Association Between Sense of Coherence, Disease-Specific Symptoms, and Health-Related Quality of Life Among Japanese Patients with Ulcerative Colitis: A Cross-Sectional Study.

INTRODUCTION: We examined the associations among disease-related symptoms, health-related quality of life (HRQOL), and sense of coherence (SOC) in Japanese patients with ulcerative colitis (UC). METHODS: This cross-sectional survey involved patients and physicians at 23 hospitals specializing in UC treatment in Japan (December 2019-December 2020). Multiple linear regression analysis was performed using scores on the Mental Health and General Health subscales of the Medical Outcomes Study 36-Item Short-Form Health Survey as outcomes and SOC as the main independent variable. Scores on the Inflammatory Bowel Disease Questionnaire (IBDQ) and Fecal Incontinence Quality of Life Scale (FIQL) were used to measure the effect of disease-related symptoms. The moderating effect of symptoms on the association between HRQOL and SOC was also tested. RESULTS: SOC was positively and independently associated with HRQOL (Mental Health: ß = 0.43, 95% confidence interval [CI] = 0.24-0.61, P < 0.001; General Health: ß = 0.41, 95% CI = 0.23-0.59, P < 0.001). The association of SOC with Mental Health scores did not differ by symptoms, whereas its association with General Health was attenuated by symptoms (interaction term of IBDQ by SOC: ß = -0.0082, 95% CI = -0.017 to 0.00064, P = 0.07; that of FIQL by SOC: ß = -0.0052, 95% CI = -0.011 to 0.0010, P = 0.10). CONCLUSIONS: SOC affected mental health independently, and its protective association with general health perception was affected by symptoms. Further research is required to determine the most effective use of SOC in interventions to improve HRQOL in patients with UC.

Elemental diet therapy plays a significant role in preventing surgical recurrence of Crohn's disease in the era of biologics.

PURPOSE: Most patients with Crohn's disease (CD) experience surgical recurrence. In this era of novel therapies, we conducted this study to clarify which treatments effectively decrease the risk of surgical recurrence in patients with CD. METHODS: The subjects of this retrospective study were 37 patients with CD. We created cumulative surgery rate curves and performed univariate and multivariate analyses. RESULTS: Univariate analysis revealed that patients who consumed an elemental diet (ED; ≥ 900 kcal/day), anti-tumor necrosis factor-alpha, and thiopurines had a significantly better prognosis than those who did not (p = 0.011, p = 0.025, and p = 0.0080, respectively). Multivariate analysis revealed that ED therapy and thiopurines were independent significant factors for controlling surgical recurrence (p = 0.046 and p = 0.032, respectively). Additional analyses showed that the most promising ED therapeutic dose was ≥ 1200 kcal/day, while an ED therapeutic dose of ≥ 900 kcal/day was acceptable. CONCLUSIONS: Although univariate analyses revealed that all three treatment strategies had significant effects on surgical recurrence in patients with CD, multivariate analysis revealed that only ED therapy was significantly associated with surgical recurrence rates. Thus, ED therapy plays an important role in the management of CD, even in the era of biological therapies.

Computed tomography and magnetic resonance imaging of a plexiform angiomyxoid myofibroblastic tumor: a case report.

BACKGROUND: Plexiform angiomyxoid myofibroblastic tumor (PAMT) is a very rare mesenchymal tumor of the stomach. Here we report a case of pathologically confirmed PAMT with an unique cyst formation. CASE PRESENTATION: A 55-year-old male with a 10-year history of a gastric subepithelial tumor underwent computed tomography (CT) and magnetic resonance imaging (MRI). Two cysts were observed in the tumor, and the cyst wall showed moderately high intensity on T2-weighted images compared with the gastric wall. On dynamic study, the cyst wall showed a gradual enhancement pattern, and prominent enhancement was observed in the delayed phase. Laparoscopic partial gastric resection was performed, and a pathological diagnosis of PAMT was rendered. CONCLUSION: We present a rare case of gastric PAMT, which was uniquely presented as cysts. One of the cysts in the tumor had an epithelial wall lining, which had never been reported before in gastric mesenchymal tumor, in addition to partial glandular structure. We reviewed our case, focusing on radiologic-pathologic correlation, and suggested hypothesis of cyst formation. According to our findings, PAMT with cyst formation would be included of differential diagnosis of gastric subepithelial tumors.

