[A case of severe colitis caused by immune checkpoint inhibitor].

A 74-year-old male with lung squamous cell carcinoma who was treated with the anti PD-1 antibody nivolumab developed frequent diarrhea four months after initiating treatment. However, his condition did not improve despite prednisolone at 20mg. Endoscopic examination revealed loss of vascular pattern, erosions, and mucosal friability, resembling ulcerative colitis. Colonoscopy revealed punch-out ulcers in the affected mucosa. Therefore, he was definitively diagnosed with severe colitis caused by immune checkpoint inhibitor treatment and cytomegalovirus colitis. Nivolumab was discontinued, and he was treated with 60mg prednisolone and ganciclovir. Although his colitis improved, he developed pneumonia and died thereafter. This case highlights adverse events that are associated with immune checkpoint inhibitors which should be treated properly.

Clinical Features of Intestinal Behçet's Disease Associated with Myelodysplastic Syndrome and Trisomy 8.

Several studies have identified a relationship between myelodysplastic syndrome and Behçet's disease (BD), especially intestinal BD, and trisomy 8 appears to play an important role in these disorders. Despite this, only few case reports or series have been reported in gastroenterology, meaning that endoscopic findings and characteristics of intestinal BD have not been clarified yet. In this report, we describe three cases of intestinal BD associated with myelodysplastic syndrome and trisomy 8, and discuss the clinical features and problems of these disorders from a gastroenterology perspective.

Slight increases in the disease activity index and platelet count imply the presence of active intestinal lesions in C-reactive protein-negative Crohn's disease patients.

OBJECTIVE: Although the serum C-reactive protein (CRP) level may, to some extent, predict the disease activity in patients with Crohn's disease (CD), it is not always elevated during periods of disease activity. This study aimed to identify factors predicting the presence of active intestinal lesions in CD patients without an elevated CRP level. METHODS: CD patients in whom the presence or absence of active intestinal lesions was evaluated using endoscopic and/or radiologic modalities were divided into two groups based on a negative (<3 mg/L) or positive (≥3 mg/L) CRP level. The correlations between the presence of active intestinal lesions and various clinical variables, including the Crohn's Disease Activity Index (CDAI), leukocyte and platelet counts and hemoglobin, serum albumin and CRP levels, were determined in the CRP-negative patients. RESULTS: Of the 128 patients examined, 70 had a negative CRP status, approximately half of whom had active intestinal lesions. The multivariate analysis revealed a CDAI of >100 and platelet count of >33×10(4)/µL to be significant predictive factors for the presence of active lesions in the CRP-negative patients [CDAI >100, odds ratio (OR) =5.55; 95% confidence interval (CI), 1.80-18.74, platelet count >33×10(4)/µL, OR =5.94; 95% CI, 1.34-28.87]. The sensitivity of fulfillment of either criterion for the presence of active intestinal lesions was 83%, while the specificity of fulfillment of both criteria was 94%. CONCLUSION: A relatively low CDAI and platelet count were identified as predictive markers of the presence of active intestinal lesions in CRP-negative CD patients. These results suggest that symptoms and laboratory data should be evaluated very carefully in such patients.

Long-term follow-up of ulcerative colitis patients treated on the basis of their cytomegalovirus antigen status.

AIM: To clarify the impact of cytomegalovirus (CMV) activation and antiviral therapy based on CMV antigen status on the long-term clinical course of ulcerative colitis (UC) patients. METHODS: UC patients with flare-up were divided into CMV-positive and -negative groups according to the CMV antigenemia assay. The main treatment strategy provided for the patients in the CMV-positive group comprised a dose reduction of corticosteroids and administration of ganciclovir. RESULTS: The median number of days to initial remission was significantly greater for the patients in the CMV-positive group (21 d vs 16 d, P = 0.009). However, the relapse rate after remission and colectomy rate during more than 30 mo of observation did not differ between the two groups. Multivariate analysis revealed that administration of ganciclovir was the only independent factor for avoiding colectomy in patients of the CMV-positive group. CONCLUSION: CMV antigen status did not significantly affect the long-term prognosis in UC patients under treatment with appropriate antiviral therapy.

Prognosis of ulcerative colitis differs between patients with complete and partial mucosal healing, which can be predicted from the platelet count.

