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Purpose The ulcerative colitis colonoscopic index of severity (UCCIS) evaluates the state of the entire colonic mucosa in ulcerative colitis. However, no cut-off values of scores for predicting clinical relapse in patients with ulcerative colitis have been established. This study aimed to determine the cut-off values for predicting clinical relapse in patients with ulcerative colitis. Methods The endoscopic scores (sum of Mayo endoscopic subscores (S-MES) and UCCIS) of 157 patients with ulcerative colitis experiencing clinical remission and their subsequent clinical course were retrospectively reviewed. The optimal cut-off values for predicting relapse and relapse-free rates were analyzed by receiver operating characteristic analysis. Results Forty patients with ulcerative colitis experienced relapse within 24 months. The median UCCIS for these patients at the time of study enrollment was significantly higher than that for patients with clinical remission (P P P = 0.004). Conclusions The data from this study indicate that the USSIC is a more relevant score than the S-MES for predicting the time to relapse in patients with ulcerative colitis in remission.

Eosinophilic infiltration is sometimes observed histologically in ulcerative colitis (UC), but the effect of the degree of infiltration on the treatment course for UC is not completely understood. We investigated whether short-term steroid administration in UC patients refractory to maintenance therapy, with high eosinophilic infiltration in the colonic mucosa, contributed to the clinical and endoscopic improvement. Ten patients with endoscopically active and pathologically high eosinophilic infiltration, based on pathological examination using endoscopic biopsy, were examined for the clinical background when starting steroid treatment. The clinical and endoscopic improvement before and after steroid use were assessed prospectively. The average initial steroid dosage and duration of use were 21.0 mg and 102.7 days, respectively. The mean values before and after steroid use of the clinical activity index, the Mayo endoscopic subscore, and the UC endoscopic index of severity were 2.4 and 1.0, 1.8 and 0.7, and 3.9 and 1.1, respectively. All scores improved significantly after steroid use (P = .042, P = .002, P = .002, respectively). Steroids were discontinued in all patients; no patients required steroid re-administration. There may be cases of UC with eosinophilic infiltration into the colonic mucosa and resistance to maintenance treatment, suggesting that short-term steroid administration may contribute to clinical and endoscopic improvements.

Background Biomarkers such as fecal calprotectin (FC) and fecal immunochemical occult blood tests (FIT) for ulcerative colitis (UC) are used in clinical practice. In this study, the effect of UC disease duration on FC was investigated and compared to that on FIT. Methods One hundred twenty-eight colonoscopic examinations and two fecal biomarkers measurements were performed. The cases of UC were divided into short- and long-term disease-duration groups or categorized into three groups with disease durations of 0–5, 6–13, and 14–38 years. We analyzed correlations between biomarker levels and endoscopic scores, including the Mayo endoscopic subscore (MES), ulcerative colitis endoscopic index of severity, and the sum of MES. Results In the analysis of short- and long-term disease durations, the three endoscopic scores and biomarker levels showed significant correlations in both long-term and short-term groups. Most of the correlation coefficients for the individual long-term group were lower than the corresponding values for all cases, while most of the correlation coefficients for the individual short-term groups were higher than the corresponding values for all cases. In the three-group analysis (disease durations of 0–5, 6–13, and 14–38 years), the two biomarkers and three endoscopic scores showed significant correlations, and most of the correlation coefficients between biomarkers and endoscopic scores tended to be lower in the long-term follow-up group. In the receiver operating characteristic analysis for predicting mucosal healing in the three groups, the area under the curve for FC and FIT concentrations in the 0–5 year disease-duration group showed particularly higher values than those for the other two groups. Conclusions Similar to FIT, FC is affected by the duration of UC, indicating that FC may be a highly useful biomarker, especially in short-term disease.

Background Oral tacrolimus is a therapeutic agent for moderate to severe steroid-dependent or resistant ulcerative colitis (UC), but remission induction is difficult, and it is necessary to treat the patient while considering the next treatment. Aim To examine serum albumin (Alb) level as a prognostic factor for the therapeutic effect of tacrolimus in clinical practice. Methods Forty-seven patients with UC treated with tacrolimus at our institution were divided into remission and failure groups (colectomy or switch to biologics), and the biological data at the start of observation and at weeks 1 and 2 were retrospectively examined. Kaplan-Meier and multivariate analyses were performed using Alb as a prognostic factor in UC treatment. Results During the three months observed, 17 (36.2%) patients failed treatment with tacrolimus. A comparison between the failure and remission groups showed a significant difference only in Alb in week 2, and in the week 2/week 0 Alb ratio, which showed the rate of change in Alb. The cut-off value of the week 2/week 0 Alb ratio that predicted failure was 1, and its area under the curve was 0.751 (95%CI: 0.604-0.898). In the Kaplan-Meier analysis, a week 2/week 0 Alb ratio ≤ 1 had a significantly higher failure rate than that of > 1; Cox proportional hazard regression analysis also showed that a week 2/week 0 Alb ratio ≤ 1 was an independent prognostic factor for failure within 3 mo after the start of tacrolimus treatment. Conclusion A week 2/week 0 Alb ratio ≤ 1 predicts failure within 3 mo of tacrolimus administration for UC. High failure risk exists with week 2 Alb values ≤ 1 on admission.