Altered expression of microRNAs in patients with pouchitis after restorative proctocolectomy.

BACKGROUND AND PURPOSE: Pouchitis is the most common long-term complication of restorative proctocolectomy with ileal pouch-anal anastomosis. We investigated alterations in the expression of microRNAs, noncoding RNAs that act as potent negative regulators of gene expression, in pouchitis. METHODS: The subjects of this study were 16 patients with diagnosed pouchitis and 48 patients without pouchitis after restorative proctocolectomy, performed for ulcerative colitis. Total RNA was extracted from biopsies and microRNAs were quantified using a real-time polymerase chain reaction. RESULTS: The expression of microRNA 21 and 223 was higher, whereas that of microRNA 192 and 196a was lower, in the inflamed mucosa from the pouchitis patients than in the mucosa from the non-pouchitis patients. The levels of 14 microRNAs were significantly lower in the mucosa from the pouchitis patients, than in the non-inflamed proximal ileal mucosal samples. The expression of microRNA 192 was remarkably reduced in pouchitis. A significant negative correlation was found between microRNA 192 and interleukin 17 receptor A mRNA levels. CONCLUSIONS: Significant alteration in miRNA expression in line with inflammatory bowel disease was evident in the mucosa from the pouchitis patients. Interleukin 17 receptor A may be involved in the pathogenesis of pouchitis through the downregulation of microRNA 192.

Surveillance for dysplasia in patients with ulcerative colitis: Discrepancy between guidelines and practice.

BACKGROUND AND AIM: The risk of developing colorectal cancer is higher in patients with ulcerative colitis (UC) than in the general population. Guidelines recommend surveillance colonoscopy (SCS) to reduce mortality; however, few studies have assessed physicians' adherence to guidelines. This study was aimed to clarify the current status of SCS and adherence to guidelines through the characteristics of cancer/dysplasia surveillance for UC patients in Japan. METHODS: A questionnaire was mailed to 541 physicians who attended meetings on inflammatory bowel disease. RESULTS: The respondents encountered a median of 100 UC cases. Thirty percent of the respondents had never managed a UC patient with cancer. Fifty-one percent of the respondents had never diagnosed colorectal cancer with UC. Forty-seven percent of the respondents considered extensive colitis and left-sided colitis as indications for SCS, and 38% carried out SCS regardless of the disease extent. Sixty-three percent of the respondents started SCS at 7-10 years after UC onset, whereas 20% started SCS at 3 years or less. Fifty-two percent of the respondents obtained targeted biopsies only, and chromoendoscopy was used by 49% of the respondents as a special technique for surveillance. Median number of biopsies at SCS was five per patient; it was three among patients whose biopsy was carried out by physicians who obtained targeted biopsies only and seven among those carried out by physicians who obtained step biopsies and targeted biopsies (P < 0.0001). CONCLUSION: A considerable proportion of the respondents did not follow the guidelines when selecting patients for surveillance and carrying out SCS.

Detection of APC mosaicism by next-generation sequencing in an FAP patient.

Familial adenomatous polyposis (FAP) of the colon is characterized by multiple polyps in the intestine and extra-colonic manifestations. Most FAP cases are caused by a germline mutation in the tumor-suppressor gene APC, but some cases of adenomatous polyposis result from germline mutations in MUTYH, POLD1 or POLE. Although sequence analysis of APC by the Sanger method is routinely performed for genetic testing, there remain cases whose mutations are not detected by the analysis. Next-generation sequencing has enabled us to analyze the comprehensive human genome, improving the chance of identifying disease causative variants. In this study, we conducted whole-genome sequencing of a sporadic FAP patient in which we did not find any pathogenic APC mutations by the conventional Sanger sequencing. Whole-genome sequencing and subsequent deep sequencing identified a mosaic mutation of c.3175G>T, p.E1059X in ~12% of his peripheral leukocytes. Additional deep sequencing of his buccal mucosa, hair follicles, non-cancerous mucosa of the stomach and colon disclosed that these tissues harbored the APC mutation at different frequencies. Our data implied that genetic analysis by next-generation sequencing is an effective strategy to identify genetic mosaicism in hereditary diseases.