AIM: To determine the difference in clinical outcome between ulcerative colitis (UC) patients with Mayo endoscopic subscore (MES) 0 and those with MES 1. METHODS: UC patients with sustained clinical remission of 6 mo or more at the time of colonoscopy were examined for clinical outcomes and the hazard ratios of clinical relapse according to MES. Parameters, including blood tests, to identify predictive factors for MES 0 and slight endoscopic recurrence in clinically stable patients were assessed. Moreover, a receiver operating characteristic curve was generated, and the area under the curve was calculated to indicate the utility of the parameters for the division between complete and partial mucosal healing. All P values were two-sided and considered significant when less than 0.05. RESULTS: A total of 183 patients with clinical remission were examined. Patients with MES 0 (complete mucosal healing: n = 80, 44%) were much less likely to relapse than those with MES 1 (partial mucosal healing: n = 89, 48%) (P < 0.0001, log-rank test), and the hazard ratio of risk of relapse in patients with MES 1 vs MES 0 was 8.17 (95%CI: 4.19-17.96, P < 0.0001). The platelet count (PLT) < 26 × 10(4)/µL was an independent predictive factor for complete mucosal healing (OR = 4.1, 95%CI: 2.15-7.99). Among patients with MES 0 at the initial colonoscopy, patients of whom colonoscopy findings shifted to MES 1 showed significant increases in PLT compared to those who maintained MES 0 (3.8 × 10(4)/µL vs -0.6 × 10(4)/µL, P < 0.0001). CONCLUSION: The relapse rate differed greatly between patients with complete and partial mucosal healing. A shift from complete to partial healing in clinically stable UC patients can be predicted by monitoring PLT.

Is presence or history of extracolonic primary malignancy a risk for colorectal neoplasia? An analysis of patients who underwent colonoscopy.

Whether presence or history of extracolonic primary malignancy is a risk for colorectal neoplasia is not fully known. In this study, 26,452 first-time colonoscopy cases were examined using a colonoscopy database. Among the analyzed subjects, 3,026 (11%) subjects had history or concomitance of extracolonic primary malignancy, while the remaining 23,426 subjects did not. Colorectal neoplasia was observed in 39% of all the subjects. A crude comparison showed that the prevalence of any type of colorectal neoplasia was higher in subjects with extracolonic malignancy than in those without (42% vs. 39%, p＝0.0012). However, after adjusting for confounding factors, the odds ratios (ORs) of subjects with extracolonic malignancy for having colorectal neoplasia, advanced neoplasia, and cancer were all less than 1.0, and all significantly different from those of subjects without extracolonic malignancy. Analysis according to the type of extracolonic malignancy revealed that gastric cancer cases had a significantly lower risk for colorectal advanced neoplasia (OR:0.81;95% CI:0.67-0.99). Among major malignancies, only esophageal squamous cell cancer cases had increased risk for colorectal neoplasia (OR:1.66;95% CI:1.20-2.29). Patients with presence or history of extracolonic malignancy did not carry a higher risk of occurrence of colorectal neoplasia.

Evaluation of mucosal healing of ulcerative colitis by a quantitative fecal immunochemical test.

OBJECTIVES: Accumulating evidence has underlined the importance of mucosal healing as a treatment goal for ulcerative colitis (UC). Quantitative fecal immunochemical tests (FITs), which can rapidly quantify fecal blood with automated equipment, have been used recently to screen for colorectal neoplasia. The aim of this study is to determine whether an FIT can evaluate mucosal healing in UC. METHODS: Feces collected from UC patients who underwent colonoscopy were examined by FITs, and results were compared with colonoscopic findings. Mucosal status was assessed using the Mayo endoscopic subscore classification. Maximum score for the colorectum in each patient was recorded. RESULTS: Evaluated were FIT results in conjunction with 310 colonoscopies that were performed in 152 UC patients. A large majority of patients with a Mayo 0 endoscopic score had negative FIT (<100 ng/ml) results (92%), and the proportion of negative FIT results decreased with increases in the Mayo score (Mayo 1: 47%, Mayo 2: 13%, Mayo 3: 12%, P<0.0001, Cochran-Armitage trend test). When the negative FIT was defined as <100 ng/ml, the sensitivity and specificity of a negative FIT for mucosal healing (Mayo 0) were 0.92 and 0.71, respectively. When mucosal healing was defined as Mayo 0 or 1, those were 0.60 and 0.87, respectively. In addition, a positive FIT (≥100 ng/ml) predicted mucosal inflammation (Mayo 2 or 3) with sensitivity 0.87 and specificity 0.60, respectively. CONCLUSIONS: The FIT can effectively and noninvasively evaluate mucosal healing in UC. This easy, rapid method can help evaluate and control disease activity of UC.

Detectability of colorectal neoplasia with fluorine-18-2-fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography (FDG-PET/CT).

