Efficacy of Dose Escalation of Oral 5-Aminosalicylic Acid for Ulcerative Colitis With a Mayo Endoscopic Subscore of 1: An Open Label Randomized Controlled Trial.

BACKGROUND: Endoscopic healing is generally defined as Mayo endoscopic subscore (MES) ≤1 in ulcerative colitis (UC). However, patients with an MES of 1 are at higher relapse risk than those with an MES of 0. This study evaluated the therapeutic efficacy of proactive dose escalation of oral 5-aminosalicylic acid (5-ASA) in UC patients with an MES of 1. METHODS: An open-label, randomized controlled trial was conducted in 5 hospitals between 2018 and 2022. Ulcerative colitis patients in clinical remission under oral 5-ASA therapy and diagnosed as having an MES of 1 were enrolled. Patients receiving maintenance therapy other than 5-ASA and immunomodulator were excluded. Patients were randomly assigned in a 1:1 ratio to receive either a dose-escalated (intervention) or constant dose (control) of 5-ASA. Concomitant immunomodulator was used as the stratification factor in the randomization. The primary end point was relapse within 1 year. The subgroup analysis was stratified for the use of immunomodulators. RESULTS: The full analysis set included 79 patients (39 intervention and 40 control). Immunomodulators were used in 20 (25.3%) patients. Relapse was less in the intervention group (15.4%) than the control group (37.5%; P = .026). In the subgroup with concomitant immunomodulators, relapse was also less in the intervention group (10.0%) than the control group (70.0%; P = .020). In patients without immunomodulators, the difference was not significant between 2 groups (intervention, 17.2%; control, 26.7%; P = .53). CONCLUSIONS: Dose escalation of 5-ASA reduced relapse within 1 year in UC patients in clinical remission with an MES of 1.

Dose escalation of 5-aminosalicylic acid for ulcerative colitis reduced relapse rate in patients in clinical remission with a Mayo endoscopic subscore of 1. The therapeutic efficacy was more evident in those whom immunomodulators were used.

Clinical outcomes of patients with remitting ulcerative colitis after discontinuation of indigo naturalis.

Indigo naturalis is an effective treatment for ulcerative colitis. However, long-term use of indigo naturalis causes adverse events, such as pulmonary hypertension. The natural history of patients with ulcerative colitis who discontinued indigo naturalis after induction therapy is unknown. Moreover, the clinical features of patients who relapsed within 52 weeks after the discontinuation of indigo naturalis are unclear. This study aimed to assess the clinical outcomes of patients with ulcerative colitis after discontinuation of indigo naturalis and to identify potential markers responsible for relapse. This single-center retrospective study investigated the follow-up of 72 patients who achieved a clinical response 8 weeks after indigo naturalis treatment. We observed relapse in patients with ulcerative colitis after the discontinuation of indigo naturalis. We analyzed the factors predicting long-term outcomes after discontinuation of indigo naturalis. Relapse was observed in 24%, 57%, and 71% of patients at 8, 26, and 52 weeks, respectively. There were no predictive markers in patients who relapsed within 52 weeks after the discontinuation of indigo naturalis. The ulcerative colitis relapse rate after indigo naturalis discontinuation was high. Follow-up treatment is required after the discontinuation of indigo naturalis in patients with ulcerative colitis.

Gastrointestinal symptoms in COVID-19 and disease severity: a Japanese registry-based retrospective cohort study.