Real-world NUDT15 genotyping and thiopurine treatment optimization in inflammatory bowel disease: a multicenter study.

BACKGROUND: This study evaluated the effectiveness of NUDT15 codon 139 genotyping in optimizing thiopurine treatment for inflammatory bowel disease (IBD) in Japan, using real-world data, and aimed to establish genotype-based treatment strategies. METHODS: A retrospective analysis of 4628 IBD patients who underwent NUDT15 codon 139 genotyping was conducted. This study assessed the purpose of the genotyping test and subsequent prescriptions following the obtained results. Outcomes were compared between the Genotyping group (thiopurine with genotyping test) and Non-genotyping group (thiopurine without genotyping test). Risk factors for adverse events (AEs) were analyzed by genotype and prior genotyping status. RESULTS: Genotyping test for medical purposes showed no significant difference in thiopurine induction rates between Arg/Arg and Arg/Cys genotypes, but nine Arg/Cys patients opted out of thiopurine treatment. In the Genotyping group, Arg/Arg patients received higher initial doses than the Non-genotyping group, while Arg/Cys patients received lower ones (median 25 mg/day). Fewer AEs occurred in the Genotyping group because of their lower incidence in Arg/Cys cases. Starting with < 25 mg/day of AZA reduced AEs in Arg/Cys patients, while Arg/Arg patients had better retention rates when maintaining ≥ 75 mg AZA. Nausea and liver injury correlated with thiopurine formulation but not dosage. pH-dependent mesalamine reduced leukopenia risk in mesalamine users. CONCLUSIONS: NUDT15 codon 139 genotyping effectively reduces thiopurine-induced AEs and improves treatment retention rates in IBD patients after genotype-based dose adjustments. This study provides data-driven treatment strategies based on genotype and identifies risk factors for specific AEs, contributing to a refined thiopurine treatment approach.

Endoscopic Lesions of Postoperative Anastomotic Area in Patients With Crohn's Disease in the Biologic Era: A Japanese Multi-Centre Nationwide Cohort Study.

BACKGROUND AND AIMS: Many patients have endoscopic evidence of recurrent Crohn's disease [CD] at 1 year after intestinal resection. These lesions predict future clinical recurrence. We endoscopically evaluated postoperative anastomotic lesions in CD patients from a large cohort of postoperative CD patients. METHODS: We retrospectively enrolled CD patients who underwent surgical resection between 2008 and 2013 at 19 inflammatory bowel disease [IBD]-specialist institutions. The initial analyses included patients who underwent ileocolonoscopy ~1 year after intestinal resection. Follow-up analyses assessed any changes in the endoscopic findings over time. We evaluated the postoperative endoscopic findings, which were classified into four categories [no lesion, mild, intermediate, severe] at the sites of the anastomotic line and peri-anastomosis. RESULTS: In total, 267 CD patients underwent postoperative ileocolonoscopy. Postoperative anastomotic lesions were widely detected in index ileocolonoscopy [61.0%] and were more frequently detected in follow-up ileocolonoscopy [74.9%]. Endoscopic severity also increased. Patients with intermediate or severe peri-anastomotic or anastomotic line lesions at the index ileocolonoscopy required significantly more interventions, including endoscopic dilatation or surgery, than patients with mild lesions or no lesions. CONCLUSIONS: Frequent anastomotic lesions were observed at the postoperative index ileocolonoscopy. These gradually increased for subsequent ileocolonoscopy, even in the biologic era. Regarding lesions on the anastomotic line, intermediate lesions on the anastomotic line [e.g. irregular or deep ulcers] might be considered recurrent disease, and mild lesions [e.g. linear superficial ulcers] might be considered non-recurrent disease. Prospective studies are needed to resolve this issue, including treatment enhancement.

Genetic Background of Mesalamine-induced Fever and Diarrhea in Japanese Patients with Inflammatory Bowel Disease.