Backgrounds: Compared to proton pump inhibitors, vonoprazan exerts a greater inhibitory effect on gastric acid secretion and is useful for treating acid-related diseases, such as gastro-esophageal reflux disease. However, there is a problem that vonoprazan causes hypergastrinemia, which confers a risk of carcinoid tumor. A previous report demonstrated that pirenzepine, an M1 muscarinic receptor antagonist, enhances the acid inhibitory effects while suppressing hypergastrinemia induced by omeprazole. Here, we examined whether pirenzepine enhances the gastric acid inhibitory effects of vonoprazan without further increasing serum gastrin levels.Methods: Eleven healthy volunteers were subjected to 24-hour intragastric pH monitoring and serum gastrin measurements on day 7 of three different regimens: pirenzepine 75mg alone, vonoprazan 10mg alone, and vonoprazan 10mg plus pirenzepine 75mg administered in a randomized crossover fashion.Results: Median pH 4 holding time ratios (range) achieved with pirenzepine 75mg, vonoprazan 10mg and vonoprazan 10mg plus pirenzepine 75mg were 6.9% (2.4–32.8%), 88.4% (54.6–100%), and 84.2% (40.3–100%), respectively. Respective serum gastrin levels were 79 (75–210) pg/ml, 310 (110–870) pg/ml, and 170 (140–930) pg/ml. In cases with hypergastrinemia (gastrin≥200pg/ml) induced by vonoprazan 10mg alone, concomitant treatment with pirenzepine significantly reduced serum gastrin levels from 370pg/ml to 180pg/ml (P=0.028).Conclusion: Although pirenzepine does not enhance acid inhibition, it does improve hypergastrinemia induced by vonoprazan to some extent.

Background Schlafen 11 (SLFN11) was recently identified as a dominant determinant of sensitivity to DNA-targeting agents including platinum-based drugs. SLFN11 also reportedly enhances cellular radiosensitivity. In this study, we examined the prognostic value of SLFN11 expression in esophageal squamous cell carcinoma (ESCC) patients treated with definitive chemoradiotherapy (dCRT), including the platinum derivative nedaplatin. Methods Seventy-three patients with ESCC who received dCRT were examined. SLFN11 expression was analyzed in pre-dCRT biopsies using immunohistochemistry and evaluated using a histo-score (H-score). Correlation between the H-score and overall survival was analyzed. An H-score ≥ 51 was provisionally defined as indicating high SLFN11 expression. Viability assays were performed using previously established isogenic human cell lines differentially expressing SLFN11 to test the usefulness of SLFN11 as marker of response to the dCRT regimen. Results High SLFN11 expression was independently associated with better prognosis in ESCC patients (hazard ratio = 0.295, 95% CI = 0.143–0.605, p = 0.001 for multivariate analysis). Kaplan-Meier survival curves showed that the prognostic value of high SLFN11 expression was most evident in patients at clinical stages II and III (p = 0.004). In in vitro study, SLFN11-proficient cells were highly sensitive to platinum derivatives compared to SLFN11-deficient cells. Conclusion SLFN11 expression is an independent prognostic factor for ESCC patients treated with dCRT and a potential biomarker for treatment selection of ESCC. Examination of SLFN11 may be particularly useful for clinical Stage II–III patients who wish to choose dCRT (instead of surgery) to preserve esophageal function.

Vonoprazan, a potassium-competitive acid blocker, inhibits gastric acid secretion and attenuates the antiplatelet function of clopidogrel more potently than esomeprazole. We investigated whether alternate-day dosing of vonoprazan might avoid this interaction with clopidogrel while providing sufficient gastric acid inhibition.Following 24 h of pH monitoring (control regimen), 12 healthy volunteers received three regimens (clopidogrel-only regimen: clopidogrel 75 mg daily [q.d.]; vonoprazan alternate-day regimen: vonoprazan 10 mg every other day [q.o.d.] + clopidogrel 75 mg q.d.; vonoprazan daily regimen: vonoprazan 10 mg q.d. + clopidogrel 75 mg q.d.) for 14 days in a randomized open-label crossover manner. Intragastric pH monitoring was performed for 24 h on day 13 in the clopidogrel-only and vonoprazan q.d. regimens and for 48 h on days 13 and 14 in the vonoprazan q.o.d. regimen. Serum gastrin and inhibition of platelet aggregation (IPA) were measured before the commencement of pH monitoring in each regimen.Twelve volunteers completed the study. Equivalent median IPA values in the q.o.d. and q.d. regimens were measured (21.8% and 25%, respectively) and were significantly lower than that with the clopidogrel-only regimen (40.8%). The median pH4 holding time ratio for the vonoprazan q.o.d. regimen (49.7%) was superior to that of the clopidogrel-only regimen (18.4%), but was significantly inferior to that of the vonoprazan q.d. regimen (77.0%; p 0.01).Alternate-day administration of vonoprazan could not prevent the interaction between vonoprazan and clopidogrel, and acid inhibition was inferior to that with vonoprazan daily administration. Alternate-day administration of vonoprazan thus appears to be of questionable clinical utility.

