The characteristics of nivolumab-induced colitis: an evaluation of three cases and a literature review.

BACKGROUND: The use of immune-checkpoint inhibitors in cancer treatment has become increasingly common, resulting in an increase in the incidence of related side effects. Diarrhoea and colitis have been previously documented as gastrointestinal tract-related side effects of immune-checkpoint inhibitors. Although PD-1/PD-L1 inhibitors produce fewer side effects than CTLA-4 inhibitors, diarrhoea and colitis continue to be reported. However, little is known about the endoscopic features associated with PD-1/PD-L1 inhibitors. In this report, we describe three cases of colitis induced by a PD-1 inhibitor nivolumab. These cases showed endoscopic findings characteristic of ulcerative colitis (UC). Treatment was in accordance with UC therapy, which resulted in beneficial outcomes. CASE PRESENTATION: Three patients with lung cancer treated with nivolumab presented with diarrhoea with (case 2) or without haematochezia (cases 1 and 3). Treatment with nivolumab was ceased and colonoscopy was performed, revealing endoscopic features similar to those of UC. These patients were diagnosed with nivolumab-induced colitis. Case 1 was treated with mesalazine, whereas cases 2 and 3 were treated with corticosteroids. Subsequently, their symptoms improved. CONCLUSIONS: Nivolumab-induced colitis exhibited similar characteristics to UC. Treatment was similar to that for UC and was successful.

Diagnostic and clinical role of serum proteinase 3 antineutrophil cytoplasmic antibodies in inflammatory bowel disease.

BACKGROUND AND AIM: Proteinase 3 antineutrophil cytoplasmic antibodies (PR3-ANCAs) are well-known serological markers for granulomatosis with polyangiitis, but their role as serological markers for inflammatory bowel disease remains uncertain. The present study aimed to evaluate the diagnostic and clinical role of PR3-ANCAs as markers for inflammatory bowel disease. METHODS: Using a new methodology with chemiluminescence enzyme immunoassay, serum PR3-ANCA titers were assessed in 102 patients with ulcerative colitis (UC), 67 patients with Crohn's disease (CD), 44 controls with other intestinal diseases, and 66 healthy controls. Associations with clinical data were investigated. The diagnostic role of PR3-ANCAs was evaluated by receiver operating characteristic analysis. RESULTS: Proteinase 3 antineutrophil cytoplasmic antibody titers were significantly higher in patients with UC than in those with CD patients, patients with intestinal diseases (intestinal controls), and healthy controls (all P < 0.001). Receiver operating characteristic analysis demonstrated an area under the curve of 0.85 (95% confidence interval: 0.83-0.87) and showed that the manufacturer's cutoff value (3.5 U/mL) had a sensitivity of 39.2% and specificity of 96.6% for UC. There was a significant difference between PR3-ANCA-positive and PR3-ANCA-negative patients with regard to disease duration (P < 0.05) and disease severity (P < 0.01). CONCLUSIONS: Proteinase 3 antineutrophil cytoplasmic antibodies were significantly more prevalent in patients with UC than in those with CD and controls. Our results suggested the role of PR3-ANCAs as serological markers for aiding in diagnosing UC and evaluating disease severity. Further prospective studies are needed across multiple populations of patients and ethnic groups.

Impaired extinction of cued fear memory and abnormal dendritic morphology in the prelimbic and infralimbic cortices in VPAC2 receptor (VIPR2)-deficient mice.

The structurally related neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) have been implicated in stress regulation and learning and memory. Several bodies of research have shown the impact of the PACAP specific receptor PAC1 on fear memory, but the roles of other PACAP receptors in regulating fear stress responses remain to be elucidated. Here we aimed to investigate the effects of genetic deletion of VIPR2 encoding the VPAC2 receptor, which binds both VIP and PACAP, on fear-related memory and on dendritic morphology in the brain regions of the fear circuitry. Male VPAC2 receptor knockout (VPAC2-KO) and littermate wild-type control mice were subjected to Pavlovian fear conditioning paradigm. VPAC2-KO mice displayed normal acquisition of fear conditioning, contextual and cued fear memory, but impaired extinction of cued fear memory. Morphological analyses revealed reductions in cell body size and total branch number and length of apical and basal dendrites of prelimbic cortex neurons in VPAC2-KO mice. In addition, Sholl analysis indicated that the amount of dendritic material distal to the soma was decreased, while proximal dendritic material was increased. In the infralimbic cortex, the amount of apical dendritic material proximal to the soma was increased in VPAC2-KO mice, while other indices of morphology did not differ. Finally, there were no differences in dendritic morphology in basolateral amygdala neurons between genotypes. These findings suggest that the VPAC2 receptor plays an important role in the fear extinction processes and the regulation of the dendritic morphology in the prelimbic and infralimbic cortices.

