encounter patients who die or undergo liver transplantation (LT) even with combination treatment. In this study, we explored prognostic indicators in patients receiving combination treatment of UDCA and BZF. METHODS: We took advantage of the Japanese PBC registry and enrolled patients who received both UDCA and BZF therapy in 2000 or later. The covariates investigated included baseline covariates as well as treatment covariates. Two main outcomes (all-cause death or LT and liver-related death or LT) were assessed using multivariable-adjusted Cox proportional hazards models. RESULTS: In total, 772 patients were included. The median follow-up was 7.1 years. Using the Cox regression model, bilirubin (hazard ratio [HR] 6.85, 95% confidence interval [CI] 1.73-27.1, p = 0.006), alkaline phosphatase (HR 5.46, 95% CI 1.32-22.6, p = 0.019), and histological stage (HR 4.87, 95% CI 1.16-20.5, p = 0.031) were found associated with LT-free survival. For survival free from liver disease-related death or LT, albumin (HR 7.72, 95% CI 1.48-40.4, p = 0.016) and bilirubin (HR 14.5, 95% CI 2.37-88.5, p = 0.004) were found significantly associated. CONCLUSION: In patients with PBC receiving combination therapy, prognostic variables were similar to those in patients receiving UDCA monotherapy. These results indicate the importance of diagnosing patients with PBC at an earlier stage because of the reduced effectiveness of BZF at advanced stages.

Long-Term Prognosis and Related Factors in Patients with Cirrhosis Treated with Balloon-Occluded Retrograde Transvenous Obliteration.

INTRODUCTION: Balloon-occluded retrograde transvenous obliteration (BRTO) was developed as an effective treatment for gastric varices in patients with cirrhosis. Because liver fibrosis in these patients is assumed to be advanced, their prognosis is expected to be poor. In this study, we investigated the prognosis and characteristics of the patients. METHODS: We enrolled 55 consecutive patients with liver cirrhosis treated with BRTO between 2009 and 2021 at our department. To evaluate factors related to variceal recurrence and long-term prognosis, survival analysis was performed on 45 patients, excluding those who died within 1 month, had an unknown prognosis, or whose treatments were converted to other treatments. RESULTS: During a mean follow-up period of 2.3 years, esophageal varices recurred in 10 patients and could be treated endoscopically. Non-alcoholic steatohepatitis (NASH) was related to the variceal recurrence (hazard ratio [HR] = 4.27, 95% CI: 1.17-15.5, p = 0.028). The survival rate after the procedure at 1, 3, and 5 years was 94.2%, 74.0%, and 63.5%, respectively, and 10 patients died of hepatocellular carcinoma (n = 6), liver failure (n = 1), sepsis (n = 1), and unknown reasons (n = 2). The estimated glomerular filtration rate (eGFR) level was proved to be a significant poor prognostic factor (HR = 0.96, 95% CI: 0.93-0.99, p = 0.023). The comorbid hypertension (HTN) was the main cause of low eGFR, and HTN was also significantly related to survival (HR = 6.18, 95% CI: 1.57-24.3, p = 0.009). Most of the patients with HTN were treated with calcium channel blocker and/or angiotensin receptor blocker. CONCLUSION: The clinical course of patients with cirrhosis treated with BRTO was dependent on the metabolic factors including renal function, comorbid HTN, and NASH.

Right hemicolectomy for ascending colon cancer using the hinotori surgical robot system: The first ever case report for colon cancer.

The hinotori Surgical Robot System obtained pharmaceutical approval for use in colorectal cancer surgery in October 2022 in Japan, and its advantages, including its operating arm with eight axes, adjustable arm base, and flexible 3D viewer, are expected to be utilized in colon cancer surgery. A 68-year-old woman presented to our hospital with abdominal pain and was diagnosed with cStageIIa (cT3N0M0) ascending colon cancer and underwent right hemicolectomy using the hinotori Surgical Robot System with the appropriate port placement on the arc around the hepatic flexure, which was available for both ileocecal manipulation and lymph node dissection, and adjustment of the angle of the arm base to further reduce interference. Herein we report the world's first surgery for colorectal cancer using the hinotori Surgical Robot System.

Development of an ultralow-latency communication system using shared internet access: promoting the implementation of telemedicine.

Telemedicine is becoming increasingly important to address the shortage of gastrointestinal surgeons and disparities in domestic and international treatment outcomes for patients with colorectal cancer. The development of a low-latency communication system using existing communication infrastructure (shared internet access: SIA) is necessary to promote the use of telemedicine. The aim of this study was to develop a low-latency communication system using SIA. We conducted an experiment between Sapporo and Tokyo using an ultralow-latency communication system for remote medical education (TELEPRO®). The latency was measured using 2000 annotations from a monitor in Sapporo, which confirmed a median latency of 27.5 ms. A low-latency communication system based on SIA with latency lower than the maximum allowable latency for telemedicine was developed successfully.