BACKGROUND: Some patients with inflammatory bowel disease (IBD) who were under mesalamine treatment develop adverse reactions called "mesalamine allergy," which includes high fever and worsening diarrhea. Currently, there is no method to predict mesalamine allergy. Pharmacogenomic approaches may help identify these patients. Here we analyzed the genetic background of mesalamine intolerance in the first genome-wide association study of Japanese patients with IBD. METHODS: Two independent pharmacogenetic IBD cohorts were analyzed: the MENDEL (n = 1523; as a discovery set) and the Tohoku (n = 788; as a replication set) cohorts. Genome-wide association studies were performed in each population, followed by a meta-analysis. In addition, we constructed a polygenic risk score model and combined genetic and clinical factors to model mesalamine intolerance. RESULTS: In the combined cohort, mesalamine-induced fever and/or diarrhea was significantly more frequent in ulcerative colitis vs Crohn's disease. The genome-wide association studies and meta-analysis identified one significant association between rs144384547 (upstream of RGS17) and mesalamine-induced fever and diarrhea (P = 7.21e-09; odds ratio = 11.2). The estimated heritability of mesalamine allergy was 25.4%, suggesting a significant correlation with the genetic background. Furthermore, a polygenic risk score model was built to predict mesalamine allergy (P = 2.95e-2). The combined genetic/clinical prediction model yielded a higher area under the curve than did the polygenic risk score or clinical model alone (area under the curve, 0.89; sensitivity, 71.4%; specificity, 90.8%). CONCLUSIONS: Mesalamine allergy was more common in ulcerative colitis than in Crohn's disease. We identified a novel genetic association with and developed a combined clinical/genetic model for this adverse event.

Portal vein thrombosis and pulmonary artery thromboembolism after laparoscopic colectomy.

Portal vein thrombosis is a rare and potentially lethal complication of laparoscopic colectomy. In this paper, we present a case of portal vein thrombosis and pulmonary artery thromboembolism on the 11(th) day after laparoscopic colectomy without an evident congenital thrombotic disorder. Laparoscopic surgeons and their patients should be aware of such events, because the patients are usually discharged before the symptoms begin.

[Weekly injection of paclitaxel plus weekly oral administration of cyclophosphamide were very effective for a case of advanced accessory breast cancer].

Reported is a case of advanced accessory breast cancer to which weekly injection of paclitaxel plus weekly oral administration of cyclophosphamide proved very effective. The patient was a 49-year-old woman who noticed a tumor in the right axilla around October 2007 but then left it alone. In October 2008, the patient visited a nearby physician who made a diagnosis of locally advanced accessory breast cancer. Because the tumor enlarged despite endocrinotherapy, the patient was referred to our hospital in July 2009. CT scan showed a tumor with a size of infant's head, multiple lymph node metastases and metastases to the skin, liver and bones. Following weekly injection of paclitaxel plus weekly oral administration of cyclophosphamide for 4 months, the tumor in the right axilla and metastases to the lymph nodes, skin and liver disappeared. Adverse events were alopecia and grade 1 peripheral neuropathy. The treatment continues at present. Weekly injection of paclitaxel plus weekly oral administration of cyclophosphamide has few adverse reactions and can be performed at an outpatient clinic, suggesting that it is a useful treatment.

Long-Term Follow-Up of Targeted Biopsy Yield (LOFTY Study) in Ulcerative Colitis Surveillance Colonoscopy.