A longitudinal study of FDG-PET in Crohn disease patients receiving granulocyte/monocyte apheresis therapy.

BACKGROUND AIMS: Endoscopy is the gold standard for the diagnosis and follow-up of patients with Crohn disease (CD). However, a less invasive approach is now being sought for the management of these patients. The objective of this study was to examine whether (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) might be relevant for monitoring the disease activity in CD patients undergoing granulocyte/monocyte apheresis (GMA). METHODS: This study was conducted in 12 patients with CD who were receiving treatment with 10 once-a-week GMA sessions with the Adacolumn. The response to treatment was monitored by measuring standard laboratory variables, Crohn's Disease Activity Index (CDAI) score, International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) score, and regional and global bowel uptakes on FDG-PET. RESULTS: In 6 of the 12 patients, significant improvement of the CDAI was observed after the final session of GMA. The patients who showed clinical response to GMA had a decrease in the regional and global bowel uptakes on FDG-PET, whereas those who did not respond showed no change. In the patients who responded to the GMA, the decrease in regional bowel uptake on FDG-PET in each disease area of the same patient varied in parallel. There was a significant correlation between decrease in the global bowel uptake on FDG-PET and improvement of the CDAI and IOIBD scores. CONCLUSIONS: The longitudinal changes in FDG-PET uptakes are of potential clinical interest for assessing the regional and global bowel disease activity in CD patients undergoing GMA therapy.

Hard X-ray photoelectron spectroscopy of LixNi1-xO epitaxial thin films with a high lithium content.

The core-level and valence-band electronic structures of LixNi1-xO epitaxial thin films with x = 0, 0.27, and 0.48 were studied by hard X-ray photoelectron spectroscopy. A double peak structure, consisting of a main peak and a shoulder peak, and a satellite structure were observed in the Ni 2p3/2 core-level spectra. The intensity ratio of the shoulder to main peak in this double peak structure increased with increasing lithium content in LixNi1-xO. This lithium doping dependence of the Ni 2p3/2 core-level spectra was investigated using an extended cluster model, which included the Zhang-Rice (ZR) doublet bound states arising from a competition between O 2p - Ni 3d hybridization and the Ni on-site Coulomb interaction. The results indicated that the change in the intensity ratio in the main peak is because of a reduction in the ZR doublet bound states from lithium substitutions. This strongly suggests that holes compensating Li doping in LixNi1-xO are of primarily ZR character.

Characteristics of Immune Checkpoint Inhibitor-Induced Colitis: A Systematic Review.

BACKGROUND: Immune checkpoint inhibitors (ICIs) including anti-CTLA-4, anti-PD-1, and anti-PD-L1 antibodies have been increasingly used for various malignancies. These ICIs activate immune functions to treat malignant tumors; however, this causes characteristic complications called immune-related adverse events (irAE). In the gastrointestinal tract, ICIs cause adverse events such as diarrhea and enterocolitis, thus warranting treatment discontinuation. These irAEs require treatment that suppresses immunity; however, no treatment strategies based on approved guidelines have been reported. This review aimed to investigate the current treatment status for refractory cases of ICI-induced colitis in accordance with their diagnosis, therapy, and prognosis. SUMMARY: We systematically reviewed studies in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) checklist. Two investigators searched PubMed and Scopus in January 2019. We extracted data, including the number of ICI-treated patients developing colitis and diarrhea. The number of cases classified as severe per the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) definitions and the progress of corticosteroid-treated and anti-TNF-α- antibody-treated cases (e.g., infliximab) were recorded. Details of further treatment were also recorded for cases that did not improve with antiTNF-α- antibody. Among patients receiving anti-CTLA-4 antibody, corticosteroids were administered to 14.6% of patients, and infliximab was administered to 5.7% of patients. Among patients receiving anti-PD-1/PD-L1 antibody, corticosteroids were administered to 2.37% of patients. For refractory cases unsuccessful with infliximab, the continuation of infliximab every 2 weeks, tacrolimus administration, prolonged corticosteroid treatment, colectomy, or vedolizumab administration were reported. KEY MESSAGES: Treatment of ICI-induced colitis is important to avoid the need to discontinue cancer treatment. Many therapeutic agents for inflammatory bowel disease are reportedly effective in treating refractory ICI-induced colitis.