BACKGROUND: Research on whether gastrointestinal symptoms correlate with the severity of Coronavirus Disease 2019 (COVID-19) has been inconclusive. This study aimed to clarify any associations between gastrointestinal symptoms and the prognosis of COVID-19. METHODS: We collected data from the Japanese nationwide registry for COVID-19 to conduct a retrospective cohort study. Data from 3498 Japanese COVID-19 patients, diagnosed at 74 facilities between February 2020 and August 2022, were analyzed in this study. Hospitalized patients were followed up until discharge or transfer to another hospital. Outpatients were observed until the end of treatment. Associations between gastrointestinal symptoms and clinical outcomes were investigated using multivariable-adjusted logistic regression models. RESULTS: The prevalence of diarrhea, nausea/vomiting, abdominal pain, and melena were 16.6% (581/3498), 8.9% (311/3498), 3.5% (121/3498), and 0.7% (23/3498), respectively. In the univariable analysis, admission to intensive care unit (ICU) and requirement for mechanical ventilation were less common in patients with diarrhea than those without (ICU, 15.7% vs. 20.6% (p = 0.006); mechanical ventilation, 7.9% vs. 11.4% (p = 0.013)). In the multivariable-adjusted analysis, diarrhea was associated with lower likelihood of ICU admission (adjusted odds ratio (aOR), 0.70; 95% confidence interval (CI), 0.53-0.92) and mechanical ventilation (aOR, 0.61; 95% CI, 0.42-0.89). Similar results were obtained in a sensitivity analysis with another logistic regression model that adjusted for 14 possible covariates with diarrhea (ICU; aOR, 0.70; 95% CI, 0.53-0.93; mechanical ventilation; aOR 0.62; 95% CI, 0.42-0.92). CONCLUSIONS: Diarrhea was associated with better clinical outcomes in COVID-19 patients.

Medical treatment selection and outcomes for hospitalized patients with severe ulcerative colitis as defined by the Japanese criteria.

BACKGROUND: Hospitalization for ulcerative colitis (UC) is potentially life-threatening. Severe disease in the Japanese criteria which modifies the Truelove-Witts' criteria might encompass more fulminant cases than the definition for acute severe UC. However, few studies have investigated the predictive factors for clinical remission (CR) after medical treatments for severe hospitalized patients by Japanese criteria. METHODS: Medical treatment selection, CR rates, and factors contributing to CR on day 14 were assessed in severe patients by Japanese criteria. We also investigated whether the reduction rate in patient-reported outcome 2 (PRO2) on day 3 could predict short-term prognosis. RESULTS: Eighty-five severe hospitalized patients were selected. Corticosteroids, tacrolimus, and infliximab were mainly selected as first-line treatments (76/85; 89.4%). The CR rates on day 14 were 26.8%, 21.4%, and 33.3% in patients receiving corticosteroids, tacrolimus, and infliximab, respectively. Extensive disease (odds ratio [OR] 0.022; 95% confidence interval [CI] 0.002-0.198), higher PRO2 (OR 0.306; 95% CI 0.144-0.821), and higher reduction rate in PRO2 on day 3 (OR 1.047; 95% CI 1.019-1.075) were independent factors predicting CR on day 14. If the cutoff value for the reduction rate in PRO2 on day 3 was 18.3%, sensitivity was 0.714 and specificity was 0.731 to predict CR on day 14. A higher reduction rate in PRO2 on day 3 (OR 0.922; 95% CI 0.853-0.995) was a negative factor to predict surgery within 28 days. CONCLUSIONS: Tacrolimus and infliximab in addition to corticosteroids were used as first-line treatment in severe hospitalized patients. PRO2 on day 3 is a useful marker for switching to second-line therapy or colectomy.

Characteristics of flat-type ulcerative colitis-associated neoplasia on chromoendoscopic imaging with indigo carmine dye spraying.

OBJECTIVES: Despite recent advances in endoscopic equipment and diagnostic techniques, early detection of ulcerative colitis-associated neoplasia (UCAN) remains difficult because of the complex background of the inflamed mucosa of ulcerative colitis and the morphologic diversity of the lesions. We aimed to describe the main diagnostic patterns for UCAN in our cohort, including lateral extension surrounding flat lesions. METHODS: Sixty-three lesions in 61 patients with flat-type dysplasia that were imaged with dye chromoendoscopy (DCE) were included in this analysis. These DCE images were analyzed to clarify the dye-chromoendoscopic imaging characteristics of flat dysplasia, and the lesions were broadly classified into dysplastic and nondysplastic mucosal patterns. RESULTS: Dysplastic mucosal patterns were classified into two types: small round patterns with round to roundish structures, and mesh patterns with intricate mesh-like structures. Lesions with a nondysplastic mucosal pattern were divided into two major types: a ripple-like type and a gyrus-like type. Of note, 35 lesions (55.6%) had a small round pattern, and 51 lesions (80.9%) had some type of mesh pattern. About 70% of lesions with small round patterns and 49% of lesions with mesh patterns were diagnosed as high-grade dysplasia or carcinoma, while about 30% of lesions with small round patterns and 51% of lesions with mesh patterns were diagnosed as low-grade dysplasia. CONCLUSION: When a characteristic mucosal pattern, such as a small round or mesh pattern, is found by DCE, the possibility of UCAN should be considered.