The fecal immunochemical occult blood test (FIT) and prostaglandin E-major urinary metabolite (PGE-MUM) have been reported to predict the relapse of ulcerative colitis (UC) during remission. In this study, we directly compared FIT and PGE-MUM in predicting relapse and examined the effect of disease duration on these biomarkers.Measurements of 2 biomarkers and endoscopic examination were performed in 73 patients with UC in remission. The patients were followed up for 12 months, and clinical relapse was evaluated. In addition, we divided the patients into long-term disease duration and short-term disease duration groups for analysis.Twenty-one patients (28.8%) relapsed within 12 months. FIT and PGE-MUM levels were significantly higher in the relapsed group than in the remission group. Cutoff values of FIT and PGE-MUM for predicting relapse using receiver operating characteristic analysis were 65.0 ng/mL (area under the curve [AUC]: 0.723) and 25.2 μg/g·Cr (AUC: 0.701), respectively. Patients with FIT ≥ 65.0 ng/mL and PGE-MUM ≥ 25.2 μg/g·Cr had a higher risk of clinical relapse. In the short-term disease duration group, the AUCs of FIT were larger than those of PGE-MUM using receiver operating characteristic analysis, in most instances. By contrast, the AUCs of PGE-MUM were larger than those of FIT in most cases in the long-term disease groups.FIT and PEG-MUM were highly accurate in predicting clinical relapse in UC patients with short and long disease durations in remission, respectively.

In 2012, Japan approved the use of a tag-less patency capsule (PC), which evaluates gastrointestinal patency before small-bowel capsule endoscopy (SBCE). This study aimed to evaluate the validity of our modification on the passage criteria for this PC in clinical practice. We retrospectively enrolled 326 consecutive patients who underwent PC examination before SBCE. If X-ray could not reveal the PC in the body during the judgement time (30–33 h after ingestion), we defined it as ‘estimated patency’ and performed SBCE. We employed plain computed tomography (CT) for the second judgement, as needed. The overall patency rate was 95.1%. By X-ray, 41 (12.6%) patients were judged to have ‘estimated patency’, and SBCE could be safely performed. Plain CT judgement was necessary in 106 patients (32.5%). One PC case had a residual coating film associated with stenosis in a patient with Crohn’s disease (CD), and one (0.3%) SBCE case had capsule retention resulting from false CT judgement. Multivariate analysis revealed that established CD and inpatient were factors related to no-patency. In conclusion, PC is useful for examining gastrointestinal patency, keeping in mind CT misjudgement. If PC was not found in the body via X-ray, performing SBCE as ‘estimated patency’ seemed appropriate.

Crohn's disease is recognized to increase the risk of gastrointestinal malignances. Adenocarcinoma is the most common malignancy in these patients. Association between Crohn's disease and adenocarcinoma in the small intestine has already been established, however, the association between neuroendocrine tumor and Crohn's disease remains uncertain. We report a 39-year-old man with Crohn's disease, who was diagnosed with NET in the rectum. He had suffered from fever and anal pain due to the anal fistula and abscess. The disease state was considered to be resistant to medical treatment. He underwent total proctocolectomy, small bowel resection, anal fistula drainage with ileostomy. Postoperative histology revealed a neuroendocrine tumor in the rectum. His postoperative course was uneventful, and he followed a good course under treatment with infliximab and mercaptopurine hydrate. This case highlights the need of careful observation of resected specimens in light of the possibility of NET, especially those with anal disorders.

Cytomegalovirus (CMV) reactivation in the colon is common in patients with severe ulcerative colitis (UC). Ganciclovir (GCV) resistance conferring CMV UL97 gene mutations have been reported in recent years. However, the prevalence of UL97 gene mutations in GCV-naive CMV infection in the colon remains unknown. We investigated the prevalence of CMV UL97 gene mutations in patients with colonic CMV infection associated with or without UC. Twenty-two GCV-naive patients with colonic CMV infection, 15 with UC and 7 with other diseases, were enrolled. Frozen biopsy samples or formalin-fixed paraffin-embedded samples were used for nested polymerase chain reaction (PCR) amplification of the UL97 gene. Sanger DNA sequencing was performed. In comparison with AD169 reference strain, natural polymorphisms were frequently detected in codons N68D (100%), I244V (100%), and D605E (86.4%). Seven polymorphisms were detected infrequently (

Adalimumab (ADA) trough level and anti-ADA antibody (AAA) positivity influence mucosal healing and loss of response in patients with inflammatory bowel disease (IBD). In this study, we clarified the correlation between ADA monitoring, including non-trough level, and real-world IBD clinical outcomes. This retrospective, observational, single-center study involved patients with ulcerative colitis (19) and Crohn’s disease (33) treated with ADA from January 2007 to August 2018. Serum ADA and AAA levels were measured 4‒14 days after ADA administration. The AAA positivity rate was 23.1% (12/52). ADA continuity was higher in AAA-negative patients than in AAA-positive patients (P = 0.223). Receiver operating characteristic (ROC) analysis revealed that a serum AAA cut-off of 9.2 μg/mL was associated with ADA continuity. The ADA level was significantly higher in the endoscopic remission group than in the non-remission group (P = 0.02). Based on the ROC curve analysis results of serum ADA level and endoscopic remission, the cut-off value of the serum ADA level was set to 11.1 μg/mL. Under the combined use of ADA with immunomodulators and AAA positivity, ADA continuity was significantly higher when the serum AAA level at 4–14 days after ADA administration was ≥9.2 μg/mL. Furthermore, endoscopic remission can be expected with a serum ADA level of ≥11.1 μg/mL. Overall, to predict clinical outcomes, it would be useful to measure the blood level of ADA regardless of the timing of the trough.

