Publications by authors named "Yoichi Kakuta"

153 Publications

Thiopurine pharmacogenomics and pregnancy in inflammatory bowel disease.

J Gastroenterol 2021 Jul 21. Epub 2021 Jul 21.

Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, 980-8574, Japan.

The thiopurine drugs azathioprine and 6-mercaptopurine are widely used for the maintenance of clinical remission in steroid-dependent inflammatory bowel disease (IBD). Thiopurines are recommended to be continued throughout pregnancy in IBD patients, but conclusive safety data in pregnant patients remain still insufficient. On the other hand, a strong association between a genetic variant of nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15 p.Arg139Cys) and thiopurine-induced myelotoxicity has been identified. Pharmacokinetic studies have revealed that thiopurine metabolism is altered in pregnant IBD patients and suggested that the fetus may be exposed to the active-thiopurine metabolite, 6-thioguaninetriphosphate, in the uterus. A recent study using knock-in mice harboring the p.Arg138Cys mutation which corresponds to human p.Arg139Cys showed that oral administration of 6-MP at clinical dose induces a severe toxic effect on the fetus harboring the homozygous or heterozygous risk allele. This suggests that NUDT15 genotyping may be required in both women with IBD who are planning pregnancy (or pregnant) and their partner to avoid adverse outcomes for their infant. The risk to the fetus due to maternal thiopurine use is minimal but there are some concerns that are yet to be clarified. In particular, a pharmacogenomic approach to the fetus is considered necessary.
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http://dx.doi.org/10.1007/s00535-021-01805-zDOI Listing
July 2021

A simple prediction score for in-hospital mortality in patients with nonvariceal upper gastrointestinal bleeding.

J Gastroenterol 2021 Jun 18. Epub 2021 Jun 18.

Department of Gastroenterology, Akita University Graduate School of Medicine, Akita, Japan.

Background: No prediction scores for the mortality of both inpatients and outpatients who developed nonvariceal upper gastrointestinal bleeding (UGIB) without endoscopic findings have been established. We aimed to derive and validate a novel prediction score for in-hospital mortality.

Methods: We conducted a three-stage, multicenter retrospective study. In the derivation stage, patients with nonvariceal UGIB at six institutions were enrolled to derive the prediction score by logistic regression analysis. External validation of the score was performed to analyze discrimination by patients at six other institutions. Then the performance of this score was compared with that of four existing scores.

Results: We enrolled 1380 and 825 patients in the derivation and validation cohorts, respectively. A prediction score (CHAMPS-R Score) comprising seven variables (Charlson Comorbidity Index ≥ 2, in-hospital onset, albumin < 2.5 g/dL, altered mental status, Eastern Cooperative Oncology Group performance status ≥ 2, steroids, and rebleeding) with equal-weight scores was established, with high discriminative ability in both derivation and validation cohorts (c statistic, 0.91 and 0.80, respectively). When rebeeding was excluded from the score (an onset model; CHAMPS Score), this score also achieved high discriminative ability (c statistic, 0.90 and 0.81, respectively). The prediction scores had significantly higher discriminative ability than the Glasgow Blatchford Score, AIMS65, ABC Score, and clinical Rockall Score in both cohorts (all, p < 0.05).

Conclusions: We derived and externally validated prediction scores for in-hospital mortality in patients with nonvariceal UGIB. The CHAMPS Score might be optimal for managing such patients. Its mobile application is freely available ( https://apps.apple.com/app/id1565716902 for iOS and https://play.google.com/store/apps/details?id=hatta.CHAMPS for Android).
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http://dx.doi.org/10.1007/s00535-021-01797-wDOI Listing
June 2021

Liquid Biopsy for Colorectal Adenoma: Is the Exosomal miRNA Derived From Organoid a Potential Diagnostic Biomarker?

Clin Transl Gastroenterol 2021 May 12;12(5):e00356. Epub 2021 May 12.

Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Introduction: MicroRNAs (miRNAs) can serve as tumor biomarkers; however, their role in evaluating colorectal adenoma (CRA) is unclear. Recently, the organoid culture system enabled long-term expansion of human colon epithelium. This study aimed to examine the potential of exosomal miRNAs extracted from CRA organoids as biomarkers in the clinical liquid biopsy CRA test.

Methods: We established organoid cultures from normal colon and CRA using resected specimens. Exosomes were isolated from the conditioned medium organoids. MiRNAs were isolated from the exosomes, and their expression profiles were compared using microarray analysis. To identify miRNA candidates for liquid biopsy, we prospectively compared changes in their expression in serum and exosomes before and after endoscopic resection in 26 patients with CRA.

Results: Seven exosomal miRNAs were overexpressed in CRA organoids: miR-4323, miR-4284, miR-1268a, miR-1290, miR-6766-3p, miR-21-5p, and miR-1246. The expression levels of 4 exosomal miRNAs (miR-4323, miR-4284, miR-1290, and miR-1246) and 2 serum miRNAs (miR-1290 and miR-1246) were significantly lower in posttreatment sera. The combined expression of 4 exosomal miRNAs could identify both CRA and large-size (>12.6 cm2) CRA with respective areas under the curve of 0.698 (95% confidence interval [CI] = 0.536-0.823) and 0.834 (95% CI = 0.660-0.929). Combinations of 2-serum miRNA expression values could identify both CRA and large-size CRA with respective area under the curves of 0.691 (95% CI = 0.528-0.817) and 0.834 (95% CI = 0.628-0.938).

Discussion: We found that exosomal miRNAs derived from the CRA organoid culture could be potential diagnostic biomarkers for CRA.
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http://dx.doi.org/10.14309/ctg.0000000000000356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116025PMC
May 2021

Localized intestinal AL amyloidosis detected as bright green using autofluorescence endoscopy.

Clin J Gastroenterol 2021 Jun 26;14(3):815-819. Epub 2021 Apr 26.

Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.