We previously performed a randomized controlled trial (RCT) comparing targeted and random biopsy in neoplasia detection in patients with ulcerative colitis (UC), which showed the short-term effectiveness of targeted biopsy with one-time colonoscopy. In this retrospective cohort study, we investigated the long-term effectiveness of targeted biopsy in tertiary care hospitals, using the follow-up data from patients with UC for ≥ 8 years who had enrolled in the initial RCT. The primary outcome was death from colorectal cancer (CRC). Secondary outcomes were advanced neoplasia (CRC or high-grade dysplasia) and colectomy due to neoplasia after the RCT. We compared these outcomes between target and random groups. Data on 195 of the 221 patients (88.2%) enrolled in the previous RCT were collected from 28 institutions between 2008 and 2019. No patients died of CRC in either group, with a median 8.8-year follow-up demonstrating a robustness for targeted biopsy in terms of CRC death prevention. Advanced neoplasia was detected in four and three patients in the target and random groups, respectively. Colectomy was required due to neoplasia in three patients in each group. The chance of developing CRC in patients with a negative colonoscopy was low, and the targeted biopsy appeared effective in this population. Conversely, patients found with low-grade dysplasia at initial RCT have 10-fold higher risk of progression to high-grade dysplasia and/or CRC. Ten extracolonic malignancies were observed during the follow-up, resulting in four deaths. Panchromoendoscopy was used only in 4.6% and targeted biopsy was only performed in 59.1% of colonoscopies. We recommend targeted biopsy rather than > 33 random biopsies in real-world settings under adequate observation by specialists.

Multimarker circulating DNA assay for assessing blood of prostate cancer patients.

BACKGROUND: Prostate cancer (PCa) detection using serum-based prostate specific antigen (PSA) is limited by frequent false-positive and -negative results. Genetic aberrations such as allelic imbalance (AI) and epigenetic changes such as promoter hypermethylation have been detected in circulating DNA of cancer patients. We hypothesized that circulating multimarker DNA assays detecting both genetic and epigenetic markers in serum would be useful in assessing PCa patients. METHODS: We assayed blood from healthy male donors (n = 40) and 83 patients with American Joint Cancer Committee (AJCC) stage I-IV PCa. DNA was assayed for AI of 6 genome microsatellites. We assessed methylation of RASSF1, RARB2, and GSTP1 using a methylation-specific PCR assay and analyzed the sensitivity of each assay for the detection of genetic or epigenetic changes in circulating DNA. The relation between circulating tumor-related DNA detection and prognostic factors was investigated. RESULTS: The proportion of patients demonstrating AI for > or =1 marker was 47% (38 of 81 patients). Methylation biomarkers were detected in 24 of 83 patients (28%). By combining 2 DNA assays, the number of PCa patients positive for > or =1 methylated or LOH marker increased (52 of 83; 63%). The combined assays detected PCa in 15 of 24 patients (63%) with normal PSA concentrations. The combination of the DNA assays detected the presence of PCa regardless of AJCC stage or PSA concentration. Combination of the DNA and PSA assays gave 89% sensitivity. CONCLUSIONS: This pilot study demonstrates that the combined circulating DNA multimarker assay identifies patients with PCa and may yield information independent of AJCC stage or PSA concentration.

Anti-apoptotic effect by the suppression of IRF1 as a downstream of Wnt/ß-catenin signaling in colorectal cancer cells.

Impaired Wnt signaling pathway plays a crucial role in the development of colorectal cancer through activation of the ß-catenin/TCF7L2 complex. Although genes upregulated by Wnt/ß-catenin signaling have been intensively studied, the roles of downregulated genes are poorly understood. Previously, we reported that interferon-induced proteins with tetratricopeptide repeats 2 (IFIT2) was downregulated by the Wnt/ß-catenin signaling, and that the suppressed expression of IFIT2 conferred antiapoptotic property to colorectal cancer (CRC) cells. However, the mechanisms underlying how Wnt/ß-catenin signaling regulates IFIT2 remain to be elucidated. In this study, we have uncovered that the expression of IFIT2 is induced by IRF1, which is negatively regulated by the Wnt/ß-catenin signaling. In addition, we found that downregulation of IRF1 is mediated by its degradation through the ubiquitination-proteasome pathway, and that decreased activity of a deubiquitinase complex containing USP1 and UAF1 is involved in the degradation of IRF1 by Wnt/ß-catenin signaling. These data should provide better understanding of the Wnt signaling pathway and human carcinogenesis.

Estrogen receptor and HER2/neu status affect epigenetic differences of tumor-related genes in primary breast tumors.