We evaluated the association between endoscopic scores of colonic inflammation and fecal calprotectin (FC), fecal immunochemical occult blood test (FIT), and C-reactive protein (CRP) in patients with ulcerative colitis (UC). Endoscopic scores reflecting the most severe lesion [maximum Mayo Endoscopic Subscore (M-MES) and Ulcerative Colitis Endoscopic Index of Severity (UCEIS)] and those reflecting the inflammation of the entire colon [sum of MES (S-MES) and Ulcerative Colitis Colonoscopic Index of Severity (UCCIS)] were evaluated. FC, FIT, and CRP were measured, and their association with the four endoscopic scores was evaluated. Endoscopic scores of 78 complete colonoscopies (66 UC patients) were evaluated using the three biomarkers. FC and CRP tended to correlate more strongly with S-MES and UCCIS than with M-MES and UCEIS. In the M-MES 0, 1 group, compared to CRP, FC and FIT showed stronger correlations with S-MES and UCCIS. Conversely, in the M-MES 2, 3 group, only CRP was significantly correlated with each descriptor. CRP more strongly reflects colon-wide mucosal inflammation than FC and allows reliable assessment of inflammation throughout the colon in active UC.

Prostaglandin E-major urinary metabolite (PGE-MUM) and C-reactive protein (CRP) are useful biomarkers in patients with ulcerative colitis. However, whether changes in endoscopic scores over time are reflected in the values of these biomarkers has not been verified. This prospective observational study aimed to assess the relationship between changes in biomarker levels and endoscopic scores in patients with ulcerative colitis. A total of 100 colonoscopy intervals of patients with ulcerative colitis were enrolled. The relationship between variations in the Mayo endoscopic subscore over time and the accompanying changes in biomarker values were investigated. PGE-MUM levels showed a significant rise in the increased endoscopic score group (P = 0.007) and a decrease with reduced endoscopic score group (P = 0.023). CRP levels showed a significant decline with lower endoscopic values (P

The Capsule Endoscopy Crohn's Disease Activity Index (CECDAI) was recently reported as a new scoring system to evaluate the mucosal lesions of patients with Crohn's disease (CD). We investigated whether CECDAI is useful for assessing the necessity of early additional treatment in patients with CD in clinical remission. Twenty-one patients with small intestinal CD in clinical remission underwent capsule endoscopy (CE). The CECDAI and Lewis score (LS) were used to evaluate the intestinal lesions. We analyzed the correlations between several biomarkers and CECDAI or LS and examined the changes in therapeutic regimens based on the CECDAI. CE identified intestinal abnormalities in most CD patients in clinical remission: 81.0% and 85.7%, as assessed using CECDAI and LS, respectively. A significant positive correlation was observed between the CDAI and LS (P = .025), as well as between CDAI and CECDAI (P = .014) in these cases. Compared to LS, CECDAI scores were more evenly distributed. No significant correlations were observed between endoscopic scores and serum markers, including CRP, hemoglobin, and albumin levels. Additional treatment was performed significantly more often in patients with moderate-severe disease activity (CECDAI ≥5.8) (P = .012) than in those with normal (CECDAI

INTRODUCTION: Prostaglandin E-major urinary metabolite (PGE-MUM) is a novel biomarker reflecting endoscopic activity in ulcerative colitis (UC). However, there are no studies investigating the efficacy of PGE-MUM as a biomarker for predicting relapse. We investigated whether PGE-MUM can predict clinical relapse of UC. METHODS: The measurement of PGE-MUM and endoscopic evaluation were performed in 70 patients with UC in clinical remission. The optimal cutoff values predicting relapse and relapse-free rate were analyzed. RESULTS: Sixteen patients (22.9%) relapsed during the 12-month follow-up. The median PGE-MUM value of relapsed patients at entry was significantly higher than that of patients in clinical remission (P = 0.008). The cutoff value of PGE-MUM predicting future relapse was 25.2 μg/g Cr by receiver-operating characteristic (ROC) analysis, and the area under the ROC curve was 0.721 (95% confidence interval: 0.556–0.886). The relapse-free rate of patients with PGE-MUM ≥25.2 μg/g Cr was significantly lower than that in patients with PGE-MUM

Background The serum N-terminal telopeptide of type I collagen (NTx) is significantly higher in patients with Crohn disease (CD) than in healthy individuals and patients with ulcerative colitis. This study aimed to investigate whether an elevated serum NTx level is a risk predictor of osteoporosis in patients with CD. Methods Based on whether the femoral Z-score decreased over a 2-year period, 41 CD patients were divided into the ΔZ-score Results Although there was no correlation between the mean CDAI and the ΔZ-score, the mean serum NTx and albumin levels were significantly correlated with the ΔZ-score (P Conclusions These observations indicated that an elevated serum NTx could be a useful marker for predicting a decrease in the femoral bone mineral density in CD patients. Anti-TNF-α therapy maintained an elevated serum NTx level, suggesting that treatment with anti-TNF-α may help control increased bone resorption in CD patients.