Artificial intelligence-based technology to make a three-dimensional pelvic model for preoperative simulation of rectal cancer surgery using MRI.

Aim: A new technique that allows visualization of whole pelvic organs with high accuracy and usability is needed for preoperative simulation in advanced rectal cancer surgery. In this study, we developed an automated algorithm to create a three-dimensional (3D) model from pelvic MRI using artificial intelligence (AI) technology. Methods: This study included a total of 143 patients who underwent 3D MRI in a preoperative examination for rectal cancer. The training dataset included 133 patients, in which ground truth labels were created for pelvic vessels, nerves, and bone. A 3D variant of U-net was used for the network architecture. Ten patients who underwent lateral lymph node dissection were used as a validation dataset. The correctness of the vascular labelling was assessed for pelvic vessels and the Dice similarity coefficients calculated for pelvic bone. Results: An automatic segmentation algorithm that extracts the artery, vein, nerve, and pelvic bone was developed, automatically producing a 3D image of the entire pelvis. The total time needed for segmentation was 133 seconds. The success rate of the AI-based segmentation was 100% for the common and external iliac vessels, but the rates for the vesical vein (75%), superior gluteal vein (60%), or accessory obturator vein (63%) were suboptimal. Regarding pelvic bone, the average Dice similarity coefficient between manual and automatic segmentation was 0.97 (standard deviation 0.0043). Conclusion: Though there is room to improve the segmentation accuracy, the algorithm developed in this study can be utilized for surgical simulation in the treatment of advanced rectal cancer.

Artificial intelligence-based technology for semi-automated segmentation of rectal cancer using high-resolution MRI.

AIM: Although MRI has a substantial role in directing treatment decisions for locally advanced rectal cancer, precise interpretation of the findings is not necessarily available at every institution. In this study, we aimed to develop artificial intelligence-based software for the segmentation of rectal cancer that can be used for staging to optimize treatment strategy and for preoperative surgical simulation. METHOD: Images from a total of 201 patients who underwent preoperative MRI were analyzed for training data. The resected specimen was processed in a circular shape in 103 cases. Using these datasets, ground-truth labels were prepared by annotating MR images with ground-truth segmentation labels of tumor area based on pathologically confirmed lesions. In addition, the areas of rectum and mesorectum were also labeled. An automatic segmentation algorithm was developed using a U-net deep neural network. RESULTS: The developed algorithm could estimate the area of the tumor, rectum, and mesorectum. The Dice similarity coefficients between manual and automatic segmentation were 0.727, 0.930, and 0.917 for tumor, rectum, and mesorectum, respectively. The T2/T3 diagnostic sensitivity, specificity, and overall accuracy were 0.773, 0.768, and 0.771, respectively. CONCLUSION: This algorithm can provide objective analysis of MR images at any institution, and aid risk stratification in rectal cancer and the tailoring of individual treatments. Moreover, it can be used for surgical simulations.

Gastrointestinal Bleeding During Direct Oral Anticoagulant Therapy in Patients With Nonvalvular Atrial Fibrillation and Risk of Polypharmacy.

Although concomitant medications have been raised as a factor affecting hemorrhage during direct oral anticoagulant (DOAC) therapy, details remain unelucidated. This study was conducted to clarify the relationship between concomitant medications with possible pharmacokinetic interactions and number of concomitant medications, and bleeding and embolism in patients with nonvalvular atrial fibrillation on DOACs. The subjects were 1010 patients prescribed DOACs from a single-center at the Teikyo University Hospital between April 2011 and June 2018. This study was an exploratory analysis and investigated their course between the first prescription and December 2018, including the presence or absence of clinically relevant bleeding, gastrointestinal bleeding, and major cardiovascular and cerebrovascular events. Impacts of medications were evaluated by the general linear model with inverse probability-weighted propensity score. The observation period was 2272 patient-years. The rate of bleeding was 4.7%/year, gastrointestinal bleeding was 2.8%/year, and major cardiovascular and cerebrovascular events were 2.0%/year. Taking 10 or more oral medications concurrently was a significant risk for gastrointestinal bleeding (hazard ratio, 2.046 [95%CI, 1.188-3.526]; P = .010). Nonsteroidal anti-inflammatory drugs were the only significant risk for gastrointestinal bleeding. Clinicians should be aware of gastrointestinal bleeding when using DOACs with patients taking more than 10 medications and/or nonsteroidal anti-inflammatory drugs.

Short-Term Outcomes with Standardized Transperineal Minimally Invasive Abdominoperineal Excision for Rectal Cancer.