Development and Validation of the Body Cognition Assessment System.

Body awareness, which comprises the sense of body possession and action ownership, is essential for the adaptive movement of humans in response to external environments. However, existing body cognition assessments include many overt elements of cognitive functional activity, but no assessment captures the latent body cognition necessary for exercise and daily life activities. Therefore, this study aimed to devise a body cognition assessment system (BCAS) to examine the functional basis of body cognition in healthy participants and investigate its usefulness. The BCAS was used to assess body cognition on three occasions, and BCAS values were calculated from the results of the assessment. The intraclass correlation coefficient (ICC) was used to determine reproducibility. Neural activity in the brain during somatocognition assessment while conducting the BCAS was measured by electroencephalogram. Moreover, the functional basis for somatocognition with the BCAS was also investigated. The results demonstrated that the BCAS values varied across the three administrations (ICC (1.3) = 0.372), and changes in the state of neural activity in the brain were observed. The results suggest that assessment using the BCAS may be a new indicator of ever-changing body cognition.

Evaluation of Intervention Effectiveness of Sensory Compensatory Training with Tactile Discrimination Feedback on Sensorimotor Dysfunction of the Hand after Stroke.

We investigated the intervention effect of training using a feedback-type tactile discrimination system on sensorimotor dysfunction of the hand after a stroke. A human male subject with sensorimotor dysfunction in his left hand after a stroke was asked to perform peg manipulation practice, a building block stacking task, and a material identification task for 10 min each for six weeks. During the activities, a tactile discrimination feedback system was used. The system is a device that detects the vibration information generated when touching an object with a hand and that feeds back the captured information in real time as vibration information. After the intervention, in addition to the reorganization of the sensorimotor areas, the deep sensation, sense of agency, numbness, amount of use, and quality of the left-hand movement improved. Our results suggest that training with the use of a feedback system could be a new form of rehabilitation for sensorimotor dysfunction of the hand.

Evaluation of Serum Calprotectin Levels in Patients with Inflammatory Bowel Disease.

BACKGROUND: Fecal calprotectin has been proposed as a useful biomarker of disease activity in inflammatory bowel disease (IBD). However, the role of calprotectin in systemic circulation is not well established. Thus, this study aimed to quantify serum calprotectin levels to identify a potential inflammatory marker for IBD. METHODS: Ninety-eight patients with ulcerative colitis (UC) and 105 patients with Crohn's disease (CD) were prospectively enrolled and clinically scored. Ninety-two healthy, age-matched subjects served as controls. Blood samples from UC and CD patients and controls were analyzed for serum calprotectin levels and routine laboratory parameters. Disease activity was assessed by partial Mayo score and Harvey-Bradshaw index for UC and CD, respectively. RESULTS: Serum calprotectin levels were higher in CD and UC patients than in controls and were higher during active disease than during inactive disease in CD but not in UC. In UC, serum calprotectin levels were correlated with C-reactive protein (CRP) but not with other laboratory parameters or disease activity. In CD, serum calprotectin levels were positively correlated with disease activity, serum CRP, and platelet count. In UC and CD, serum calprotectin and CRP levels increased during the acute phase and decreased towards remission. CONCLUSIONS: Serum calprotectin is an inflammatory marker in IBD but might be more effective in evaluating patients with CD than those with UC. Further studies are needed to confirm these findings and to better determine the specific uses of serum calprotectin in routine practice.

Leukocyte Apheresis Using a Fiber Filter Suppresses Colonic Injury Through Calcitonin Gene-Related Peptide Induction.