INTRODUCTION: Estrogen receptor (ER)-positive breast cancers are considered prognostically more favorable than ER-negative tumors, whereas human epidermal growth factor receptor (HER)2/neu-positive breast cancers are associated with worse prognosis. The objective of the present study was to determine whether ER-positive and ER-negative status relates to epigenetic changes in breast cancer-related genes. To evaluate epigenetic differences in tumor-related genes relating to ER and HER2/neu status of primary tumors, we examined the promoter methylation status of the promoter region CpG islands of eight major breast tumor-related genes (RASSF1A, CCND2, GSPT1, TWIST, APC, NES1, RARbeta2, and CDH1). METHODS: Paired ER-positive (n = 65) and ER-negative (n = 65) primary breast tumors (n = 130) matched for prognostic factors were assessed. DNA was extracted from paraffin-embedded tumor tissue after microdissection, and methylation-specific PCR and capillary-array electrophoresis analysis were performed. RESULTS: In early stages of tumor progression (T1 and N0), RASSF1A and CCND2 were significantly (P < 0.05) more methylated in ER-positive than in ER-negative tumors. GSTP1 hypermethylation was more frequent in the lymph node metastasis positive group than in the negative group. Double negative (ER-negative, HER2/neu-negative) breast cancers had significantly lesser frequencies of RASSF1A, GSTP1, and APC methylation (P < 0.0001, P < 0.0001, and P = 0.0035, respectively). Both ER and HER2/neu status correlated independently with these epigenetic alterations. CONCLUSION: We demonstrated significant differences in tumor-related gene methylation patterns relevant to ER and HER2/neu status of breast tumors. This may be of significance in the assessment of targeted therapy resistance related to ER and HER2/neu status in breast cancer patients.

Utility of circulating B-RAF DNA mutation in serum for monitoring melanoma patients receiving biochemotherapy.

PURPOSE: Somatic B-RAF gene mutation has been identified in many malignancies and detected at a high frequency in cutaneous malignant melanoma. However, the significance of the B-RAF mutation (B-RAFmt) in terms of its prognostic and predictive capabilities for treatment response or disease outcome is not known. We hypothesized that circulating serum B-RAFmt (B-RAFsmt) at V600E, detected in serum, predicts response in melanoma patients receiving concurrent biochemotherapy. EXPERIMENTAL DESIGN: A real-time clamp quantitative reverse transcription-PCR assay was designed to assess B-RAFsmt by peptide nucleic acid clamping and a locked nucleic acid hybrid probe. Normal (n = 18) and American Joint Committee on Cancer stage I to IV melanoma patients (n = 103) were evaluated. These included stage IV patients (n = 48) with blood drawn before and after biochemotherapy. Patients were classified as biochemotherapy responders or nonresponders. Responders (n = 24) had a complete or partial response following biochemotherapy; nonresponders (n = 24) developed progressive disease. RESULTS: Of the 103 melanoma patients, 38 (37%) had B-RAFsmt DNA, of which 11 of 34 (32%) were stage I or II, and 27 of 69 (39%) were stage III or IV. Of the 48 biochemotherapy patients, 10 of 24 (42%) patients were positive for the B-RAFsmt in the respective responder and nonresponder groups before treatment. After biochemotherapy, B-RAFsmt was detected in only 1 of 10 patients (10%) in the responder group and 7 of 10 patients (70%) in the nonresponder group. B-RAFsmt is associated with significantly worse (P = 0.039) overall survival in patients receiving biochemotherapy. CONCLUSION: These studies show the presence and utility of circulating B-RAFsmt DNA in melanoma patients.

Abdominal CT-aided diagnosis of acute appendicitis in the presence of mobile cecum: A case report.

INTRODUCTION: A mobile cecum is a frequently encountered congenital anomaly. It is important to recognize this atypical position of the cecum as it may interfere with an accurate diagnosis of acute appendicitis. PRESENTATION OF CASE: A 48-year-old man presented with abdominal pain, anorexia, and fever. He had mild lower abdominal discomfort, and rebound tenderness in the suprapubic region, but no guarding or right lower quadrant findings. Laboratory tests identified an elevated white blood cell count (12350 cells/mL) and C-reactive protein level (4.56 mg/dL). In view of the clinical picture suggestive of localized peritonitis, an abdominal computed tomography (CT) was performed, which revealed a caudally located cecum, lying in the pelvis, along with evidence of an acutely inflamed appendix. An urgent surgical procedure was performed, which confirmed the diagnosis of acute appendicitis accompanying a mobile cecum. DISCUSSION: In the presence of a mobile cecum, the clinical findings of acute appendicitis may be atypical owing to the abnormal position of the appendix. In such cases, there is the possibility of a missed diagnosis. In our case, a CT examination that was performed in view of the clinical diagnosis of mild peritonitis aided in establishing the diagnosis of acute appendicitis and a mobile cecum. CONCLUSION: Anatomical variations of the cecum and the appendix may result in atypical presentation of acute appendicitis. A high index of suspicion, and a CT examination may be helpful in establishing the diagnosis in such cases.