Although the Crohn's Disease Activity Index (CDAI) is often used to evaluate the disease activity in Crohn's disease (CD), the number of liquid or soft stools cannot be precisely evaluated, and thus accurate scores cannot be calculated, in patients with enterostomy. Therefore, we created the modified CDAI (mCDAI), without the defecation frequency item from the CDAI, and examined its usefulness.Study participants comprised 9 patients with CD with enterostomy and 20 patients with CD without enterostomy. Correlations between the mCDAI and serum albumin (Alb) levels or C-reactive protein (CRP) levels were examined using regression analysis. Additionally, regression analyses were conducted in patients with CD without enterostomy to determine the Alb and CRP levels corresponding to the CDAI at its cutoff value for remission status (150). The obtained values were applied to the mCDAI regression equations to determine the equivalent mCDAI cutoff value.mCDAI and Alb levels were significantly negatively correlated (P

Decreased trough level of infliximab (TLI) is associated with diminished efficacy in patients with Crohn disease (CD). We examined whether TLI at 14 weeks subsequent to the start of infliximab (IFX) treatment would impact long-term clinical course. Serum IFX levels and antibodies to IFX (ATI) at 14 and 54 weeks after IFX administration were measured in 12 patients with mild to moderate CD. We examined patient background, clinical severity, blood test values, and the relationship between ATI and TLI up to 108 weeks. We compared the group with TLI 3 μg/mL (TLI(14) ≥ 3 group). Patients in the TLI(14) ≥ 3 group were significantly more likely to use immunomodulators before IFX treatment induction (P = .01). At 54 weeks, 2 cases of ATI production were observed in the TLI(14)

The efficacy of sustained-release preparations of mesalazine as a remission maintenance treatment for Crohn's disease remains to be established. We aimed to examine the changes in compliance rate and clinical data 2 years after switching from mesalazine tablet to granule formulation at our facility among patients with Crohn's disease in remission. We investigated the rate of continuous treatment of mesalazine granules and examined the changes in Crohn’s Disease Activity Index (CDAI) and serum C-reactive protein (CRP), albumin, and hemoglobin (Hb) levels 2 years after the switch. Compliance rate (continuous treatment vs. additional treatment) and continuous treatment rate [good (rate of ≥ 70%) vs. poor (rate P = 0.023) and Hb levels increased significantly (P = 0.002). No change in the compliance rate was found. Our results suggest that mesalazine granule formulation may have a remission maintenance effect that is superior to that of mesalazine tablets.

Purpose: The effects of ulcerative colitis (UC) duration on biomarker accuracy are unknown. We investigated the effects of UC duration on the predictive accuracy of biomarkers including immunochemical fecal occult blood test (FOBT, also known as FIT), prostaglandin E-major urinary metabolite (PGE-MUM), and C-reactive protein (CRP).Methods: We divided 133 samples into groups based on disease duration. Clinical and endoscopic remission was defined as Lichtiger’s clinical activity index (CAI) of ≤4, Mayo endoscopic subscore (MES) of 0, and UC endoscopic index of severity (UCEIS) of ≤1.Results: FIT results were significantly correlated with all activity scores when the disease duration was

Background Although autoimmune gastritis (AIG) is generally considered relatively rare, we frequently encounter AIG among patients at to our hospital who have experienced at least two episodes of Helicobacter pylori eradication failure. Aims We investigated the incidence of AIG in consecutive patients who consulted our department for H. pylori eradication with reference to eradication history. Methods A total of 404 consecutive patients who visited the H. pylori-specific out-patient unit of our hospital from June 2015 to June 2017 were enrolled. Of these, 137 were treatment-naive, 47 had failed treatment once (single failure), and 220 had failed treatment twice or more (multiple failures) by 13 C-UBT. Gastroscopy was performed in all patients. Culture tests of gastric mucosal samples were performed for H. pylori and other bacteria positive for urease activity. Anti-parietal cell antibody (APCA) was measured. Patients with severe atrophy in the gastric corpus and positivity for APCA were diagnosed as having AIG. Results A total of 43 patients were diagnosed as having AIG, of whom two were treatment-naive (1.5%, 2/137), 1 failed eradication once (2.1% 1/47), and 40 failed treatment at least twice (18.2%, 40/220). The incidence of AIG was significantly higher in the multiple failure group than in the single failure or treatment-naive groups. Urease-positive bacteria, such as Klebsiella pneumoniae and alpha-streptococcus, were identified in 33 of the 35 AIG patients who underwent culture testing. Conclusion AIG patients were often misdiagnosed as refractory to eradication therapy, probably because achlorhydria in AIG might allow urease-positive bacteria other than H. pylori to colonise the stomach, causing positive 13 C-UBT results.

Background Prostaglandin E-major urinary metabolite (PGE-MUM) may be a novel biomarker for evaluating disease activity in ulcerative colitis (UC). We compared its usefulness to that of the fecal immunochemical occult blood test (FIT). Methods PGE-MUM and FIT measurements were performed of 92 urinary and fecal samples obtained from 60 patients with UC. Endoscopic activity was determined by Mayo endoscopic subscore (eMayo) and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score. Results PGE-MUM levels and FIT results showed a significant correlation with respect to eMayo (P P P = 0.012). Both biomarkers were significantly correlated with the UCEIS score (P P P = 0.012). PGE-MUM and FIT were significantly correlated with eMayo in the group with a disease duration P = 0.041 and P P = 0.012), FIT was not correlated with eMayo (P = 0.101). Conclusions PGE-MUM is useful as a biomarker as FIT for evaluating the endoscopic activity, particularly in long-term affected patients with UC.