BACKGROUND: The aim of this study was to address whether the therapeutic effect of leukocytapheresis (LCAP) depends on calcitonin gene- related peptide (CGRP) induction. METHODS: An HLA-B27 transgenic rat model was treated with an LCAP column. The effects of LCAP on clinical, endoscopic, and histologic disease activity, the colony-forming ability of colony-forming unit (CFU)-granulocyte macrophages (GMs), colonic blood flow, and tissue expression of tumor necrosis factor (TNF)-α and CGRP were examined. Changes in the effects of LCAP after pretreatment with the CGRP antagonist CGRP8-37 were also observed. A dextran sulfate sodium-induced colitis rat model included treatment with CGRP, and the effect was assessed based on clinical, endoscopic, and histologic disease activity, colonic blood flow, the colony-forming ability of CFU-GMs, and tissue expression of inflammatory cytokines and CGRP receptor families. RESULTS: LCAP improved disease activity, enhanced colonic blood flow, and induced the bone marrow colony-forming ability of CFU-GMs with an increase in CGRP mRNA levels. These effects were abolished by pretreatment with CGRP8-37. The administration of CGRP suppressed colitis, promoting colonic blood flow, inducing bone marrow-derived cells, downregulating inflammatory cytokines, and upregulating receptor activity-modifying protein-1. The mRNA and protein levels of inflammatory cytokines in lipopolysaccharide-stimulated mononuclear cells were also decreased after CGRP treatment. CONCLUSIONS: The therapeutic effects of LCAP depend on CGRP induction. CGRP can effectively suppress colitis through the downregulation of inflammatory events and upregulation of protective events.

Safety and efficacy of single-needle leukocyte apheresis for treatment of ulcerative colitis.

Leukocyte apheresis (LCAP) is a safe and effective treatment for active ulcerative colitis (UC) in Japan. Nevertheless, a limitation of LCAP is its requirement for two puncture sites (double-needle [DN] apheresis), sometimes leading to problems with needle puncture. Single-needle (SN) apheresis is useful in hemodialysis and reduces needle puncture pain. If SN apheresis were found to be useful in LCAP for UC, it may reduce patient burden. The aim of this study was to compare the safety and efficacy of SN apheresis with that of DN apheresis. Twenty-four patients with active UC were retrospectively enrolled. They underwent either SN apheresis (n = 12) or conventional double-needle (DN) apheresis (n = 12) at the Kurume University Hospital from February 2014 to March 2018. At each session, we recorded access problems defined by the time required to initiate apheresis and the frequency of puncture-related problems, as well as blood circuit clotting, defined as clotting necessitating interruption of apheresis and changing of the circuit. Efficacy was assessed using partial Mayo scores. The number of apheresis sessions was comparable between SN and DN apheresis (9.0 ± 2.0 times vs 9.6 ± 1.4 times, mean ± SEM). SN significantly reduced the time required to start apheresis (10.0 ± 5.4 minutes vs 19.4 ± 11.9 minutes, P < .05) as well as needle puncture troubles (0.9% vs 11.5%, P < .05). SN had comparable frequency of blood clotting episodes (5.6% vs 8.7%). SN apheresis had similar clinical efficacy (P < .001 in SN and P < .01 in DN). The improvement and remission rates were comparable between groups. SN apheresis may be safe and effective and may reduce patient burden during UC treatment. Nevertheless, further comparative studies are needed.

Activation of the VPAC2 Receptor Impairs Axon Outgrowth and Decreases Dendritic Arborization in Mouse Cortical Neurons by a PKA-Dependent Mechanism.

Clinical studies have shown that microduplications at 7q36.3, containing VIPR2, confer significant risk for schizophrenia and autism spectrum disorder (ASD). VIPR2 gene encodes the VPAC2 receptor for vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP). Lymphocytes from patients with these mutations exhibited higher VIPR2 gene expression and VIP-induced cAMP responsiveness, but mechanisms by which overactive VPAC2 signaling may lead to these psychiatric disorders are unknown. We have previously found that repeated administration of a selective VPAC2 receptor agonist Ro25-1553 in the mouse during early postnatal development caused synaptic alterations in the prefrontal cortex and sensorimotor gating deficits. In this study, we aimed to clarify the effects of VPAC2 receptor activation on neurite outgrowth in cultured primary mouse cortical neurons. Ro25-1553 and VIP caused reductions in total numbers and lengths of both neuronal dendrites and axons, while PACAP38 facilitated elongation of dendrites, but not axons. These effects of Ro25-1553 and VIP were blocked by a VPAC2 receptor antagonist PG99-465 and abolished in VPAC2 receptor-deficient mice. Additionally, Ro25-1553-induced decreases in axon and dendritic outgrowth in wild-type mice were blocked by a protein kinase A (PKA) inhibitor H89, but not by a PKC inhibitor GF109203X or a mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitor U0126. PACAP38- induced facilitation of dendritic outgrowth was blocked by U0126. These results suggest that activation of the VPAC2 receptor impairs neurite outgrowth and decreases branching of cortical neurons by a PKA-dependent mechanism. These findings also imply that the VIPR2-linkage to mental health disorders may be due in part to deficits in neuronal maturation induced by VPAC2 receptor overactivation.

