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.

Divergent Routes toward Wnt and R-spondin Niche Independency during Human Gastric Carcinogenesis.

Recent sequencing analyses have shed light on heterogeneous patterns of genomic aberrations in human gastric cancers (GCs). To explore how individual genetic events translate into cancer phenotypes, we established a biological library consisting of genetically engineered gastric organoids carrying various GC mutations and 37 patient-derived organoid lines, including rare genomically stable GCs. Phenotype analyses of GC organoids revealed divergent genetic and epigenetic routes to gain Wnt and R-spondin niche independency. An unbiased phenotype-based genetic screening identified a significant association between CDH1/TP53 compound mutations and the R-spondin independency that was functionally validated by CRISPR-based knockout. Xenografting of GC organoids further established the feasibility of Wnt-targeting therapy for Wnt-dependent GCs. Our results collectively demonstrate that multifaceted genetic abnormalities render human GCs independent of the stem cell niche and highlight the validity of the genotype-phenotype screening strategy in gaining deeper understanding of human cancers.

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.

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.

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.

Somatic inflammatory gene mutations in human ulcerative colitis epithelium.

With ageing, normal human tissues experience an expansion of somatic clones that carry cancer mutations1-7. However, whether such clonal expansion exists in the non-neoplastic intestine remains unknown. Here, using whole-exome sequencing data from 76 clonal human colon organoids, we identify a unique pattern of somatic mutagenesis in the inflamed epithelium of patients with ulcerative colitis. The affected epithelium accumulates somatic mutations in multiple genes that are related to IL-17 signalling-including NFKBIZ, ZC3H12A and PIGR, which are genes that are rarely affected in colon cancer. Targeted sequencing validates the pervasive spread of mutations that are related to IL-17 signalling. Unbiased CRISPR-based knockout screening in colon organoids reveals that the mutations confer resistance to the pro-apoptotic response that is induced by IL-17A. Some of these genetic mutations are known to exacerbate experimental colitis in mice8-11, and somatic mutagenesis in human colon epithelium may be causally linked to the inflammatory process. Our findings highlight a genetic landscape that adapts to a hostile microenvironment, and demonstrate its potential contribution to the pathogenesis of ulcerative colitis.

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.

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.

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.

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.

Development of an Indigo Naturalis Suppository for Topical Induction Therapy in Patients with Ulcerative Colitis.

BACKGROUND: Indigo naturalis (IN) consists of ligands for the aryl hydrocarbon receptor and exhibits anti-inflammatory effects. Previously, we demonstrated that an 8-week treatment with oral IN is effective in inducing a clinical response in patients with ulcerative colitis (UC). Some UC patients with proctitis are refractory to topical mesalamine or corticosteroids and therefore require an alternative topical treatment. OBJECTIVES: We aimed to prospectively evaluate the safety and efficacy of IN suppositories in UC patients. METHOD: We performed an open-label, single-center, prospective pilot study from February 2018 to October 2018. A total of 10 patients with active UC, who had moderate to severe inflammation from the rectum to the sigmoid colon, were enrolled. The patients received a daily dose of 50 mg IN suppository for 4 weeks. The primary endpoint was safety at week 4. RESULTS: Although 1 patient experienced anal pain, no serious adverse events were observed. At week 4, the rates of clinical remission and mucosal healing were 30 and 40%, respectively. Mayo rectal bleeding subscores significantly improved after treatment (1.80 ± 0.13 vs. 0.90 ± 0.28; p = 0.009). Approximately 80% of the patients with a baseline Mayo endoscopic subscore in the rectum (r-MES) of 2 achieved mucosal healing, but those with a baseline r-MES of 3 did not. CONCLUSIONS: We found that 4 weeks of IN suppository can be tolerated by UC patients, but its efficacy was limited by the severity of the disease. Further investigation will be needed in order to confirm the optimum dose of IN suppository for patients with UC.

Factors contributing to the systemic clearance of infliximab with long-term administration in Japanese patients with Crohn's disease: Analysis using population pharmacokinetics
.