Background Abdominal compartment syndrome (ACS) is associated with mortality in patients with critical illness such as severe acute pancreatitis, but it remains unclear whether decompressive laparotomy for ACS can improve the prognosis of patients. Case presentation A woman in her 60s visited our hospital because of upper abdominal pain. On the basis of her laboratory data and abdominal contrast-enhanced computed tomography findings, acute gallstone pancreatitis was diagnosed. She underwent endoscopic sphincterotomy for the removal of the common bile duct stone. Then, a drainage tube was placed in the bile duct. However, on the 5th hospital day, her intra-abdominal pressure increased to 22 mmHg and renal dysfunction was observed, which led to the diagnosis of ACS. As intensive medical treatments did not improve her ACS, she underwent decompressive laparotomy on the 9th hospital day. Postoperatively, her laboratory data and intravesical pressure improved, and she was discharged from the hospital after abdominal closure, continuous drainage, and antibiotic therapy. Conclusion As the effectiveness of decompressive laparotomy for ACS has not been established, this treatment indication remains controversial. Decompressive laparotomy is considered useful for the management of ACS, if it is performed at an appropriate time, as in the present case.

Vonoprazan (VPZ) is the first clinically available potassium competitive acid blocker. This class of agents provides faster and more potent acid inhibition than proton pump inhibitors. Most strains of Helicobacter pylori are sensitive to amoxicillin. We hypothesized that dual therapy with VPZ and amoxicillin would provide the sufficient eradication rate for H. pylori infection. To evaluate this, we compared the eradication rate by the dual VPZ/amoxicillin therapy with that by the standard triple VPZ/amoxicillin/clarithromycin therapy.Non-inferiority of the eradication rate of H. pylori by the dual therapy with VPZ 20 mg twice daily (bid) and amoxicillin 500 mg 3 times daily (tid) for 1 week to that by the triple therapy with VPZ 20 mg bid, amoxicillin 750 mg bid and clarithromycin 200 mg bid for 1 week was retrospectively studied. Propensity score matching was performed to improve comparability between 2 regimen groups. Successful eradication was diagnosed using the [13C]-urea breath test at 1-2 months after the end of eradication therapy.The intention-to-treat analysis demonstrated that the eradication rate by the dual therapy (92.9%; 95% CI 82.7-98.0%, 52/56) was not inferior to that of the triple therapy (91.9%; 95% CI 80.4-97.0%, 51/56; OR 1.275, 95% CI 0.324-5.017%, p = 0.728). There were no statistically significant differences in incidences of adverse events between 2 regimens.VPZ-based dual therapy (VPZ 20 mg bid and amoxicillin 500 mg tid for 1 week) provides an acceptable eradication rate of H. pylori infection without the need for second antimicrobial agents, such as clarithromycin.

Objective To date, no randomised trials have compared the efficacy of vonoprazan and amoxicillin dual therapy with other standard regimens for Helicobacter pylori treatment. This study aimed to investigate the efficacy of the 7-day vonoprazan and low-dose amoxicillin dual therapy as a first-line H. pylori treatment, and compared this with vonoprazan-based triple therapy. Design This prospective, randomised clinical trial was performed at seven Japanese institutions. Patients with H. pylori–positive culture test and naive to treatment were randomly assigned in a 1:1 ratio to either VA-dual therapy (vonoprazan 20 mg+amoxicillin 750 mg twice/day) or VAC-triple therapy (vonoprazan 20 mg+amoxicillin 750 mg+clarithromycin 200 mg twice/day) for 7 days, with stratification by age, sex, H. pylori antimicrobial resistance and institution. Eradication success was evaluated by 13C-urea breath test at least 4 weeks after treatment. Results Between October 2018 and June 2019, 629 subjects were screened and 335 were randomised. The eradication rates of VA-dual and VAC-triple therapies were 84.5% and 89.2% (p=0.203) by intention-to-treat analysis, respectively, and 87.1% and 90.2% (p=0.372) by per-protocol analysis, respectively. VA-dual was non-inferior to VAC-triple in the per-protocol analysis. The eradication rates in strains resistant to clarithromycin for VA-dual were significantly higher than those for VAC-triple (92.3% vs 76.2%; p=0.048). The incidence of adverse events was equal between groups. Conclusion The 7-day vonoprazan and low-dose amoxicillin dual therapy provided acceptable H. pylori eradication rates and a similar effect to vonoprazan-based triple therapy in regions with high clarithromycin resistance. Trial registration number UMIN000034140.