Questionnaire Survey from the 1st Kurume University Inflammatory Bowel Disease Center Educational Lecture.

INTRODUCTION: The number of inflammatory bowel disease (IBD) patients is increasing steadily in Japan, and it is expected that patient groups and patient education will improve the quality of life of patients and IBD care. The 1st Kurume University IBD Center educational lecture was held and a questionnaire survey was administered at this lecture. METHODS: We asked 78 participants to answer a questionnaire survey on the occasion of the 1st Kurume University IBD Center educational lecture. RESULTS: We obtained responses from 56 (71.8%) participants; 31 (55.4%) had IBD [21 (37.4%) had ulcerative colitis (UC) and 10 (17.9%) had Crohn's disease (CD)]. Most participants were female (37, 66%). The age range with the highest number of participants was 40 to 69 (27, 48.2%). Most had heard about this educational lecture through "notification by the patient's doctor" 23 (41.1%). A total of 30 (53.6%) of participants answered "good" about the lecture content, while 50 (89.7%) of participants answered "very good" and "good" about the impression of this lecture. Meanwhile, 10 (32.3%) of patients were interested in patient groups. The percentage of patients who were interested in patient groups was higher in patients with CD 4 (66.7%) than those with UC 2 (33.3%). CONCLUSION: We held the 1st Kurume University IBD center educational lecture. Further studies are needed to assess whether educational lectures and/or patient groups can improve patients' quality of life (QOL) and IBD care in our hospital.

Detection of calprotectin in inflammatory bowel disease: Fecal and serum levels and immunohistochemical localization.

The aim of the present study was to quantify calprotectin levels using an enzyme-linked immunosorbent assay (ELISA) and a point-of-care test (POCT) in patients with inflammatory bowel disease. Overall, 113 patients with ulcerative colitis (UC; 51 men and 62 women) and 42 patients with Crohn's disease (CD; 29 men and 13 women), who were scheduled to undergo a colonoscopy, were prospectively enrolled and scored endoscopically and clinically. An additional 96 healthy, age-matched subjects served as the normal controls. Feces and blood samples from the patients with UC and CD, and the normal controls were analyzed. These patients had received adequate medical treatment. The tissue distribution of calprotectin was investigated using immunohistochemistry. The fecal calprotectin levels, as measured using an ELISA, were correlated with the endoscopic and clinical disease activities and laboratory parameters, including serum levels of hemoglobin (Hb), albumin and C-reactive protein, and erythrocyte sedimentation rate, particularly among the patients with UC. The fecal Hb level was close to that of the fecal calprotectin level (r=0.57; P<0.0001). The fecal calprotectin level measured using an ELISA was well-correlated with the fecal calprotectin level measured using the POCT (r=0.81; P<0.0001), but was not correlated with the serum calprotectin level (r=0.1013; P=0.47). An immunohistochemical investigation revealed that patients with both UC and CD had higher neutrophil and monocyte/macrophage calprotectin-positive cell expression levels, compared with those in the normal controls. Fecal calprotectin was considered a reliable marker for disease activity, and the assessment of fecal calprotectin via POCT showed potential as a rapid and simple measurement in clinical settings.

Stereomicroscopic features of colitis-associated tumors in mice: Evaluation of pit pattern.

Patients with longstanding ulcerative colitis have an increased risk of colorectal cancer. Mouse models for colitis-associated tumors are indispensable for the development of novel strategies for prevention and intervention, as well as an improved understanding of the mechanisms underlying tumor formation. The present study examined whether stereomicroscopic observations with dye-application were able to detect and discriminate tumors in a colitis-associated tumor model in mice. Colonic tumors were induced in C57BL/6 mice by 15 cycles of treatment with dextran sulfate sodium (DSS) in drinking water. The mice were then divided into 4 groups: normal mice fed a control diet, normal mice fed an iron-supplemented diet, 0.7% DSS mice fed an iron diet and 1.5% DSS mice fed an iron diet. The entire colons were characterized with respect to both morphology and histology. The pit pattern architecture was analyzed using stereomicroscopy with dye agents (0.2% indigo carmine or 0.06% crystal violet). The tumor histology was graded as negative, indefinite or positive for dysplasia. The positive category was divided into two subcategories: low-grade dysplasia (LGD) and high-grade dysplasia (HGD). The tumor incidences and multiplicity were significantly higher in mice fed an iron diet and 1.5% DSS compared with in mice fed an iron diet and 0.7% DSS. Compared with LGD, HGD was predominantly located in the distal colon, was larger in size and had a higher incidence of elevated lesions (Is and IIa) and a lower incidence of flat lesions (IIb). In regards to the pit pattern, HGD had a high incidence of VI pits and a low incidence of IV, IIIL and II pits. In conclusion, evaluation of the pit pattern using stereomicroscopy with dye-application is useful for detecting and discriminating neoplastic changes in DSS mice and may further our understanding of the mechanisms that induce tumor formation in patients with ulcerative colitis and the characterization of pharmaceutical responses.