Real-world efficacy and safety of advanced therapies in hospitalized patients with ulcerative colitis.

BACKGROUND: This multicenter observational cohort study aimed to evaluate the utilization and short-term efficacy of advanced therapy (AT) in hospitalized patients with acute severe ulcerative colitis (ASUC). METHODS: In total, 221 patients with ASUC were enrolled between August 2020 and July 2021. The primary endpoint was clinical remission (CR, defined as a patient-reported outcome score < 2 with no blood in the stool) rate on Day 7 and 14 in hospitalized patients who received corticosteroids (CS) and AT. RESULTS: Among patients with ASUC, 120 and 101 patients received CS or any AT as first-line treatment, respectively. The CR rates on Day 7 and 14 were 22.5% and 35.0%, respectively, in hospitalized patients who received CS as first-line treatment. Most patients who used ATs had CS-dependent or frequent recurrences. Eight different ATs (apheresis, tacrolimus, infliximab, golimumab, tofacitinib, vedolizumab, ustekinumab, and cyclosporine) were used as first-line treatment in patients with ASUC, and the CR rates on Day 7 and 14 were 16.8% and 29.7%, respectively. Twenty-five patients received the second ATs after hospitalizations, and the CR rates on Day 7 and 14 were 0% and 12%, respectively. The CR rates on Day 14 were significantly higher in patients who changed to AT than in those whose dose of CS increased (34.0% vs 10.7%, p = 0.020) among patients who had already used CS before hospitalization. CONCLUSION: Most first-use ATs were effective for patients with ASUC, while second-use ATs might have had limited benefits in inducing CR. These findings may contribute to considerations for the management of hospitalized patients.

Evolutionary histories of breast cancer and related clones.

Recent studies have documented frequent evolution of clones carrying common cancer mutations in apparently normal tissues, which are implicated in cancer development1-3. However, our knowledge is still missing with regard to what additional driver events take place in what order, before one or more of these clones in normal tissues ultimately evolve to cancer. Here, using phylogenetic analyses of multiple microdissected samples from both cancer and non-cancer lesions, we show unique evolutionary histories of breast cancers harbouring der(1;16), a common driver alteration found in roughly 20% of breast cancers. The approximate timing of early evolutionary events was estimated from the mutation rate measured in normal epithelial cells. In der(1;16)(+) cancers, the derivative chromosome was acquired from early puberty to late adolescence, followed by the emergence of a common ancestor by the patient's early 30s, from which both cancer and non-cancer clones evolved. Replacing the pre-existing mammary epithelium in the following years, these clones occupied a large area within the premenopausal breast tissues by the time of cancer diagnosis. Evolution of multiple independent cancer founders from the non-cancer ancestors was common, contributing to intratumour heterogeneity. The number of driver events did not correlate with histology, suggesting the role of local microenvironments and/or epigenetic driver events. A similar evolutionary pattern was also observed in another case evolving from an AKT1-mutated founder. Taken together, our findings provide new insight into how breast cancer evolves.

Risk of venous thromboembolism with a central venous catheter in hospitalized Japanese patients with inflammatory bowel disease: a propensity score-matched cohort study.