BACKGROUND: Transperineal abdominoperineal excision (TpAPE) is an emerging approach for low rectal cancers but is technically challenging. Based on an anatomical study we conducted previously, we have standardized the TpAPE procedure. Here, we aimed to validate the feasibility of the standardized TpAPE by investigating the short-term outcomes. METHODS: From January 2018 to November 2020, a total of 405 patients underwent laparoscopic or robotic rectal resection for rectal cancer in our institution. For the current study, we analyzed data for the 31 patients who underwent TpAPE. The abdominal phase was performed synchronously with the perineal phase using either a laparoscopic or robotic approach. Short-term outcomes included operative and pathological results. RESULTS: Of the 31 cases, we identified anterior quadrant tumor invasion in 21. Most of the cases were advanced, with 6 staged as cT3 and 20 as T4. Of the 27 cases not involving distant metastasis, neoadjuvant therapy was performed in 19. No inadvertent rectal perforation or urethral injury was found intraoperatively. The median procedural duration to specimen removal was 250 min (interquartile range, 204-287), and the median intraoperative blood loss was 10 ml (interquartile range, 5-40). Regarding postoperative complications, perineal wound infection developed in 11 cases. A positive circumferential resection margin was found in 3, corresponding to the positive rate of 9.7%. These three cases were among the first 12 cases involving standardized TpAPE. CONCLUSIONS: The current results indicate that TpAPE can be performed safely and might represent a useful option for low rectal cancer resection.

Budd-Chiari Syndrome during Long-term Follow-up after Allogeneic Umbilical Cord Blood Transplantation.

A series of abdominal computed tomography scans of an asymptomatic 40-year-old woman with a history of umbilical cord blood transplantation (CBT) for leukemia at 19 years old revealed the long-term gradual development of a right hepatic vein thrombus and stenosis of the inferior vena cava, leading to a diagnosis of Budd-Chiari syndrome. The Budd-Chiari syndrome in this case might have been influenced by the patient's history of multiple liver abscesses after CBT and associated thrombus formation, in addition to the hormone replacement therapy with estradiol and dydrogesterone she was taking. This case provides insight into the development of Budd-Chiari syndrome.

A modified method for resected specimen processing in rectal cancer: Semi-opened with transverse slicing for measuring of the circumferential resection margin.

Circumferential resection margin (CRM) is essential for oncological quality assessment in rectal cancer surgery. CRM represents a surrogate parameter for oncological outcomes and is important for stratifying treatment strategies in Western nations. In Japan, the mesentery is removed for specimen processing in order to extract as many lymph nodes (LNs) as possible; consequently, CRM cannot be measured. Given the diversification of treatment strategies for rectal cancer, the lack of measurement of CRM to assess surgical outcomes is a crucial issue that must be resolved. Therefore, it is necessary to establish a method enabling measurement of CRM while enjoying the advantages of the Japanese method. In the method we developed, the mesentery is removed from the rectum more than 2 cm away from the tumor, and the vicinity of the tumor is circularized. It is necessary to investigate the usefulness of this method prospectively in a multi-center study.

Environmental factors, medical and family history, and comorbidities associated with primary biliary cholangitis in Japan: a multicenter case-control study.

BACKGROUND: Primary biliary cholangitis (PBC) is considered to be caused by the interaction between genetic background and environmental triggers. Previous case-control studies have indicated the associations of environmental factors (tobacco smoking, a history of urinary tract infection, and hair dye) use with PBC. Therefore, we conducted a multicenter case-control study to identify the environmental factors associated with the development of PBC in Japan. METHODS: From 21 participating centers in Japan, we prospectively enrolled 548 patients with PBC (male/female = 78/470, median age 66), and 548 age- and sex-matched controls. These participants completed a questionnaire comprising 121 items with respect to demographic, anthropometric, socioeconomic features, lifestyle, medical/familial history, and reproductive history in female individuals. The association was determined using conditional multivariate logistic regression analysis. RESULTS: The identified factors were vault toilet at home in childhood [odds ratio (OR), 1.63; 95% confidence interval (CI), 1.01-2.62], unpaved roads around the house in childhood (OR, 1.43; 95% CI, 1.07-1.92), ever smoking (OR, 1.70; 95% CI, 1.28-2.25), and hair dye use (OR, 1.57; 95% CI, 1.15-2.14) in the model for lifestyle factors, and a history of any type of autoimmune disease (OR, 8.74; 95% CI, 3.99-19.13), a history of Cesarean section (OR, 0.20; 95% CI, 0.077-0.53), and presence of PBC in first-degree relatives (OR, 21.1; 95% CI, 6.52-68.0) in the model for medical and familial factors. CONCLUSIONS: These results suggest that poor environmental hygiene in childhood (vault toilets and unpaved roads) and chronic exposure to chemicals (smoking and hair dye use) are likely to be risk factors for the development of PBC in Japan.