Study to determine guidelines for pediatric colonoscopy.

AIM: To investigated characteristics, diagnosis, bowel-cleansing preparation, sedation, and colonoscope length and diameter in Japanese pediatric patients receiving total colonoscopy. METHODS: The present study evaluated consecutive patients aged ≤ 15 years who had undergone their first colonoscopy in Kurume University between January 2007 and February 2015. Data were retrospectively analyzed. We identified 110 pediatric patients who had undergone colonoscopy that had reached the cecum, allowing the observation of the total colon. RESULTS: Hematochezia, abdominal pain, and diarrhea were the most common symptoms. For bowel-cleansing preparation, pediatric patients aged ≤ 12 years were treated with magnesium citrate, and patients aged 13-15 years were treated with polyethylene glycol 4000. For sedation, thiamylal with pentazocine, which has an analgesic effect, was used in patients aged ≤ 6 years, and midazolam with pentazocine was used in patients aged ≥ 7 years. Regarding the choice of endoscope, short and thin endoscopes were selected for younger patients, particularly patients aged ≤ 3 years. Positive diagnoses were made in 78 patients (70.9%). Inflammatory bowel disease (n = 49, 44.5%), including ulcerative colitis (n = 37, 33.6%) and Crohn's disease (n = 12, 10.9%), was the most common diagnosis. CONCLUSION: Colonoscopy offers a high diagnostic capability for pediatric patients with gastrointestinal symptoms. The selection of appropriate management the performance of colonoscopy is important in pediatric patients.

Real-world Experience of Anti-tumor Necrosis Factor Therapy for Internal Fistulas in Crohn's Disease: A Retrospective Multicenter Cohort Study.

BACKGROUND: Internal fistula in Crohn's disease is a condition likely to require surgery, although few reports showed successful medical treatments such as anti-tumor necrosis factor (TNF) therapy. We performed a multicenter retrospective cohort study to investigate the outcome of anti-TNF therapy for internal fistula in Crohn's disease. METHODS: Data were retrospectively collected from patients with Crohn's disease diagnosed with internal fistula treated with anti-TNF agents (infliximab or adalimumab) between January 2002 and November 2015. Need for surgery and fistula closure were assessed as primary and secondary endpoints. Cumulative rate of surgery was evaluated by the Kaplan-Meier analysis. Prognostic factors for the outcomes were also assessed by univariate and multivariate analyses. RESULTS: A total of 93 Crohn's disease cases were included in the study with a mean follow-up period of 1452.8 days. Fistula locations were entero-entero/colonic (n = 72, 77.4%), enterovesical (n = 16, 17.2%), or enterovaginal (n = 5, 5.4%). Cumulative surgery rate was 47.2%, and fistula closure rate was 27.0% at 5 years from the induction of anti-TNF agents. Lower Crohn's Disease Activity Index and shorter duration from the diagnosis of fistula were independently associated with the lower risk of surgery (P = 0.017 and 0.048, respectively). Single fistula was associated with the successful fistula closure. Second-line surgical treatments were mostly successful for anti-TNF failures. CONCLUSIONS: In the present retrospective cohort study, approximately half of patients with internal fistulas avoided surgery for long periods. It may be reasonable to treat quiescent single internal fistulas with anti-TNF agents soon after the diagnosis of internal fistulas.

Increased levels of circulating adrenomedullin following treatment with TU­100 in patients with Crohn's disease.