BACKGROUND/AIMS: Thromboprophylaxis is recommended for hospitalized patients with inflammatory bowel disease (IBD) in Western countries, although it is selectively administered to high-risk patients in East Asia. A central venous catheter (CVC) is commonly placed in patients with IBD. Although CVC placement is considered a risk factor for venous thromboembolism (VTE), the degree of increased risk in patients with IBD is uncertain. This study aimed to identify the risk of VTE with CVC placement in hospitalized Japanese patients with IBD without thromboprophylaxis. METHODS: This retrospective cohort study included patients with ulcerative colitis or Crohn's disease who were admitted for disease flares at Keio University Hospital between January 2016 and December 2020. Patients who already had thrombosis or were administered any antithrombotic treatment on admission were excluded. VTE development during the hospitalization was surveyed, and VTE risk associated with CVC indwelling was estimated using propensity score matching and inverse probability of treatment weighting analyses. RESULTS: Altogether, 497 hospitalized patients with IBD (ulcerative colitis, 327; Crohn's disease, 170) were enrolled. VTE developed in 9.30% (12/129) of catheterized patients and in 0.82% (3/368) of non-catheterized patients. The propensity score matching yielded 127 matched pairs of patients. The catheterized group demonstrated higher odds for VTE than the non-catheterized group (odds ratio, 13.15; 95% confidence interval, 1.68-102.70). A similar result was obtained in the inverse probability of treatment weighting analysis (odds ratio, 11.02; 95% confidence interval, 2.64-46.10). CONCLUSIONS: CVC placement is a major risk factor for VTE among hospitalized Japanese patients with IBD without thromboprophylaxis.

Usefulness of texture and color enhancement imaging in assessing mucosal healing in patients with ulcerative colitis.

BACKGROUND AND AIMS: Endoscopic remission is known to be defined as a Mayo endoscopic subscore (MES) of ≤1 in patients with ulcerative colitis (UC). However, some individuals experience relapse even after showing endoscopic remission under white-light imaging (WLI), and no tool exists that can detect these individuals. The aim of this study was to clarify the usefulness of texture and color enhancement imaging (TXI) in the assessment of inflammation in patients with UC. METHODS: This was a prospective, single-arm, observational study conducted at a university hospital. From January 2021 to December 2021, 146 UC patients with endoscopic remission were enrolled. Images were evaluated by WLI, TXI, and pathologic evaluation, followed by prognostic studies. The primary endpoint of the study was the cumulative relapse of UC in each TXI score. The secondary endpoints were the association between TXI and pathologic scores, predictors of relapse, and interobserver agreement between the MES and TXI scores. RESULTS: Patients with TXI score 2 had significantly lower UC relapse-free rates than did those with TXI scores 0-1 (log-rank test, P < .01). When pathologic remission was defined as Matts grade ≤2, the rate of pathologic remission decreased significantly with higher TXI scores (P = .01). In multivariate analysis, TXI score 2 was the only risk factor for UC relapse (P < .01; hazard ratio, 4.16; 95% confidence interval, 1.72-10.04). Interobserver agreement on the TXI score was good (κ = 0.597-0.823). CONCLUSION: TXI can be used to identify populations with poor prognosis in MES 1, for whom treatment intensification has been controversial.

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force.

Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection.

Cell-matrix interface regulates dormancy in human colon cancer stem cells.

Cancer relapse after chemotherapy remains a main cause of cancer-related death. Although the relapse is thought to result from the propagation of resident cancer stem cells1, a lack of experimental platforms that enable the prospective analysis of cancer stem cell dynamics with sufficient spatiotemporal resolution has hindered the testing of this hypothesis. Here we develop a live genetic lineage-tracing system that allows the longitudinal tracking of individual cells in xenotransplanted human colorectal cancer organoids, and identify LGR5+ cancer stem cells that exhibit a dormant behaviour in a chemo-naive state. Dormant LGR5+ cells are marked by the expression of p27, and intravital imaging provides direct evidence of the persistence of LGR5+p27+ cells during chemotherapy, followed by clonal expansion. Transcriptome analysis reveals that COL17A1-a cell-adhesion molecule that strengthens hemidesmosomes-is upregulated in dormant LGR5+p27+ cells. Organoids in which COL17A1 is knocked out lose the dormant LGR5+p27+ subpopulation and become sensitive to chemotherapy, which suggests that the cell-matrix interface has a role in the maintenance of dormancy. Chemotherapy disrupts COL17A1 and breaks the dormancy in LGR5+p27+ cells through FAK-YAP activation. Abrogation of YAP signalling prevents chemoresistant cells from exiting dormancy and delays the regrowth of tumours, highlighting the therapeutic potential of YAP inhibition in preventing cancer relapse. These results offer a viable therapeutic approach to overcome the refractoriness of human colorectal cancer to conventional chemotherapy.

Digestive Decolonization of Colorectal Carriage of Vancomycin-resistant Enterococcus faecium in a Japanese Adult.