Background: When administered at a standard dose, proton pump inhibitors (PPIs) do not always provide sufficient acid inhibition for all subjects, particularly in extensive metabolizers (EMs) of CYP2C19. Whether esomeprazole at a dose of 20 mg four times daily dosing (q.i.d.) can attain sufficient acid inhibition throughout 24 h in EMs remains unclear. We therefore investigated the efficacy of esomeprazole q.i.d. for acid inhibition. Methods: In a randomized cross-over design, 30 Helicobacter pylori-negative healthy young Japanese volunteers received esomeprazole at a dose of 20 mg two times a day (b.i.d.) or q.i.d. for 7 days. A pH monitoring was conducted before the trial as a control and on day 7 of both regimens. Results: Median pH values in the q.i.d. regimen were significantly higher than those with the b.i.d. regimen in EMs (b.i.d.: 5.3, q.i.d.: 6.6, p = 0.022), intermediate metabolizer (IM) (b.i.d.: 5.5, q.i.d.: 6.8, p = 0.005) and poor metabolizer (PM) (b.i.d.: 6.2, q.i.d.: 7.0, p = 0.047), respectively. Median pH with the b.i.d. regimen differed significantly by CYP2C19 genotypes (p = 0.004), but not the q.i.d. regimen (p = 0.384). Conclusion: Esomeprazole q.i.d. achieved potent acid inhibition in all Helicobacter pylori-negative subjects, irrespective of CYP2C19 genotype, which might be one of the rescue regimens for patients' refractory to PPI treatment.

Vonoprazan, a novel potassium-competitive acid blocker, elicits potent acid inhibition and hypergastrinemia at a dose of 20 mg. Its recommended maintenance dose for gastro-esophageal reflux disease is 10 mg, which is sometimes insufficient for preventing nocturnal acid breakthrough (NAB). Concomitant use of a histamine 2 receptor antagonist (H2RA) is effective for NAB. However, further acid inhibition by addition of H2RA has concern of hypergastrinemia again. Lafutidine (H2RA) is known to stimulate somatostatin release. The aim of this study is to compare the levels of acid inhibition and serum gastrin attained by addition of lafutidine to vonoprazan 10 mg with levels after a dose increase of vonoprazan from 10 to 20 mg. Thirteen healthy volunteers underwent 24-h intragastric pH monitoring and serum gastrin measurements on day 7 of three different regimens: vonoprazan 10 mg, vonoprazan 10 mg plus lafutidine 10 mg, and vonoprazan 20 mg. Median pH 4 holding time ratios (range) by vonoprazan 10 mg, vonoprazan 10 mg plus lafutidine 10 mg, and vonoprazan 20 mg were 82% (47–88%), 88% (76–93%), and 99% (95–100%) while those at nighttime from 10 p.m. to 8 a.m. were 94% (29–100%), 100% (95–100%), and 100%, respectively. The incidences of NAB with vonoprazan 10 mg, vonoprazan plus lafutidine, and vonoprazan 20 mg were 38, 8, and 0%, respectively. Respective serum gastrin levels were 420 (173–508), 323 (196–521), and 504 (400–812) pg/ml. Addition of lafutidine 10 mg to vonoprazan 10 mg achieved sufficient acid inhibition, especially at nighttime, without further increase of serum gastrin levels.

Proton pump inhibitors (PPIs) at low doses can effectively prevent gastrointestinal bleeding due to aspirin and are widely used in Japan for gastroprotection in patients taking anti-platelet agents. We examined the influence of different PPIs at low doses administered concomitantly or separately on anti-platelet functions of clopidogrel. In 41 healthy Japanese volunteers with different CYP2C19 genotypes who took clopidogrel 75 mg in the morning alone, or with omeprazole 10 mg, esomeprazole 10 mg, lansoprazole 15 mg, or rabeprazole 10 mg, either concomitantly in the morning or separately in the evening, we measured the inhibition of platelet aggregation (IPA, %) using VerifyNow P2Y12 assay at 4 h after the last clopidogrel dose on Day 7 of each regimen. IPA by clopidogrel with rabeprazole administered at lunchtime, approximately 4 h after clopidogrel, was also measured. Mean IPAs in those concomitantly receiving omeprazole, esomeprazole, lansoprazole or rabeprazole (47.2 ± 21.1%, 43.2 ± 20.2%, 46.4 ± 18.8%, and 47.3 ± 19.2%, respectively) were significantly decreased compared with those receiving clopidogrel alone (56.0%) (all ps

Methyl-CpG binding domain protein 4 (MBD4) is a DNA glycosylase that can remove 5-fluorodeoxyuracil from DNA as well as repair T:G or U:G mismatches. MBD4 is a target for frameshift mutation with DNA mismatch repair (MMR) deficiency, creating a truncated MBD4 protein (TruMBD4) that lacks its glycosylase domain. Here we show that TruMBD4 plays an important role for enhancing 5-fluorouracil (5FU) sensitivity in MMR-deficient colorectal cancer cells. We found biochemically that TruMBD4 binds to 5FU incorporated into DNA with higher affinity than MBD4. TruMBD4 reduced the 5FU affinity of the MMR recognition complexes that determined 5FU sensitivity by previous reports, suggesting other mechanisms might be operative to trigger cytotoxicity. To analyze overall 5FU sensitivity with TruMBD4, we established TruMBD4 overexpression in hMLH1-proficient or -deficient colorectal cancer cells followed by treatment with 5FU. 5FU-treated TruMBD4 cells demonstrated diminished growth characteristics compared to controls, independently of hMLH1 status. Flow cytometry revealed more 5FU-treated TruMBD4 cells in S phase than controls. We conclude that patients with MMR-deficient cancers, which show characteristic resistance to 5FU therapy, may be increased for 5FU sensitivity via secondary frameshift mutation of the base excision repair gene MBD4.