BACKGROUND: The purpose of this study was to analyze the detectability of colorectal neoplasia with fluorine-18-2-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (FDG-PET/CT). METHODS: Data for a total of 492 patients who had undergone both PET/CT and colonoscopy were analyzed. After the findings of PET/CT and colonoscopy were determined independently, the results were compared in each of the six colonic sites examined in all patients. The efficacy of PET/CT was determined using colonoscopic examination as the gold standard. RESULTS: In all, 270 colorectal lesions 5 mm or more in size, including 70 pathologically confirmed malignant lesions, were found in 172 patients by colonoscopy. The sensitivity and specificity of PET/CT for detecting any of the colorectal lesions were 36 and 98%, respectively. For detecting lesions 11 mm or larger, the sensitivity was increased to 85%, with the specificity remaining consistent (97%). Moreover, the sensitivity for tumors 21 mm or larger was 96% (48/50). Tumors with malignant or high-grade pathology were likely to be positive with PET/CT. A size of 10 mm or smaller [odds ratio (OR) 44.14, 95% confidence interval (95% CI) 11.44-221.67] and flat morphology (OR 7.78, 95% CI 1.79-36.25) were significant factors that were associated with false-negative cases on PET/CT. CONCLUSION: The sensitivity of PET/CT for detecting colorectal lesions is acceptable, showing size- and pathology-dependence, suggesting, for the most part, that clinically relevant lesions are detectable with PET/CT. However, when considering PET/CT for screening purposes caution must be exercised because there are cases of false-negative results.

Externalization of saw-tooth architecture in small serrated polyps implies the presence of methylation of IGFBP7.

INTRODUCTION: Serrated polyps have been considered to be precursors of colorectal cancer with microsatellite instability. However, the biological and/or morphological changes which occur during the course of serrated polyp to cancer remain to be elucidated. METHODS: Twenty-eight colorectal serrated polyps including five mixed polyps (MP) from 20 patients were observed by chromoendoscopy with magnification, and subsequently resected endoscopically. The presence of mutations in two genes (K-ras and BRAF) and the methylation status of six genes (MLH1-A, MLH1-C, ESR1, P16, SOCS1, and IGFBP7) were examined. RESULTS: The 28 polyps included 32 histological serrated lesions (22 sessile serrated adenomas [SSA], six hyperplastic polyps [HP], and four traditional serrated adenoma [TSA]-like lesions). BRAF mutation was frequently observed in SSAs (19/22), while K-ras mutation was dominant in HPs (5/6). The externalization of saw-tooth architecture in serrated polyps was endoscopically observed more frequently in those with high levels of IGFBP7 methylation (P = 0.03). Moreover, the endoscopic finding was observed in five of six small serrated lesions (<10 mm) which contained both BRAF mutation and high levels of IGFBP7 methylation. TSA-like lesions in small MPs demonstrated the endoscopic finding with no or little MLH1 methylation, while the counterparts in the mixed polyps had high levels of MLH1 methylation with relatively low levels of IGFBP7 methylation. CONCLUSIONS: Our data suggests two distinct pathways may be involved in the early stages of the serrated pathway: one where MLH1 is primarily methylated, and a second where methylated IGFBP7 is associated with an externalization of saw-tooth architecture.

Colorectal endoscopic submucosal dissection for elderly patients at least 80 years of age.

BACKGROUND: Endoscopic submucosal dissection (ESD) has been used recently for successful en bloc resection of even large lesions, although no consensus appears in medical literature concerning its application to elderly patients. This prospective cohort study aimed to evaluate the efficacy and safety of colorectal ESD for patients 80 years of age or older. METHODS: Colorectal ESD procedure findings were compared with clinical outcomes, including associated complications and mortalities, for two age groups totaling 196 consecutive patients with 202 colorectal lesions. Of the 196 patients, 31 patients (16%) were 80 years of age or older (group E), and 165 patients (84%) were younger than 80 years (group Y). RESULTS: The median ages were 82 years in group E and 68 years in group Y. The frequency of chronic concomitant diseases was significantly higher in group E (65%) than in group Y (27%) (p = 0.003). No significant pressure decrease or need for oxygenation was observed in either group. In addition, groups E and Y did not differ significantly in terms of mean lesion sizes (40.9 vs. 39.7 mm) en bloc resection rates (84% vs. 93%), curative rates (78% vs. 84%), median procedure times (65 vs. 70 min), or associated complications (no perforation or delayed bleeding cases [0%] vs. 5 perforations [3%]) The median postprocedure hospitalization period was 3 days in both groups. Except for 10 cases requiring subsequent lymph node dissection surgery, follow-up colonoscopy examinations showed no recurrences or ESD-related mortalities in either group. CONCLUSION: Colorectal ESD is a safe and effective treatment for elderly patients (age ≥ 80 years) despite a significantly higher frequency of chronic concomitant diseases than among younger patients.

Analysis of K-ras, BRAF, and PIK3CA mutations in laterally-spreading tumors of the colorectum.