Patients with vancomycin-resistant Enterococcus (VRE) colonization should be managed in an isolation room with contact precautions. We herein report a patient whose colorectal carriage of VRE was successfully decolonized using concomitant bowel irrigation with polyethylene glycol, probiotics, and oral antimicrobials, linezolid and orally-administered daptomycin, for release from isolation and contact precautions. We therefore would like to suggest a potential strategy for managing patients with VRE colonization.

Effectiveness and Durability of Ustekinumab Therapy With or Without Immunomodulators for Ulcerative Colitis Patients in Japan.

Background and Aims: The effectiveness and durability of ustekinumab therapy with or without thiopurine immunomodulators (IMs) for ulcerative colitis (UC) in real-world Asian, Japanese patients have not yet been elucidated. Methods: To evaluate the additive effects of IMs on ustekinumab, a retrospective cohort study of UC patients receiving ustekinumab with or without thiopurine IMs, azathioprine or 6-mercaptopurine, was conducted from March 2020 to August 2021. The primary endpoint was clinical remission or response rate at week 8. The secondary endpoints were clinical remission or response rates at weeks 24 and 52, the durability of each treatment, and adverse events. Results: Of the 50 patients with UC treated with ustekinumab, 42 were enrolled. Sixteen patients were treated with a combination of ustekinumab and an IM. The clinical response rates of all patients at weeks 8, 24, and 52 were 53.7%, 63.3%, and 42.9%, respectively. There was no significant difference in the clinical responses or remission rates between the combination therapy and monotherapy groups at weeks 8, 24, and 52. (50.0% vs. 56.0%, P = .757; 70.0% vs. 60.0%, P = .702; and 42.9% vs. 42.9%, P = 1.00, respectively). A Kaplan-Meier analysis showed no difference in IM use on the durability of ustekinumab treatment (log-rank test; P = .955). Conclusions: The response rate for Japanese UC patients is similar to previous reports based on American and European UC patients. There was no significant difference between the ustekinumab monotherapy group and the ustekinumab and IM combination group in the real world.

Efficacy of Calcineurin Inhibitors for Induction of Remission in Intestinal Behçet's Disease.

Background: The efficacy of calcineurin inhibitors (CNIs) for induction of remission in intestinal Behçet's disease (intestinal BD) has not been explored. Methods: A multicenter retrospective case series study of patients with active intestinal BD treated with CNIs (cyclosporin and tacrolimus) was conducted. Results: Of 16 patients, 12 (75%) showed a clinical response and 5 (31.3%) achieved clinical remission after 2 weeks of CNI treatment. Similar efficacy of CNIs was observed even in 7 patients refractory to antitumor necrosis factor-alpha therapies. Endoscopic improvement was observed in 11 of 12 patients. Conclusions: CNIs may be promising treatment options for refractory intestinal BD.

Predictors of necessity for endoscopic balloon dilatation in patients with Crohn's disease-related small bowel stenosis.

BACKGROUND AND AIM: In patients with Crohn's disease (CD) and small bowel stenosis, endoscopic balloon dilation (EBD) is considered to be useful in improving stenotic symptoms and avoiding surgery. However, it carries risks such as bleeding and perforation. The aim of this study was to identify the indications for endoscopic intervention in patients with CD and small bowel stenosis. METHODS: From November 2007 to March 2020, 143 CD patients with small bowel stenosis were enrolled in this study. We identified the factors associated with not requiring endoscopic intervention during long-term follow-up of these patients. RESULTS: Forty of the 143 patients had abdominal symptoms of stenosis and had undergone EBD, whereas the remaining 103 were asymptomatic and had not undergone endoscopic intervention. During long-term follow-up, 95 of those 103 patients never required endoscopic or surgical intervention. Multivariate logistic regression analysis revealed that not consuming an elemental diet (OR 3.18, 95% CI 1.48-6.82; p < .01) and ileocecal valve (ICV) stenosis (OR 0.30, 95% CI 0.11-0.83; p = .02) were independently associated with not requiring EBD. The cumulative emergency hospitalisation-free rate also tended to be higher in patients not consuming an elemental diet or with ICV stenosis. CONCLUSIONS: Two factors, namely not consuming an elemental diet and ICV stenosis, predict a long-term intervention-free prognosis in CD patients with small bowel stenosis.Key messagesWhen an endoscopically impassable small bowel stenosis is found in a CD patient, long-term follow-up without endoscopic intervention may be possible if the patient is asymptomatic, is not using an elemental diet, and the stenosis is ICV.