Amyloidosis is classifiable as systemic, with amyloid deposition in organs throughout the body, or localized, involving only one organ. Amyloidosis localized in the intestinal tract is rare. This report describes three cases of localized AL amyloidosis in the intestinal tract and presents their clinical characteristics, endoscopic findings, and prognoses. All three cases were asymptomatic, and were found accidentally during endoscopy for closer examination after a positive fecal occult blood test. Endoscopic findings included patchy redness and meandering dilated vessels of the lesion. Using autofluorescence (AFI) endoscopy, the lesion of amyloid deposition was enhanced as bright green. We used fluorescence microscopy to observe unstained specimens obtained from an amyloid deposition site with excitation light. Autofluorescence was detected with the broad excitation wavelength at amyloid deposition lesion sites of the specimen. Results revealed that AL amyloid has autofluorescence that engenders its detection by AFI endoscopy as bright green. In none of the three cases was systemic amyloidosis or organ failure observed. The long-term course of all the cases was favorable.
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http://dx.doi.org/10.1007/s12328-021-01378-7DOI Listing
June 2021

Long-term endoscopic remission in Crohn's disease after allogeneic hematopoietic stem cell transplantation for diffuse large B cell lymphoma: case report and literature review.

Clin J Gastroenterol 2021 Aug 30;14(4):1108-1114. Epub 2021 Mar 30.

Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.

A 31-year-old man with Crohn's disease in remission after 6-year treatment with infliximab developed nasopharyngeal diffuse large B cell lymphoma. Infliximab was discontinued, and complete remission was achieved following chemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. However, the patient subsequently experienced severely symptomatic Crohn's disease relapse. Therapy with adalimumab was initiated, and the patient attained remission. However, after 3 months, he suffered a recurrence of the lymphoma. Adalimumab was discontinued, and the patient received further chemotherapy (with rituximab, etoposide, cisplatin, methylprednisolone, and high-dose cytarabine) treatment and underwent allogeneic hematopoietic stem cell transplantation. Following the procedure, Crohn's disease and lymphoma have remained in complete remission for 5 years. There are limited reports on Crohn's disease remission after allogeneic hematopoietic stem cell transplantation. Therefore, we present this case report and a review of the existing literature on allogeneic stem cell transplantation for Crohn's disease.
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http://dx.doi.org/10.1007/s12328-021-01389-4DOI Listing
August 2021

Distinct autoantibodies against endothelial protein C receptor in ulcerative colitis.

Gastroenterology 2021 Mar 24. Epub 2021 Mar 24.

Department of Rheumatology, Tohoku University Hospital, Sendai, Japan.

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http://dx.doi.org/10.1053/j.gastro.2021.03.037DOI Listing
March 2021

Comprehensive Analysis of microRNA Profiles in Organoids Derived from Human Colorectal Adenoma and Cancer.

Digestion 2021 Mar 1:1-10. Epub 2021 Mar 1.

Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Introduction: Exosomes are membrane-enclosed nanovesicles, which are increasingly being recognized as important cell communication components for their role in transmitting microRNAs (miRNAs). No previous study has addressed the exosomal miRNA profile in colorectal adenomas (CRAs) because the long-term culture of CRA is challenging. This study aimed to identify the miRNA signature in organoid exosomes derived from human CRA and colorectal cancer (CRC) samples.

Methods: Organoid cultures were developed from resected colorectal tissues of patients with CRA or CRC undergoing surgery or endoscopic mucosal resection. Exosomes were prepared from the conditioned medium of the organoids. miRNAs were prepared from the exosomes and their source organoids. The miRNA expression profiles were compared using microarray analysis. The impact of alteration of miRNA expression on cell proliferation was examined using miRNA mimics or inhibitors in HT-29 human CRC cells.

Results: We established 6 organoid lines from CRC and 8 organoid lines from CRA. Exosomal miRNA signatures were different between the organoids derived from CRA and CRC. Both exosomal and cellular miR-1246 expressions were upregulated in CRC-derived organoids compared to their expression in CRA-derived organoids. Alteration of miR-1246 expression by the miR-1246 mimic or inhibitor increased or decreased cell proliferation in HT-29 cells, respectively.

Conclusions: We report for the first time the miRNA profiles of exosomes in CRA- and CRC-derived organoids. The upregulation of miR-1246 might play a role in increased cell proliferation in the process of CRA-carcinoma transition.
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http://dx.doi.org/10.1159/000513882DOI Listing
March 2021

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

Inflamm Bowel Dis 2021 Jan 27. Epub 2021 Jan 27.

Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, Mitaka, Japan.

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.
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http://dx.doi.org/10.1093/ibd/izab004DOI Listing
January 2021

Capsule Endoscopy Is Useful for Postoperative Tight Control Management in Patients with Crohn's Disease.

Dig Dis Sci 2021 Jan 25. Epub 2021 Jan 25.

Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.

Background: In Crohn's disease, postoperative endoscopic activity of small bowel lesions outside the scope of ileocolonoscopy has been insufficiently studied.

Aims: We aimed to assess this postoperative activity using capsule endoscopy (CE) and analyze the association between treatment optimization based on CE findings and the long-term course.

Methods: In patients who underwent intestinal resection, we performed CE and assessed the endoscopic activity using the Lewis score within 3 months postoperatively (1st CE) and during follow-up. Postoperative treatments were adjusted according to clinical symptoms or CE findings (severity of 1st CE or worsening of follow-up CEs). Hospitalization, repeat surgery, or endoscopic dilation defined the primary outcome.

Results: Among the CE group (N = 48), 85.7% (1st CE) and 79.2% (2nd CE) exhibited endoscopic activities indicating residual or recurrent lesions. Postoperative treatments were adjusted according to clinical symptoms in the non-CE group (N = 57) and clinical symptoms or CE findings in the CE group. Compared to the non-CE group, the CE group had significantly fewer primary outcomes. Patients with treatment adjustments based on CE findings had even lower primary outcome rate. Multivariate analysis identified the CE group as an independent protective factor (hazard ratio = 0.45, 95% confidence interval = 0.20-0.96). Treatment adjustments based on CE findings showed a stronger protective effect (0.30, 0.10-0.75).