BACKGROUND AND AIMS: Laterally-spreading tumors (LST) are a newly-recognized category of colorectal neoplasia, and are defined as lesions larger than 10 mm in diameter and extending circumferentially rather than vertically. However, genetic features of this new category of tumors are not fully elucidated. The aim of this study was to evaluate genetic alterations in LST. METHODS: We examined K-ras, BRAF, and phosphoinositide-3-kinase catalytic-α polypeptide (PIK3CA) mutations in 101 LST, including 68 LST-granular type (LST-G) and 33 LST-non-granular type by direct sequencing. As controls, we examined these gene mutations in 66 protruded colon adenomas (10 mm or larger) and 44 advanced colon cancers. RESULTS: K-ras, BRAF, and PIK3CA mutations were observed in 59 (58%), zero (0%), and three (3%) LST, respectively. LST-G morphology in the right-sided colon was significantly correlated with the existence of K-ras mutations, whereas a size of 20 mm or larger was the only predictor of mutations in the left-sided colorectum. The frequency of K-ras mutations in LST was particularly marked in the left-sided colorectum compared to protruded adenomas or advanced cancers (LST vs protruded adenomas, P < 0.001; LST vs advanced cancers, P = 0.002), whereas in the right-sided colon, K-ras mutations were equally frequent. PIK3CA mutations were not familiar in either LST (3%) or advanced cancers (9%). CONCLUSIONS: K-ras mutations were involved in colorectal LST in different manners according to tumor location.

Tolerability and usefulness of mercaptopurine in azathioprine-intolerant Japanese patients with ulcerative colitis.

BACKGROUND AND AIM: Azathioprine (AZA) and mercaptopurine (6-MP) are established as effective therapeutic drugs for the induction and maintenance of remission in patients with ulcerative colitis (UC). However, AZA is often intolerable due to adverse effects. Evidence regarding the approach of switching from AZA to 6-MP in patients of Asian ethnicity is lacking. We assessed the tolerability and usefulness of 6-MP in Japanese UC patients who had shown intolerance to AZA. METHODS: One-hundred and ten UC patients who had been treated with AZA and/or 6-MP from January 1985 to October 2008 were examined retrospectively. RESULTS: Among 110 patients, 107 were treated first with AZA; only three were treated first with 6-MP. Thirty-five (33%) of the 107 patients were intolerant of AZA, with adverse effects including myelosuppression (8/35, 23%), hepatotoxicity (8/35, 23%), and abdominal symptoms (6/35, 17%). Among 35 AZA-intolerant patients, 23 were switched to 6-MP treatment. The cumulative probability of colectomy was significantly higher in patients not treated with 6-MP than in patients treated with 6-MP (log-rank test, P =0.0002). Among the 26 patients (23 AZA-intolerant and three AZA-untreated) treated with 6-MP, 22 (85%) could tolerate the therapy. Adverse effects due to 6-MP were abdominal symptoms (2/4), myelosuppression (1/4), and rash (1/4). The median initial dose of 6-MP was 20 mg/day, and the median final dose was 30 mg/day. CONCLUSIONS: 6-MP was tolerated in 83% of AZA-intolerant patients, and it was effective for maintenance therapy of UC patients. 6-MP treatment should be considered in AZA-intolerant patients.

Advantages of using thin endoscope-assisted endoscopic submucosal dissection technique for large colorectal tumors.

BACKGROUND: Our purpose was to evaluate the effectiveness of a newly developed non-invasive traction technique known as thin endoscope-assisted endoscopic submucosal dissection (TEA-ESD) procedure for the removal of colorectal laterally spreading tumors (LST). PATIENTS AND METHODS: A total of 37 LST located in the rectum and distal sigmoid colons of 37 patients were eligible for outcome analysis. Twenty-one LST were treated with TEA-ESD and were then retrospectively compared to 16 LST that had previously been treated with standard ESD. Tumor size, en bloc resection rate, procedure time, combined number of different electrical surgical knives used during each procedure and associated complications were evaluated in this case-control study. RESULTS: There was no statistically significant difference in tumor size between the TEA-ESD group and the ESD control group (43.6+/-16 mm and 42.4+/-14 mm, respectively). All LST were successfully resected en bloc in both groups. Procedure duration was shorter for the TEA-ESD group than the ESD control group, although the difference was not statistically significant (96+/-53 minutes vs 116+/-74 minutes; P=0.18). The percentage of cases in which only one electrical surgical knife was used during the entire procedure was significantly higher in the TEA-ESD group compared to the ESD control group (85.7% vs 31.3%; P=0.0005). There were no perforations in the TEA-ESD group while the ESD control group experienced one perforation. At the present time, TEA-ESD is limited to the rectum and distal sigmoid colon. CONCLUSION: It was technically easier, safer and more cost-effective to perform ESD for LST in the rectum and the distal sigmoid colon using the newly developed TEA-ESD traction technique.