OBJECTIVE: Crohn's disease (CD) is a chronic inflammatory gastrointestinal disease with repeated cycles of exacerbation and remission. Infliximab (IFX), a chimeric anti-TNF-α monoclonal antibody, has been widely used for the treatment of CD. However, no study in Japanese CD patients receiving continuous IFX for more than 1 year has been reported. To avoid therapeutic failure during long-term administration in Japanese CD patients, we evaluated the variable factors of IFX pharmacokinetics and the optimal trough IFX concentration at 8 weeks after administration. MATERIALS AND METHODS: Population pharmacokinetic (PPK) analysis was performed using the nonlinear mixed-effect model based on the IFX serum concentration in 832 samples from 121 patients. A one-compartment model was used to examine interindividual variability in the systemic clearance (CL) of intravenously administered IFX. RESULTS: PPK estimates (estimated value, RSE%) were total clearance (CL: 0.018 L/h, 9.1) and volumes of distribution (Vd: 7.35 L, 12.0). Interindividual variability for CL and Vd of 0.11 and 0.16, respectively, was found. Body weight, antibody to IFX (ATI), and albumin level were factors affecting the IFX CL. IFX CL was greater in the ATI-positive than in the ATI-negative group. CL was also greater in nonremission patients. There was a significant association between the predicted serum IFX trough concentration at 8 weeks and therapeutic response with long-term continuous administration (p < 0.05), with a higher concentration at 8 weeks seen in the remission group. CONCLUSION: Using these variables including body weight, ATI, and albumin level, the IFX dose could be calculated for individual CD patients to achieve the optimal therapeutic range.

Long-term effect of NUDT15 R139C on hematologic indices in inflammatory bowel disease patients treated with thiopurine.

BACKGROUND AND AIM: A missense variant of the nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene (R139C) predisposes Asian patients with inflammatory bowel disease (IBD) to thiopurine-induced leukopenia. This study evaluates the long-term effect of NUDT15 R139C heterozygosity on hematological parameters during thiopurine administration. METHODS: We enrolled 83 Japanese IBD patients who were on anti-tumor necrosis factor-α agents and had used thiopurine. NUDT15 R139C was genotyped by polymerase chain reaction. We retrospectively reviewed patient clinical charts to collect data on white blood cell (WBC) count, mean corpuscular volume (MCV), hemoglobin, and platelet count during the 24 months following thiopurine initiation. RESULTS: The included patients had either Crohn's disease (54; 65.1%) or ulcerative colitis (29; 34.9%). Genotyping of NUDT15 R139C identified 62 patients (74.7%) of genotype C/C and 21 (25.3%) of genotype C/T. The median dose of thiopurine was lower in the C/T group than in the C/C group after starting thiopurine. At 6 months, the mean WBC count of the C/T group became significantly lower than that of the C/C group (P = 0.008) and remained lower through the 24 months. The C/T group developed grade 2-4 leukopenia by 6 months, which persisted through 12-24 months. The mean MCV in the C/T group became higher than that of the C/C group after 3 months. CONCLUSIONS: NUDT15 R139C heterozygosity affected the WBC count and MCV for 24 months after thiopurine administration. Our results indicate that careful monitoring of leukopenia and dose adjustment are necessary throughout treatment in IBD patients heterozygous for the NUDT15 R139C.

Intramucosal poorly differentiated and signet-ring cell components in patients with ulcerative colitis-associated high-grade dysplasia.

Despite the rarity of colorectal poorly differentiated adenocarcinoma (Por) and signet-ring cell carcinoma (Sig), they are more frequent in patients with ulcerative colitis (UC). However, little is known about these components of early colitis-associated cancer due to the difficulty of detection at an early stage. Here, we reviewed colitis-associated high-grade dysplasia/cancer with Por/Sig components within the submucosa among 103 lesions of 79 UC patients who presented between 1997 and 2017. In total, one Sig in situ, three intramucosal and two submucosal carcinomas (8.7%) were identified among 69 lesions within the submucosa. Depressed appearance, loss of crypt architecture and amorphous surface pattern suggested the presence of Por/Sig, rather than submucosal infiltration. All lesions were located in the rectosigmoid colon and included high-grade dysplasia. While the surrounding noncancerous mucosa expressed E-cadherin and MUC5AC, the expression of E-cadherin was reduced and the expression of MUC5AC was negative in all of the carcinomas except for the Sig in situ. The gastric type metaplasia associated with altered MUC5AC profiles may be a sign of the stepwise accumulation of molecular alterations, including TP53 defects and a reduced expression level of E-cadherin.

Endoscopic morphologic features of ulcerative colitis-associated dysplasia classified according to the SCENIC consensus statement.