Conclusions: Postoperative repeated CE enabled us to assess residual and recurrent lesions accurately before clinical symptoms appeared. The regular assessment of endoscopic activity and subsequent treatment optimization have the potential for improving postoperative course.
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http://dx.doi.org/10.1007/s10620-021-06841-6DOI Listing
January 2021

Long-term efficacy and tolerability of dose-adjusted thiopurine treatment in maintaining remission in inflammatory bowel disease patients with NUDT15 heterozygosity.

Intest Res 2021 Jan 22. Epub 2021 Jan 22.

Department of Gastroenterology and Hematology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.

Background/aims: Thiopurines are key drugs for inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD). Recently, NUDT15 polymorphism (R139C, c.415C > T) has been shown to be associated with thiopurineinduced adverse events in Asian populations. In patients with the C/T genotype, low-dose thiopurine treatment is recommended, but its long-term efficacy and tolerability remain unclear. This study aimed to uncover the long-term efficacy and appropriate dosage of thiopurine for IBD patients with the C/T genotype.

Methods: A total of 210 patients with IBD (103 UC and 107 CD) determined to have NUDT15 R139C variants were enrolled. Clinical data were retrospectively reviewed from medical records.

Results: Of 46 patients (21.9%) with the C/T genotype, 30 patients (65.2%) were treated with thiopurines. Three of whom (10.0%) discontinued thiopurine treatment due to adverse events and 27 of whom continued. The median maintenance dosage of 6-mercaptopurine was 0.25 mg/kg/day (range, 0.19-0.36 mg/kg/day), and 6-thioguanine nucleotides level was 230 (104-298) pmol/8 × 108 red blood cells. Cumulative thiopurine continuation rates for 120 months for patients with the C/C and C/T genotypes were not significantly different (P= 0.895). Cumulative non-relapse rates in the patients with UC treated with thiopurine monotherapy and surgery-free rates in CD patients treated with combination therapy (thiopurines and anti-tumor necrosis factor-α agents) for maintenance remission were not significantly different at 60 months (C/C vs. C/T, P= 0.339 and P= 0.422, respectively).

Conclusions: Low-dose thiopurine treatment is an effective and acceptable treatment for patients with C/T genotype.
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http://dx.doi.org/10.5217/ir.2020.00133DOI Listing
January 2021

Development and validation of a risk score for the prediction of cardiovascular disease in living donor kidney transplant recipients.

Nephrol Dial Transplant 2021 01;36(2):365-374

Department of Medicine and Clinical Science, Kyushu University, Fukuoka, Japan.

Background: Cardiovascular disease (CVD) is a major cause of death in kidney transplant (KT) recipients. To improve their long-term survival, it is clinically important to estimate the risk of CVD after living donor KT via adequate pre-transplant CVD screening.

Methods: A derivation cohort containing 331 KT recipients underwent living donor KT at Kyushu University Hospital from January 2006 to December 2012. A prediction model was retrospectively developed and risk scores were investigated via a Cox proportional hazards regression model. The discrimination and calibration capacities of the prediction model were estimated via the c-statistic and the Hosmer-Lemeshow goodness of fit test. External validation was estimated via the same statistical methods by applying the model to a validation cohort of 300 KT recipients who underwent living donor KT at Tokyo Women's Medical University Hospital.

Results: In the derivation cohort, 28 patients (8.5%) had CVD events during the observation period. Recipient age, CVD history, diabetic nephropathy, dialysis vintage, serum albumin and proteinuria at 12 months after KT were significant predictors of CVD. A prediction model consisting of integer risk scores demonstrated good discrimination (c-statistic 0.88) and goodness of fit (Hosmer-Lemeshow test P = 0.18). In a validation cohort, the model demonstrated moderate discrimination (c-statistic 0.77) and goodness of fit (Hosmer-Lemeshow test P = 0.15), suggesting external validity.

Conclusions: The above-described simple model for predicting CVD after living donor KT was accurate and useful in clinical situations.
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http://dx.doi.org/10.1093/ndt/gfaa275DOI Listing
January 2021

() genotype affects the long-term therapeutic outcomes of anti-TNFα antibodies for Crohn's disease patients.

JGH Open 2020 Dec 1;4(6):1108-1113. Epub 2020 Aug 1.

Division of Gastroenterology, Department of Internal Medicine Tohoku University Graduate School of Medicine Sendai Japan.

Background And Aim: () is a major Crohn's disease (CD) susceptibility gene, especially in the East Asian population, and is also known to be associated with some clinical phenotypes, such as stricturing and penetrating behavior. This study aims to investigate the association between genotype and the long-term therapeutic outcomes of infliximab and adalimumab in Japanese CD patients.

Methods: We investigated 119 biologic-naïve CD patients treated with infliximab or adalimumab. -358C/T (rs6478109) was genotyped as a tag single nucleotide polymorphism (SNP) for CD risk or nonrisk haplotype of (the -358C allele is a risk allele for CD development). We compared the long-term therapeutic outcomes of anti-tumor necrosis factor (TNF) antibodies between the -358C/C group and the C/T+T/T group.

Results: Sixty-nine cases (58.0%) were homozygous for the risk allele ( -358C/C group), and 50 cases (42.0%) were heterozygous for the risk allele or homozygous for the protective allele ( -358C/T+T/T group). No significant differences were found in the cumulative retention rates and the relapse-free survival between the genotypes. However, the surgery-free survival was significantly lower in the -358C/C group than in the C/T+T/T group (log-rank test,  < 0.05). Multivariate analysis showed that -358C/C was identified as an independent risk factor for surgery (hazard ratio, 4.67; 95% confidence interval, 1.39-22.1; = 0.025).

Conclusion: An association was found between the genotype and the therapeutic outcomes of anti-TNF therapy. Our data indicate that the design of customized therapy with anti-TNF antibodies using genomic information could be effective in the future.
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http://dx.doi.org/10.1002/jgh3.12398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7731806PMC
December 2020

Cumulative cancer incidence and mortality after kidney transplantation in Japan: A long-term multicenter cohort study.