A series of seton techniques involving "top-down therapy" for patients with Crohn's disease who initially presented with perianal fistulas.

OBJECTIVES: We determined the outcomes of seton treatment through a series of techniques using biological agents (BIOs) in 18 patients with Crohn's disease (CD) who initially presented with perianal fistulas. METHODS: The patients underwent seton drainage using three seton types: a Penrose tube for fistulas with massive purulent discharge, a vessel loop for a small amount of discharge, and a rubber band for unproductive fistulas. If the distal end of the fistula extended more than 4 cm from the anal orifice, the skin and subcutaneous tissue were dissected along the outer edge of the anal sphincter to divide the fistulous tract into two portions. One seton encircled the sphincter from the primary opening throughout the anal canal (medial seton), and the other was inserted through the distal tract outside the sphincter (lateral seton). A BIO was then introduced immediately. When discharge ceased, the Penrose tube or vessel loop was replaced sequentially with a rubber band, which was tied fittingly and subsequently removed in medial to lateral order. RESULTS: The mean interval between fistula onset and CD diagnosis was 2.1 years, and that between CD diagnosis and introduction of BIOs was 0.5 years. The mean follow-up duration was 4 years. The BIOs currently used were infliximab in 10 patients, adalimumab in 7, and ustekinumab in 1. The overall success rate was 94.4%, including unproductive fistulas in 10 (55.6%) patients and fistula disappearance in 7 (38.9%). CONCLUSIONS: Our seton drainage techniques via the "top-down" approach represent a promising avenue for treating perianal fistulas in patients with CD.

NUDT15 codon 139 is the best pharmacogenetic marker for predicting thiopurine-induced severe adverse events in Japanese patients with inflammatory bowel disease: a multicenter study.

BACKGROUND: Despite NUDT15 variants showing significant association with thiopurine-induced adverse events (AEs) in Asians, it remains unclear which variants of NUDT15 or whether additional genetic variants should be tested to predict AEs. To clarify the best pharmacogenetic test to be used clinically, we performed association studies of NUDT15 variants and haplotypes with AEs, genome-wide association study (GWAS) to discover additional variants, and ROC analysis to select the model to predict severe AEs. METHODS: Overall, 2630 patients with inflammatory bowel disease (IBD) were enrolled and genotyped for NUDT15 codon 139; 1291 patients were treated with thiopurines. diplotypes were analyzed in 970 patients, and GWASs of AEs were performed with 1221 patients using population-optimized genotyping array and imputation. RESULTS: We confirmed the association of NUDT15 p.Arg139Cys with leukopenia and alopecia (p = 2.20E-63, 1.32E-69, OR = 6.59, 12.1, respectively), and found a novel association with digestive symptoms (p = 6.39E-04, OR = 1.89). Time to leukopenia was significantly shorter, and when leukopenia was diagnosed, thiopurine doses were significantly lower in Arg/Cys and Cys/Cys than in Arg/Arg. In GWASs, no additional variants were found to be associated with thiopurine-induced AEs. Despite strong correlation of leukopenia frequency with estimated enzyme activities based on the diplotypes (r2 = 0.926, p = 0.0087), there were no significant differences in the AUCs of diplotypes from those of codon 139 to predict severe AEs (AUC = 0.916, 0.921, for acute severe leukopenia, AUC = 0.990, 0.991, for severe alopecia, respectively). CONCLUSIONS: Genotyping of NUDT15 codon 139 was sufficient to predict acute severe leukopenia and alopecia in Japanese patients with IBD.