An organoid-based organ-repurposing approach to treat short bowel syndrome.

The small intestine is the main organ for nutrient absorption, and its extensive resection leads to malabsorption and wasting conditions referred to as short bowel syndrome (SBS). Organoid technology enables an efficient expansion of intestinal epithelium tissue in vitro1, but reconstruction of the whole small intestine, including the complex lymphovascular system, has remained challenging2. Here we generate a functional small intestinalized colon (SIC) by replacing the native colonic epithelium with ileum-derived organoids. We first find that xenotransplanted human ileum organoids maintain their regional identity and form nascent villus structures in the mouse colon. In vitro culture of an organoid monolayer further reveals an essential role for luminal mechanistic flow in the formation of villi. We then develop a rat SIC model by repositioning the SIC at the ileocaecal junction, where the epithelium is exposed to a constant luminal stream of intestinal juice. This anatomical relocation provides the SIC with organ structures of the small intestine, including intact vasculature and innervation, villous structures, and the lacteal (a fat-absorbing lymphatic structure specific to the small intestine). The SIC has absorptive functions and markedly ameliorates intestinal failure in a rat model of SBS, whereas transplantation of colon organoids instead of ileum organoids invariably leads to mortality. These data provide a proof of principle for the use of intestinal organoids for regenerative purposes, and offer a feasible strategy for SBS treatment.

Wnt Signaling Shapes the Histologic Variation in Diffuse Gastric Cancer.

BACKGROUND AND AIMS: Diffuse-type gastric cancer (GC) is currently subdivided into signet-ring cell carcinoma (SRCC) and non-SRCC, referred to as poorly cohesive carcinoma not otherwise specified (PCC-NOS). Although these subtypes are considered to be independent, they often coexist in the same tumors, raising a question of whether they clonally differ or not. To tackle this question, we established an experimental platform for human diffuse GC that enables accurate modeling of histologic subtypes. METHODS: Seven patient-derived diffuse GC organoid lines were established, characterized by histopathologic analysis, in situ hybridization, and gene expression analysis. For genetic modeling of diffuse GC, we knocked out CDH1 and/or TP53 in human normal gastric organoids. Green fluorescent protein-labeled GC organoids were xenotransplanted into immune-deficient mice for in vivo assessment. RESULTS: PCC-NOS organoids transformed into SRCC-like structures on removal of Wnt and R-spondin from the culture medium. This morphologic change paralleled downregulation of Wnt-target and gastric stem cell genes, including LGR5, and elevation of differentiation markers, such as KRT20 and MUCs. The association between Wnt target gene expression and histologic subtypes was confirmed in 3 patient-derived GC tissues. In vivo, single clone-derived organoids formed tumors that comprised 2 distinct histologic compartments, each corresponding to SRCC and PCC-NOS. The transition from PCC-NOS to SRCC histology reflected the abundance of surrounding R-spondin-expressing fibroblasts. CONCLUSIONS: SRCC and PCC-NOS were clonally identical, and their morphology was regulated by extracellular Wnt and R-spondin expression. Our results decoded how genetic mutations and the tumor environment shape pathohistologic and biologic phenotypes in human diffuse GCs.

Significance of endoscopic deep small bowel evaluation using balloon-assisted enteroscopy for Crohn's disease in clinical remission.