Cancer Med 2021 04 13;10(7):2205-2215. Epub 2020 Dec 13.

Department of Urology, Osaka University Graduate School of Medicine, Suita Osaka, Japan.

Kidney transplantation is the most promising treatment to improve mortality and life quality in end-stage kidney disease; however, cancer remains a leading cause of death. Several factors including immunosuppressants might be associated with a gradual increase in cumulative cancer incidence after kidney transplantation. Risk factors for cancer and overall and cancer-specific survival were analyzed in 1973 kidney transplant recipients from three study institutions in Japan. The 5-, 10-, 20-, and 30-year overall and cancer-specific survival rates were 93.3%, 88.4%, 78.0%, and 63.6% and 99.4%, 98.0%, 95.3%, and 91.7%, respectively. The overall survival rate was significantly higher and the graft survival rate was significantly lower in recipients without cancer than in those with cancer. Older recipient age, longer dialysis duration before kidney transplantation, and history of transfusion were significant predictors of cancer. Dialysis duration before kidney transplantation was a prognostic factor of overall survival rate. Regarding cancer-specific survival rates, older recipient age and dialysis duration before kidney transplantation were prognostic factors of worse cancer-specific survival rates. The type of immunosuppressant was not associated with an increased cancer rate. Aggressiveness of immunosuppressant regimens or potent immunosuppressants might improve graft survival rate while inducing de novo cancer after kidney transplantation. Older age and longer dialysis duration before kidney transplantation were risk factors of cancer-specific survival rate.
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http://dx.doi.org/10.1002/cam4.3636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982608PMC
April 2021

Influence of a low-dose tacrolimus protocol on the appearance of de novo donor-specific antibodies during 7 years of follow-up after renal transplantation.

Nephrol Dial Transplant 2021 May;36(6):1120-1129

Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.

Background: Tacrolimus (TAC) is a key immunosuppressant drug for kidney transplantation (KTx). However, the optimal serum trough level of TAC for good long-term outcomes remains unclear. This study aimed to investigate the relationship between the maintenance TAC trough level and the appearance of de novo donor-specific anti-human leukocyte antigen (HLA) antibodies (dnDSAs).

Methods: A total of 584 KTx recipients were enrolled in this study, of whom 164 developed dnDSAs during the follow-up period and 420 did not.

Results: We found no significant relationship between TAC trough level during the follow-up period and dnDSA incidence. Patients who developed dnDSAs had a significantly greater number of HLA-A/B/DR mismatches (3.4 ± 1.3 versus 2.8 ± 1.5; P < 0.001), were more likely to have preformed DSAs (48.2% versus 27.1%; P < 0.001) and showed poor allograft outcome.

Conclusions: There was no clear relationship between TAC trough level and dnDSA incidence for KTx recipients whose TAC trough levels were kept within the narrow range of 4-6 ng/mL during the immunosuppression maintenance period.
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http://dx.doi.org/10.1093/ndt/gfaa258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160958PMC
May 2021

Successful recovery from coronavirus disease 2019 in a living kidney transplant recipient using low-dose methylprednisolone.

IJU Case Rep 2020 Oct 5. Epub 2020 Oct 5.

Department of Urology Osaka General Medical Cancer Osaka City Osaka Japan.

Introduction: The data of immunosuppressive therapy management on solid organ transplant recipients with coronavirus disease 2019 are insufficient. We report a kidney transplant recipient who developed coronavirus disease 2019 pneumonia, with successful management of low-dose mPSL.

Case Presentation: A 36-year-old man, who underwent living kidney transplantation 1.5 year prior, developed fever. After 10 days, he developed dyspnea, and his blood oxygen levels decreased. Computed tomography showed pulmonary ground-glass shadow on both lungs, and the coronavirus disease 2019 real-time polymerase chain reaction test was positive. After reducing the immunosuppressive agents, the C-reactive protein levels continued elevating, and the pulmonary shadow spread. Subsequently, low-dose methylprednisolone (40 mg/day) was administered for 4 days and his C-reactive protein and blood oxygen levels increased and improved, respectively. The coronavirus disease 2019 real-time polymerase chain reaction test was negative and the pulmonary shadow disappeared.

Conclusion: Low-dose methylprednisolone may prevent the development of severe coronavirus disease 2019.
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http://dx.doi.org/10.1002/iju5.12226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675346PMC
October 2020

Efficacy of urgent colonoscopy for colonic diverticular bleeding: A propensity score-matched analysis using a nationwide database in Japan.

J Gastroenterol Hepatol 2021 Jun 20;36(6):1598-1604. Epub 2020 Nov 20.

Division of Gastroenterology, Department of Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.

Background And Aim: Although colonic diverticular bleeding (CDB) is considered to have good prognosis with conservative therapy, some cases are severe. The efficacy of urgent colonoscopy for CDB and clinical factors affecting CDB prognosis are unclear. This study aimed to evaluate the efficacy of urgent colonoscopy for CDB and identify risk factors for unfavorable events, including in-hospital death during admission, owing to CDB.

Methods: We collected CDB patients' data using the Diagnosis Procedure Combination database system. We divided eligible patients into urgent and elective colonoscopy groups using propensity score matching and compared endoscopic hemostasis and in-hospital death rates and length of hospital stay. We also conducted logistic regression analysis to identify clinical factors affecting CBD clinical events, including in-hospital death, a relatively rare CDB complication.

Results: Urgent colonoscopy reduced the in-hospital death rate (0.35% vs 0.58%, P = 0.033) and increased the endoscopic hemostasis rate (3.0% vs 1.7%, P < 0.0001) compared with elective colonoscopy. Length of hospitalization was shorter in the urgent than in the elective colonoscopy group (8 vs 9 days, P < 0.0001). Multivariate analysis also revealed that urgent colonoscopy reduced in-hospital death (odds ratio = 0.67, 95% confidence interval: 0.46-0.97, P = 0.036) and increased endoscopic hemostasis (odds ratio = 1.84, 95% confidence interval: 1.53-2.22, P <  0.0001).