BACKGROUND AND AIMS: Recent advances in endoscopic equipment and diagnostic techniques have made possible the detection of early dysplasia in the inflamed mucosa of ulcerative colitis (UC). The SCENIC consensus statement recommends the use of unified terminology for the morphology of dysplasia. In this study, we investigated the endoscopic features of high-grade dysplasia (HGD) in a clinical setting. METHODS: We retrospectively identified 62 patients with UC who were diagnosed with colitis-associated cancer or HGD between 1997 and 2015. A total of 39 lesions of HGD detected by targeted biopsy sampling in 31 patients were reviewed, and the endoscopic morphology was classified according to the SCENIC guidelines. RESULTS: In total, 0 (0%), 6 (15.4%), 19 (48.7%), 12 (30.8%), and 2 (5.1%) lesions with HGD were classified as pedunculated, sessile, superficial elevated, flat, and depressed, respectively. Nearly 80% of the lesions were located in the rectum or sigmoid colon. All flat and depressed lesions were red in color. Typically, sessile/superficial elevated lesions accompanied a flat area (Is+IIb/IIa+IIb). Ulceration was observed in 2 depressed lesions (5.1%). Although the borders were indistinct in 21 lesions (53.8%) without the use of magnifying colonoscopy, all lesions could be distinguished from the surrounding mucosa using magnifying endoscopy. CONCLUSIONS: This is the first study to classify the morphologic features of HGD using the SCENIC guidelines in a clinical setting. Based on our findings, endoscopists should recognize that HGD is frequently associated with a flat/superficial elevated area and red discoloration and should inspect particularly carefully in the rectum and sigmoid colon. The findings of chromoendoscopy and magnifying colonoscopy may also be useful in distinguishing lesions from the surrounding mucosa.

Endocytoscopy can be used to assess histological healing in ulcerative colitis.

Background and study aim Endocytoscopy (ECS) is used in the in vivo microscopic inspection of microstructural mucosal features and enables endoscopists to assess the histological severity of ulcerative colitis (UC). The aim of this study was to assess histological healing in UC patients by using ECS. Patients and methods A total of 64 patients in clinical and endoscopic remission who underwent ECS were selected. The correlation between the ECS score and Geboes score at the rectum was evaluated in patients with a Mayo endoscopic score (MES) of 0. The diagnostic accuracy of the ECS score for histological remission (Geboes score ≤ 2) was also assessed. Results The ECS score ranged from 0 to 5 in patients with endoscopic remission on conventional white-light images (MES of 0). The agreement between histological remission regarding the ECS score and the Geboes score had a κ value of 0.72, and the ECS score showed high accuracy for histological remission, with a sensitivity of 0.77, a specificity of 0.97, and a diagnostic accuracy of 0.86. Conclusion ECS can be used to assess histological healing in patients with UC without the need for biopsy specimens.

Clinical Efficacy and Safety of Oral Qing-Dai in Patients with Ulcerative Colitis: A Single-Center Open-Label Prospective Study.

BACKGROUND/AIMS: Chinese herbal medicine Qing-Dai (also known as indigo naturalis) has been used to treat various inflammatory conditions. However, not much has been studied about the use of oral Qing-Dai in the treatment for ulcerative colitis (UC) patients. Studies exploring alternative treatments for UC are of considerable interest. In this study, we aimed at prospectively evaluating the safety and efficacy of Qing-Dai for UC patients. METHODS: The open-label, prospective pilot study was conducted at Keio University Hospital. A total of 20 patients with moderate UC activity were enrolled. Oral Qing-Dai in capsule form was taken twice a day (daily dose, 2 g) for 8 weeks. RESULTS: At week 8, the rates of clinical response, clinical remission, and mucosal healing were 72, 33, and 61%, respectively. The clinical and endoscopic scores, CRP levels, and fecal occult blood results were also significantly improved. We observed 2 patients with mild liver dysfunction; 1 patient discontinued due to infectious colitis and 1 patient discontinued due to mild nausea. CONCLUSION: This is the first prospective study indicating that oral Qing-Dai is effective for inducing remission in patients with moderate UC activity and can be tolerated. Thus, Qing-Dai may be considered an alternative treatment for patients, although further investigation is warranted.

Endoscopic Severity Predicts Long-Term Prognosis in Crohn's Disease Patients with Clinical Remission.