BACKGROUND: Small bowel lesions of Crohn's disease (CD) are known to be associated with a poor prognosis; however, endoscopic healing leads to favorable patients' outcome. The aim of this study was to clarify the clinical impact of assessing deep small bowel lesions (DSB) using balloon-assisted enteroscopy (BAE) on CD patients in clinical remission. METHODS: From January 2012 to July 2018, a total of 100 CD patients in clinical remission were enrolled to undergo trans-anal enteroscopy using single-balloon enteroscope. Endoscopic evaluations at the terminal ileum (TI) were performed using a partial Simple Endoscopic Score for CD (pSES-CD). Endoscopic evaluations at the DSB used a modified partial SES-CD (mpSES-CD). We evaluated the factors associated with relapse, and the correlation of endoscopic score between the TI and DSB. For this study, relapse was defined as hospitalization within a year from enteroscopy. RESULTS: 30 patients (30.0%) relapsed within a year from enteroscopy. Multivariate logistic regression analysis revealed that the Harvey-Bradshaw Index (OR 1.77, 95% CI 1.18-2.65; p = 0.003) and an mpSES-CD at DSB (OR 3.10, 95% CI 1.86-5.15; p = 0.001) were independent predictors for relapse, whereas a SES-CD at the TI did not exhibit independence. There was a significant correlation trend between the relapse rate and greater than 5 points of an mpSES-CD at DSB; however, there was no correlation between the relapse rate and pSES-CD at the TI. CONCLUSION: Even when Crohn's disease is in remission, it is important to evaluate DSB using BAE to assess endoscopic mucosal healing.

An Organoid Biobank of Neuroendocrine Neoplasms Enables Genotype-Phenotype Mapping.

Gastroenteropancreatic (GEP) neuroendocrine neoplasm (NEN) that consists of neuroendocrine tumor and neuroendocrine carcinoma (NEC) is a lethal but under-investigated disease owing to its rarity. To fill the scarcity of clinically relevant models of GEP-NEN, we here established 25 lines of NEN organoids and performed their comprehensive molecular characterization. GEP-NEN organoids recapitulated pathohistological and functional phenotypes of the original tumors. Whole-genome sequencing revealed frequent genetic alterations in TP53 and RB1 in GEP-NECs, and characteristic chromosome-wide loss of heterozygosity in GEP-NENs. Transcriptome analysis identified molecular subtypes that are distinguished by the expression of distinct transcription factors. GEP-NEN organoids gained independence from the stem cell niche irrespective of genetic mutations. Compound knockout of TP53 and RB1, together with overexpression of key transcription factors, conferred on the normal colonic epithelium phenotypes that are compatible with GEP-NEN biology. Altogether, our study not only provides genetic understanding of GEP-NEN, but also connects its genetics and biological phenotypes.

Mucosal concentrations of N-acetyl-5-aminosalicylic acid related to endoscopic activity in ulcerative colitis patients with mesalamine.

BACKGROUND AND AIM: 5-Aminosalicylic acid (5-ASA) is a fundamental treatment for mild-to-moderate ulcerative colitis (UC). 5-ASA is taken up into the colonic mucosa and metabolized to N-acetyl-5-ASA (Ac-5-ASA). Few studies have assessed whether mucosal 5-ASA and Ac-5-ASA concentrations are associated with endoscopic remission. This study aimed to investigate differences in 5-ASA and Ac-5-ASA concentrations according to endoscopic activity. METHODS: This single-center, prospective, cross-sectional study was conducted between March 2018 and February 2019. UC patients who were administered with 5-ASA medication for at least 8 weeks before sigmoidoscopy were enrolled. Mucosal 5-ASA and Ac-5-ASA concentrations were measured using liquid chromatography with tandem mass spectrometry. The primary endpoint was defined as the difference in mucosal concentrations of 5-ASA and Ac-5-ASA, according to the Mayo endoscopic subscore (MES). RESULTS: Mucosal concentrations were analyzed in 50 patients. In the sigmoid colon, the median 5-ASA concentration in patients with MES of 0 (17.3 ng/mg) was significantly higher than MES ≥ 1 (6.4 ng/mg) (P = 0.019). The median 5-ASA concentrations in patients with Ulcerative Colitis Endoscopic Index of Severity ≤ 1 (16.4 ng/mg) were also significantly higher than in patients with Ulcerative Colitis Endoscopic Index of Severity ≥ 2 (4.63 ng/mg) (P = 0.047). In the sigmoid colon, the concentration of Ac-5-ASA was higher in patients with MES of 0 (21.2 ng/mg) than in patients with MES ≥ 1 (5.81 ng/mg) (P = 0.022). CONCLUSIONS: The present study showed that mucosal Ac-5-ASA concentrations, as well as 5-ASA concentrations, are higher in UC patients with endoscopic remission. Ac-5-ASA may be useful for a biomarker of 5-ASA efficacy.