Conclusion: Urgent colonoscopy for CDB may facilitate identification of the bleeding site and reduce in-hospital death. The necessity and appropriate timing of urgent colonoscopy should be considered based on patients' condition.
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http://dx.doi.org/10.1111/jgh.15316DOI Listing
June 2021

Factors Associated with Fibrosis during Colorectal Endoscopic Submucosal Dissection: Does Pretreatment Biopsy Potentially Elicit Submucosal Fibrosis and Affect Endoscopic Submucosal Dissection Outcomes?

Digestion 2021 31;102(4):590-598. Epub 2020 Aug 31.

Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Background: Submucosal fibrosis observed during colorectal endoscopic submucosal dissection (ESD) is an important factor related to incomplete resection. Biopsy is generally accepted as having the potential to elicit submucosal fibrosis, but few reports have presented definitive proof. This study investigated the relation between submucosal fibrosis and colorectal ESD outcomes and assessed factors related to fibrosis, including pretreatment biopsy.

Methods: After reviewing 369 records of colorectal ESD performed between January 2011 and December 2016, we assessed the relation between fibrosis and ESD outcomes. Multiple logistic regression analysis revealed fibrosis risk factors.

Results: Severe fibrosis was related significantly to ESD outcomes such as the mean procedure time (p < 0.001), en bloc resection rate (p < 0.001), and R0 resection rate (p = 0.011). Multivariate analyses indicated residual lesions (ORs 175.4, p < 0.001), pretreatment biopsy (ORs 8.30, p = 0.002), nongranular-type laterally spreading tumors (LST-NG; ORs 5.86, p = 0.025), and invasive carcinoma (ORs 5.83, p = 0.03) as independent risk factors of severe fibrosis. In each macroscopic type, LST-NG was more strongly related to fibrosis induced by pretreatment than granular-type laterally spreading tumors with adjust ORs of 50.8 and 4.69.

Conclusions: Pretreatment biopsy causes submucosal fibrosis resulting in prolonged procedure times and incomplete resection. These findings suggest important benefits of avoiding biopsy before ESD.
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http://dx.doi.org/10.1159/000510145DOI Listing
August 2020

Repertoire analysis of memory T-cell receptors in Japanese patients with inflammatory bowel disease.

JGH Open 2020 Aug 6;4(4):624-631. Epub 2020 Feb 6.

Division of Gastroenterology Tohoku University Graduate School of Medicine Sendai Japan.

Background And Aim: The T-cell receptor (TCR) repertoire was assessed in response to various antigens and was considered to be associated with the pathogenesis of inflammatory bowel disease (IBD). Thus, we performed TCR repertoire analysis to examine the pathology of IBD from changes in the TCR repertoire of memory T cells in the intestinal lamina propria mononuclear cells (LPMCs) and peripheral blood mononuclear cells (PBMCs) of patients with IBD.

Methods: LPMCs in the surgical specimens and PBMCs were isolated from 12 patients with IBD (5 patients with ulcerative colitis [UC] and 7 patients with Crohn's disease [CD]). PBMCs were collected from 10 healthy individuals as controls. Comprehensive TCR sequence analyses of adaptor-ligation polymerase chain reaction (PCR) products were performed using MiSeq.

Results: The diversity of TCR-α and TCR-β in PBMCs was significantly lower in patients with IBD than that in controls ( = 0.00084 and 0.0013, respectively). Comparisons of TCR diversity in LPMCs and PBMCs between CD and UC showed that the diversity in LPMC was not affected by diseases, whereas that in PBMCs was significantly lower in CD than in UC ( = 0.045 and 0.049, respectively). Some TCR clones may have shown a specific increase or decrease in CD and UC, and many clones were common to both LPMCs and PBMCs in the same patients.

Conclusion: The diversity of TCR clones in LPMCs and PBMCs in patients with IBD was significantly lower than that of PBMCs in controls. TCR diversity in PBMCs was particularly low in patients with CD.
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http://dx.doi.org/10.1002/jgh3.12305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411559PMC
August 2020

Possible abscopal effect in urothelial carcinoma of the upper urinary tract after treatment with immune checkpoint inhibitors.

IJU Case Rep 2020 Jan 3;3(1):25-27. Epub 2019 Dec 3.

Department of Urology Tokyo Women's Medical University Tokyo Japan.

Introduction: Regression of non-irradiated metastatic lesions after radiation therapy is known as the abscopal effect. We report a case of urothelial carcinoma in which the abscopal effect was possibly observed after immune checkpoint inhibitor administration.

Case Presentation: A 68-year-old woman diagnosed with left renal pelvic cancer underwent total nephroureterectomy and regional lymph node dissection. Eight months later, imaging studies detected local recurrence and paraaortic lymph node metastasis. The tumor progressed despite cisplatin + gemcitabine, pembrolizumab, and gemcitabine + docetaxel therapy. Radiation therapy was administered to a painful back lesion, which resulted in dramatic symptom relief. Computed tomography 2 months after radiation therapy indicated reduced size of the irradiated lesion and some non-irradiated lymph nodes.

Conclusion: Combined radiation therapy and immune checkpoint inhibitors can provide additional benefits for certain cancers, possibly due to negative immunomodulatory response blockade. Thus, this combined therapy may be a new metastatic urothelial carcinoma treatment strategy.
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http://dx.doi.org/10.1002/iju5.12133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292173PMC
January 2020

An Integrated Genomic and Transcriptomic Analysis Reveals Candidates of Susceptibility Genes for Crohn's Disease in Japanese Populations.

Sci Rep 2020 06 24;10(1):10236. Epub 2020 Jun 24.

Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Expression quantitative trait locus (eQTL) analyses have enabled us to predict the function of disease susceptibility SNPs. However, eQTL for the effector memory T cells (TEM) located in the lamina propria mononuclear cells (LPMCs), which play an important role in Crohn's disease (CD), are not yet available. Thus, we conducted RNA sequencing and eQTL analyses of TEM cells located in the LPMCs from IBD patients (n = 20). Genome-wide association study (GWAS) was performed using genotyping data of 713 Japanese CD patients and 2,063 controls. We compared the results of GWAS and eQTL of TEM, and also performed a transcriptome-wide association study using eQTL from Genotype Tissue Expression project. By eQTL analyses of TEM, correlations of possible candidates were confirmed in 22,632 pairs and 2,463 genes. Among these candidates, 19 SNPs which showed significant correlation with tenascin-XA (TNXA) expression were significantly associated with CD in GWAS. By TWAS, TNFSF15 (FDR = 1.35e-13) in whole blood, ERV3-1 (FDR = 2.18e-2) in lymphocytes, and ZNF713 (FDR = 3.04e-2) in the sigmoid colon was significantly associated with CD. By conducting integration analyses using GWAS and eQTL data, we confirmed multiple gene transcripts are involved in the development of CD.
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http://dx.doi.org/10.1038/s41598-020-66951-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314801PMC
June 2020

Significance of revised criteria for chronic active T cell-mediated rejection in the 2017 Banff classification: Surveillance by 1-year protocol biopsies for kidney transplantation.

Am J Transplant 2021 01 13;21(1):174-185. Epub 2020 Jul 13.

Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Diagnostic criteria for chronic active T cell-mediated rejection (CA-TCMR) were revised in the Banff 2017 consensus, but it is unknown whether the new criteria predict graft prognosis of kidney transplantation. We enrolled 406 kidney allograft recipients who underwent a 1-year protocol biopsy (PB) and investigated the diagnostic significance of Banff 2017. Interobserver reproducibility of the 3 diagnosticians showed a substantial agreement rate of 0.68 in Fleiss's kappa coefficient. Thirty-three patients (8%) were classified as CA-TCMR according to Banff 2017, and 6 were previously diagnosed as normal, 12 as acute TCMR, 10 with borderline changes, and 5 as CA-TCMR according to Banff 2015 criteria. Determinant factors of CA-TCMR were cyclosporine use (vs tacrolimus), previous acute rejection, and BK polyomavirus-associated nephropathy. In survival analysis, the new diagnosis of CA-TCMR predicted a composite graft endpoint defined as doubling serum creatinine or death-censored graft loss (log-rank test, P < .001). In multivariate analysis, CA-TCMR was associated with the second highest risk of the composite endpoint (hazard ratio: 5.42; 95% confidence interval, 2.02-14.61; P < .001 vs normal) behind antibody-mediated rejection. In conclusion, diagnosis of CA-TCMR in Banff 2017 may facilitate detecting an unfavorable prognosis of kidney allograft recipients who undergo a 1-year PB.
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http://dx.doi.org/10.1111/ajt.16093DOI Listing
January 2021

Therapeutic Effects and Functional Mechanism of Intravenous Immunoglobulin in Preclinical Rat Renal Transplant Model of Antibody-Mediated Rejection.

Transplant Proc 2020 Jul - Aug;52(6):1901-1905. Epub 2020 May 1.

Department of Urology, Osaka University Graduate School of Medicine, Osaka, Japan.

Background: Intravenous immunoglobulin (Ig) therapy is used based on empirical findings for treatment of antibody-mediated rejection (AMR) in cases of renal transplantation, although its therapeutic efficacy has not been proven and the functional mechanism of an administered Ig remains elusive. In this study, the therapeutic effects of an Ig were examined in a preclinical rat renal transplant model of AMR to investigate this mechanism.

Methods: To establish an AMR renal graft model, skin graft specimens were obtained from Brown-Norway (BN) rats and transplanted to Lewis rats to produce donor-specific antibodies (DSAs), after which kidney transplantation from the Brown-Norway to Lewis rats was performed. AMR model rats were administered the Ig at a dose of 2 g/kg or saline as a control. Survival period, renal graft histopathology, complement factors, and DSA levels were assessed.

Results: The survival period of the group administered the Ig was significantly prolonged. Histopathological examinations of renal grafts also showed significant suppression of glomerulitis and peritubular capillaritis in the Ig group, and real-time polymerase chain reaction analysis results demonstrated significantly lower levels of expression of the complement factors C1q and C3. When the Ig was given to rats that underwent skin grafting but not renal transplantation, DSA was decreased after 6 hours and remained lower than the baseline level for at least 7 days.

Conclusion: Ig administration suppressed DSA production. The present results showed that suppression of the complement system contributed to effective Ig treatment for AMR.
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http://dx.doi.org/10.1016/j.transproceed.2020.01.137DOI Listing
November 2020

Prognostic impact of sarcopenia in patients with metastatic hormone-sensitive prostate cancer.

Jpn J Clin Oncol 2020 Aug;50(8):933-939

Department of Urology, Kidney Center, Tokyo Women's Medical University, Tokyo, Japan.

Background: Cancer cachexia is associated with a poor prognosis. This study aimed to investigate the association between sarcopenia and survival in patients with metastatic hormone-sensitive prostate cancer.

Methods: We retrospectively evaluated 197 patients diagnosed with metastatic hormone-sensitive prostate cancer in our department and its affiliated institution between January 2008 and December 2015. Sarcopenia was diagnosed according to the sex-specific consensus definition. Castration-resistance prostate cancer-free survival, cancer-specific survival and overall survival from the metastatic hormone-sensitive prostate cancer diagnoses were calculated using the Kaplan-Meier method and compared using the log-rank test. Risk factors affecting the survival outcomes were analyzed using the Cox proportional regression analysis.