INTRODUCTION: Mucosal healing has emerged as a desirable treatment goal in clinical practice for patients with Crohn's disease (CD). The aim of this study was to assess the relationship between endoscopic activity and the long-term prognosis of CD using simple endoscopic score for Crohn's disease (SESCD) and Rutgeerts' score. METHODS: We conducted a cohort study in clinical practice at a single center. Among CD patients who underwent colonoscopy between July 2008 and June 2011 at our hospital, 131 patients with clinical remission were selected, and the patients were divided into 2 groups: a non-surgical group (n = 84) and a surgical group (n = 47). The primary endpoint of this study was to assess the associations between variables and clinical relapse after endoscopic procedures. The cut-off levels of SESCD or Rutgeerts' score for the prediction of relapse were also assessed in patients with clinical remission. RESULTS: In the non-surgical group, SESCD and C-reactive protein at baseline were significantly higher in patients who had clinical recurrence than in patients who maintained remission. A factor of SESCD ≤2 was independently associated with sustained remission, even in patients with clinical remission. In the surgical group, patients with Rutgeerts' scores ≤1 had significantly prolonged clinical remission compared to patients with Rutgeerts' scores ≥3. CONCLUSION: A cut-off value of SESCD ≤2 and a Rutgeerts' score ≤1 enabled the prediction of long-term prognosis. These cut-off values could be used in clinical trials of endoscopic remission from the point of view of the clinical outcomes of CD.

Ulcerative colitis endoscopic index of severity is associated with long-term prognosis in ulcerative colitis patients treated with infliximab.

BACKGROUND AND AIM: Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is characterized by periods of remission and episodes of relapse. Mucosal healing is an emerging therapeutic target in UC and various scoring systems have been used. The UC endoscopic index of severity (UCEIS) is the only validated endoscopic index at present, with minimum interobserver variation. Correlation of UCEIS scores after treatment and clinical outcomes of UC has not been examined. In the present study, we aimed to evaluate the usefulness of UCEIS after treatment with infliximab. METHODS: The medical records of 82 UC patients, treated with infliximab at Keio University Hospital between October 2010 and July 2013, were reviewed retrospectively. Endoscopic findings were evaluated based on the UCEIS. RESULTS: Mean pre-therapeutic UCEIS score was 5.1. Pre-therapeutic UCEIS scores were not associated with short-term outcomes. Forty-five patients underwent colonoscopy at 3-12 months after starting treatment; mean post-therapeutic UCEIS score was 2.4, with a score of 0-1 in 16 (35.6%) patients, 2-4 in 19 (42.2%) patients, and 5-8 in 10 (22.2%) patients. Importantly, a post-therapeutic UCEIS score of 0 or 1 after treatment was associated with a favorable long-term outcome. CONCLUSION: UCEIS score is a useful instrument for evaluating endoscopic improvement in UC patients treated with infliximab, and mucosal healing may be defined with a UCEIS score of 0 or 1.

Early intervention with adalimumab may contribute to favorable clinical efficacy in patients with Crohn's disease.

BACKGROUND: We evaluated the clinical efficacy of adalimumab (ADA) for Crohn's disease (CD) and analyzed predictive factors for clinical remission and long-term prognosis. METHODS: We retrospectively reviewed the medical records of 45 patients treated with ADA for CD at Keio University Hospital between October 2010 and March 2014. Clinical remission was defined as a Harvey-Bradshaw index of ≤4. RESULTS: Twenty-eight of 45 patients (62.2%) achieved clinical remission at week 4. Among these 28 patients, 18 patients (64.3%) maintained clinical remission at week 26, and among these, 16 patients (88.9%) maintained clinical remission at week 52. Absence of a history of bowel resection and absence of prior anti-tumor necrosis factor (anti-TNF) therapy were significant predictive factors for clinical remission at week 4 upon multivariate logistic regression analyses. Younger age and a disease duration of ≤3 years correlated with clinical remission at week 26 upon univariate analyses. Patients without a history of bowel resection showed significantly better long-term prognosis than those with a history of bowel resection (p = 0.01). None of the patients contracted a serious infectious disease. CONCLUSIONS: Younger age, shorter duration of disease, being naive to anti-TNF antagonists, and absence of a history of bowel resection were associated with the efficacy of ADA in CD patients.