Daikenchuto (TU­100) is a traditional Japanese medicine that is widely used to treat intestinal symptoms. The mechanisms underlying it effects on the circulating levels of adrenomedullin (ADM) are of interest. In addition, the effect of TU­100 in the treatment of Crohn's disease (CD) in humans remains to be elucidated. The primary objective of the present study was to evaluate the effect of TU­100 on the circulating ADM levels in patients with active CD. An additional objective was to assess the effect of the drug on the disease activity and its potential side effects. In an open­label study, 10 patients with active CD received 15 g TU­100 per day for 8 consecutive weeks, and baseline anti­inflammatory therapy was continued. The pre­ and post­treatment blood plasma levels of total ADM (t­ADM) and mature­ADM (m­ADM) were determined using enzyme­linked immunosorbent assays. The response of patients to the treatment was evaluated clinically using the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) score. The plasma levels of t­ADM (16.4±1.1 vs. 20.2±1.7 fmol/ml, P=0.0218) and m­ADM (1.7±0.1 vs. 2.2±0.1 fmol/ml, P=0.0284) increased following 8 weeks of TU­100 treatment, compared with control. The IOIBD score of patients also improved, with a significant decrease in the score from 3.9±0.5 at 0 weeks to 2.4±0.4 at 8 weeks (P=0.0284). Out of the 10 components of the IOIBD scoring system, the scores for abdominal pain and tenderness, decreased significantly (P=0.014 and P=0.046). Therefore, TU­100 was safe and well­tolerated by the patients that participated in the current study. The present study determined that the pharmacologic action of TU­100 is associated with changes in the circulating ADM levels and that treatment with TU­100 may aid in the management of CD. These promising findings warrant further investigation in larger, multicenter studies.

Antibody markers in the diagnosis of inflammatory bowel disease.

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic intestinal inflammation of unknown etiology. The diagnosis of IBD is based on endoscopic, radiologic and histopathologic criteria. Recently, the search for a noninvasive marker that could augment or replace part of this diagnostic process has become a focus of IBD research. In this review, antibody markers, including microbial antibodies, autoantibodies and peptide antibodies, will be described, focusing on their common features. At present, no single marker with qualities that are satisfactory for the diagnosis and treatment of IBD has been identified, although panels of some antibodies are being evaluated with keen interest. The discovery of novel IBD-specific and sensitive markers is anticipated. Such markers could minimize the use of endoscopic and radiologic examinations and could enable clinicians to implement individualized treatment plans designed to improve the long-term prognosis of patients with IBD.

Advanced endoscopic features of ulcerative colitis-associated neoplasias: Quantification of autofluorescence imaging.

Ulcerative colitis (UC) patients are well known to carry a higher risk of developing colorectal dysplasia/cancer. However, it is hard to detect the lesion in the early phase during colonoscopy. This pilot study was conducted to analyze the endoscopic characteristics of neoplastic lesions associated with UC using advanced imaging techniques. This is a retrospective analysis of 15 colorectal neoplastic lesion obtained from 11 UC patients during remission who underwent white-light- and advanced endoscopic imaging techniques, including chromoendoscopy, narrow-band imaging and autofluorescence imaging (AFI), and were treated with surgery. These lesions were analyzed for histology, location, size, shape, color and endoscopic features. The green/red ratio was also assessed to quantify the AFI intensity. All 11 patients had extensive colitis with the median disease duration of 14.0 years. A total of 15 lesions, consisting of 8 high-grade dysplasia and 7 cancer, was mostly located in the distal colon (86.7%, 13/15) with the mean size of 8.6 mm. The shape was protruding in 46.7% (7/15), flat elevated in 40.0% (6/15) and flat in 13.3% (2/15) and the color was red in 60.0% (9/15), same colored in 33.3% (5/15) and discolored in 6.7% (1/15). The lesion predominantly showed Kudo's neoplastic pit pattern in 86.7% (13/15; 5 type IIIL, 7 type IV and 1 type VI) on chromoendoscopy and Sano's neoplastic capillary pattern (type IIIa) in 63.6% (7/11) on narrow-band imaging, but were colored purple as neoplastic lesions in only 37.5% (3/8) on AFI. Of note, the AFI green/red ratio was significantly lower in the neoplastic lesions than UC-involved areas (p=0.00014) and UC-uninvolved areas (p=0.00651) irrespective of the lesion's size and histological type. In conclusion, endoscopic analysis based on advanced imaging, in particular AFI quantitation, may be helpful to detect early stage neoplastic lesions in long standing UC. Large-scale, prospective studies are needed.