Results: In total, 163 patients (82.7%) had sarcopenia. Cancer-specific survival and overall survival were significantly shorter in sarcopenic patients than in non-sarcopenic patients (median cancer-specific survival: 77.0 months vs. not reached, P = 0.0099; overall survival: 72.0 months vs. not reached, P = 0.0465), whereas castration-resistance prostate cancer-free survival did not significantly differ between the groups (P = 0.6063). Multivariate analyses showed that sarcopenia was an independent factor for cancer-specific survival (hazard ratio: 2.18, P = 0.0451), together with the Gleason score (hazard ratio: 1.87, P = 0.0272) and LATITUDE risk classification (hazard ratio: 2.73, P = 0.0008). Moreover, the prognostic association of sarcopenia was remarkable in patients aged <73.0 years (cancer-specific survival: 82.0 months vs. not reached, P = 0.0027; overall survival: 72.0 months vs. not reached, P = 0.0078 in sarcopenic vs. non-sarcopenic patients), whereas the association was not significant in patients aged ≥73.0 years (cancer-specific survival: 76.0 and 75.0 months, respectively, P = 0.7879; overall survival: 67.0 and 52.0 months, respectively, P = 0.7263).

Conclusion: Sarcopenia was an independent risk factor of cancer-specific survival in patients with metastatic hormone-sensitive prostate cancer, especially in younger patients.
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http://dx.doi.org/10.1093/jjco/hyaa045DOI Listing
August 2020

Rare Genotype of His/His in NUDT15 Codon 139 and Thiopurine-associated Adverse Events in a Case of Ulcerative Colitis.

Intern Med 2020 Jul 9;59(13):1611-1613. Epub 2020 Apr 9.

Division of Gastroenterology, Niigata University Medical and Dental Hospital, Japan.

Thiopurine drugs are commonly used to treat immunologic diseases. However, the narrow therapeutic safety margin demands evidence-based precision medicine approaches. NUDT15 variants are associated with thiopurine-induced adverse events, particularly in Asians. We herein report a rare genotype of His/His in NUDT15 codon 139 in a case of ulcerative colitis and review the relevant literature. The patient experienced severe thiopurine-associated adverse events, including leukopenia and alopecia. There is no literature on the His/His genotype in NUDT15 codon 139, and our case suggests cautious use or the contraindication of thiopurines for patients with this genotype.
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http://dx.doi.org/10.2169/internalmedicine.4261-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402964PMC
July 2020

Long-Term Prognosis of Japanese Patients with Crohn's Disease Treated by Switching Anti-Tumor Necrosis Factor-α Antibodies.

Inflamm Intest Dis 2020 Feb 20;5(1):11-19. Epub 2019 Dec 20.

Division of Gastroenterology, Department of Internal Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan.

Introduction: The long-term prognosis of Japanese patients with Crohn's disease (CD) treated by switching anti-tumor necrosis factor-α (anti-TNFα) antibodies remains unclear.

Objective: This study aimed to clarify the long-term prognosis and clinical factors that affect the long-term prognosis and outcomes of such patients.

Methods: This retrospective, observational, single-center cohort study analyzed Japanese patients with CD treated by switching between infliximab and adalimumab in the Tohoku University Hospital between March 2003 and December 2017. Cumulative relapse-free survival and cumulative surgery-free survival rates were analyzed using the Kaplan-Meier method. Clinical factors that affected the long-term outcomes were identified using both a log-rank test and the Cox proportional hazards model.

Results: The cumulative relapse-free survival rates were 68.6, 33.7, and 22.9% at 1, 3, and 5 years, respectively. The surgery-free survival rates were 91.7, 75.7, and 57.4% at 1, 3, and 5 years, respectively. The cumulative relapse-free survival rate was significantly higher in the group with ileal lesions (HR = 0.12; 95% CI 0.0066-0.64, = 0.0086), stricture (HR = 0.24; 95% CI 0.0094-0.59, = 0.0021), and a penetrating type (HR = 0.34; 95% CI 0.14-0.84, = 0.020). Intolerance (HR = 0.29; 95% CI 0.12-0.63, = 0.0013) and switching after surgery (HR = 0.41; 95% CI 0.17-0.87, = 0.019) were clinical factors that reduced the risk of recurrence. The cumulative surgery-free survival rate was significantly higher in the group that switched after surgery (HR = 0.28; 95% CI 0.074-0.91, = 0.034) and used concomitant thiopurine (HR = 0.32; 95% CI 0.10-0.90, = 0.030).

Conclusion: We should clarify the reason for switching anti-TNFα antibodies and investigate bowel complications before switching. Surgical reset of bowel complications including stricture and fistula could reduce the risk of recurrence after switching anti-TNFα antibodies. Concomitant thiopurine administration might reduce the risk of bowel surgery after switching anti-TNFα antibodies.
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http://dx.doi.org/10.1159/000504803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098278PMC
February 2020

Impact of donor-related arteriosclerosis in pretransplant biopsy on long-term outcome of living-kidney transplantation: A propensity score-matched cohort study.

Int J Urol 2020 May 11;27(5):423-430. Epub 2020 Mar 11.

Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.

Objectives: To compare the long-term outcome and complications of living-kidney grafts with arteriosclerosis to those without abnormal findings diagnosed using pretransplant graft biopsy, and to assess the impact of the arteriosclerosis in living-donor kidneys.

Methods: The influence of arteriosclerosis in pretransplant biopsy on long-term outcomes and complications was evaluated in both unmatched (n = 1351, without arteriosclerosis n = 788 vs with arteriosclerosis n = 563) and propensity score-matched cohorts (n = 984, without arteriosclerosis n = 492 vs with arteriosclerosis n = 492) of adults who underwent living-kidney transplant.

Results: In both the unmatched and matched cohort, there was no significant difference in patient and death-censored graft survival at 10 years between the without arteriosclerosis and with arteriosclerosis groups. The with arteriosclerosis group had a higher incidence rate of overall rejection than did the without arteriosclerosis group in both the unmatched (P = 0.026) and matched (P = 0.060) cohorts. The with arteriosclerosis group had significantly higher chronic antibody-mediated rejection than did the without arteriosclerosis group (P = 0.006) in the unmatched cohort. The with arteriosclerosis group had a significantly lower estimated glomerular filtration rate in recipients, but there was no significant difference after matching. The incidence rates of calcineurin inhibitor nephrotoxicity and post-transplant anemia were significantly higher in the with arteriosclerosis group than in the without arteriosclerosis group in both the unmatched and matched cohorts. Long-term postoperative kidney function of living donors was lower in the with arteriosclerosis group.

Conclusions: Kidney graft with arteriosclerosis might affect the incidence of rejection, complications and postoperative kidney function of donors. Long-term careful observation is required for both the recipients who received grafts with arteriosclerosis and the donors who had kidneys with arteriosclerosis.
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http://dx.doi.org/10.1111/iju.14212DOI Listing
May 2020

[Pretreatment screening for inflammatory bowel diseases;significance and problems in genotyping of NUDT15].

Nihon Shokakibyo Gakkai Zasshi 2020;117(3):195-207

Division of Gastroenterology, Tohoku University Graduate School of Medicine.

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http://dx.doi.org/10.11405/nisshoshi.117.195DOI Listing
May 2020

Identification of two major autoantigens negatively regulating endothelial activation in Takayasu arteritis.

Nat Commun 2020 03 9;11(1):1253. Epub 2020 Mar 9.

Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan.

The presence of antiendothelial cell antibodies (AECAs) has been documented in Takayasu arteritis (TAK), a chronic granulomatous vasculitis. Here, we identify cell-surface autoantigens using an expression cloning system. A cDNA library of endothelial cells is retrovirally transfected into a rat myeloma cell line from which AECA-positive clones are sorted with flow cytometry. Four distinct AECA-positive clones are isolated, and endothelial protein C receptor (EPCR) and scavenger receptor class B type 1 (SR-BI) are identified as endothelial autoantigens. Autoantibodies against EPCR and SR-BI are detected in 34.6% and 36.5% of cases, respectively, with minimal overlap (3.8%). Autoantibodies against EPCR are also detected in ulcerative colitis, the frequent comorbidity of TAK. In mechanistic studies, EPCR and SR-BI function as negative regulators of endothelial activation. EPCR has also an effect on human T cells and impair Th17 differentiation. Autoantibodies against EPCR and SR-BI block the functions of their targets, thereby promoting pro-inflammatory phenotype.
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http://dx.doi.org/10.1038/s41467-020-15088-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062749PMC
March 2020

Robot-Assisted Radical Cystectomy With Orthotopic Neobladder as a Urinary Diversion for a Kidney Transplant Recipient: A Case Report.

Transplant Proc 2020 Mar 19;52(2):608-613. Epub 2020 Feb 19.

Department of Urology, Tokyo Women's Medical University, Tokyo, Japan.

Background: A higher prevalence of bladder cancer is reported in solid organ recipients, and advanced cancer requires radical cystectomy combined with urinary diversion. Surgery is technically challenging in kidney transplant recipients because of urinary tract abnormalities. Here, we describe the use of a robot-assisted approach in a kidney transplant recipient.

Case Presentation: The etiology of the patient's end-stage renal disease was bilateral hypoplastic kidney. The patient started to receive hemodialysis at 19 years of age and underwent living-related kidney transplant at 23 years of age. Thirteen years later, he was diagnosed with invasive urothelial carcinoma and underwent robot-assisted radical cystectomy with extracorporeal neobladder construction under open laparotomy. Surgery was indicated to enhance suture flexibility and dissection of the peribladder tissues. Although the patient had an intraperitoneal infection caused by leakage from the vesicourethral anastomosis site and required drainage of the abscess, his condition stabilized after antibiotic treatment.

Conclusion: This case outlines the effectiveness of the robot-assisted approach in patients with urinary tract abnormalities, such as kidney transplant recipients.
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http://dx.doi.org/10.1016/j.transproceed.2019.12.002DOI Listing
March 2020

Genetic Analysis of Ulcerative Colitis in Japanese Individuals Using Population-specific SNP Array.

Inflamm Bowel Dis 2020 07;26(8):1177-1187

Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.

Background: To clarify the genetic background of ulcerative colitis (UC) in the Japanese population, we conducted a genome-wide association study (GWAS) using a population-specific single nucleotide polymorphism (SNP) array.

Methods: We performed a GWAS and replication study including 1676 UC patients and 2381 healthy controls. The probability of colectomy was compared between genotypes of rs117506082, the top hit SNP at HLA loci, by the Kaplan-Meier method. We studied serum expression of miR-622, a newly identified candidate gene, from 32 UC patients and 8 healthy controls by quantitative reverse-transcription polymerase chain reaction.

Results: In the GWAS, only the HLA loci showed genome-wide significant associations with UC (rs117506082, P = 6.69E-28). Seven nominally significant regions included 2 known loci, IL23R (rs76418789, P = 6.29E-7) and IRF8 (rs16940202, P = 1.03E-6), and 5 novel loci: MIR622 (rs9560575, P = 8.23E-7), 14q31 (rs117618617, P = 1.53E-6), KAT6B (rs12260609, P = 1.81E-6), PAX3-CCDC140-SGPP2 (rs7589797, P = 2.87E-6), and KCNA2 (rs118020656, P = 4.01E-6). Combined analysis revealed that IL23R p.G149R (rs76418789, P = 9.03E-11; odds ratio [OR], 0.51) had genome-wide significant association with UC. Patients with GG genotype of rs117506082 had a significantly lower probability of total colectomy than those with the GA+AA genotype (P = 1.72E-2). Serum expression of miR-622 in patients with inactive UC tended to be higher than in healthy controls and patients with active UC (inactive UC vs healthy controls, P = 3.03E-02; inactive UC vs active UC, P = 6.44E-02).

Conclusions: IL23R p.G149R is a susceptibility locus for UC in Japanese individuals. The GG genotype of rs117506082 at HLA loci may predict a better clinical course.
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http://dx.doi.org/10.1093/ibd/izaa033DOI Listing
July 2020