SPG3A-linked hereditary spastic paraplegia (HSP) is a rare autosomal dominant motor disorder caused by a mutation in the SPG3A gene, and is characterized by progressive motor weakness and spasticity in the lower limbs, without any other neurological abnormalities. SPG3A-linked HSP caused by a R239C mutation has been reported to present a pure phenotype confined to impairment of the corticospinal tract. However, there is still a debate about the etiology of this motor deficit with regard to whether it is peripheral or central. We herein report two patients who were heterozygous for a R239C mutation in the SPG3A gene. Two middle-aged Japanese sisters had been suffering from a pure phenotype of HSP since their childhood. Both patients had a significant decrease in glucose metabolism in the frontal cortex medially and dorsolaterally in a [(18)F]-fluorodeoxyglucose (FDG) positron emission photography (PET) study and low scores on the Frontal Assessment Battery. A real-time PCR analysis in normal subjects showed the frontal cortex to be the major location where SPG3A mRNA is expressed. The present finding that the frontal glucose hypometabolism was associated with frontal cognitive impairment indicates that widespread neuropathology associated with mutations in the SPG3A gene may be present more centrally than previously assumed.

Pancreatic ductal adenocarcinoma (PDAC) prognosis remains poor even after complete resection owing to no valuable biomarkers for recurrence and chemosensitivity. Tumors not expressing MSH3 show elevated microsatellite alterations at selected tetranucleotide repeats (EMAST). EMAST reportedly occurs in several tumors. In colorectal cancer (CRC), EMAST was reportedly correlated with 5-fluorouracil (5-FU) sensitivity. However, EMAST prevalence in PDAC and its significance as a prognostic biomarker are unknown. This study aimed to investigate EMAST prevalence in PDAC and the associations between EMAST and pathological factors, EMAST and prognosis, and EMAST and MSH3 expression via immunohistochemistry (IHC). We assessed 40 PDAC patients undergoing surgery. Genomic DNA was extracted from tumors and normal tissues. EMAST and microsatellite instability-high (MSI-H) were analyzed using five polymorphic tetranucleotide markers and five mononucleotide markers, respectively. Tumor sections were stained for MSH3, and staining intensity was evaluated via the Histoscore (H-score). Eighteen of 40 (45%) PDAC patients were EMAST-positive; however, none were MSI-H-positive. Clinicopathological characteristics including overall survival (OS) and recurrence-free survival (RFS) were not significantly different between EMAST-positive and EMAST-negative patients (P = 0.45, 0.98 respectively). IHC was performed to evaluate MSH3 protein expression levels for the PDAC tissue specimens. H-scores of EMAST-positive patients ranged from 0 to 300 (median, 40) and those of EMAST-negative patients ranged from 0 to 300 (median, 170). MSH3 protein was not significantly downregulated in EMAST-positive patients (P = 0.07). This study is a preliminary study and the number of cases investigated was small, and thus, study of a larger cohort will reveal the clinical implication of EMAST.

Ceruloplasmin plays an essential role in cellular iron efflux by oxidizing ferrous iron exported from ferroportin. Ferroportin is posttranslationally regulated through internalization triggered by hepcidin binding. Aceruloplasminemia is an autosomal recessive disorder of iron homeostasis resulting from mutations in the ceruloplasmin gene. The present study investigated the biological effects of glycosylphosphatidylinositol (GPI)-linked ceruloplasmin on the hepcidin-mediated internalization of ferroportin. The prevention of hepcidin-mediated ferroportin internalization was observed in the glioma cells lines expressing endogenous ceruloplasmin as well as in the cells transfected with GPI-linked ceruloplasmin under low levels of hepcidin. A decrease in the extracellular ferrous iron by an iron chelator and incubation with purified ceruloplasmin in the culture medium prevented hepcidin-mediated ferroportin internalization, while the reconstitution of apo-ceruloplasmin was not able to prevent ferroportin internalization. The effect of ceruloplasmin on the ferroportin stability was impaired due to three distinct properties of the mutant ceruloplasmin: namely, a decreased ferroxidase activity, the mislocalization in the endoplasmic reticulum, and the failure of copper incorporation into apo-ceruloplasmin. Patients with aceruloplasminemia exhibited low serum hepcidin levels and a decreased ferroportin protein expression in the liver. The in vivo findings supported the notion that under low levels of hepcidin, mutant ceruloplasmin cannot stabilize ferroportin because of a loss-of-function in the ferroxidase activity, which has been reported to play an important role in the stability of ferroportin. The properties of mutant ceruloplasmin regarding the regulation of ferroportin may therefore provide a therapeutic strategy for aceruloplasminemia patients.

We previously reported that fecal cyclooxygenase 2 (COX-2) mRNA assay, detecting COX-2 mRNA in feces, is useful for identifying subjects with colorectal cancer (CRC). To further improve the sensitivity, we evaluated the usefulness of the combination of COX-2 mRNA and matrix metalloproteinase 7 (MMP-7) mRNA assays as a marker of CRC. The study cohort included 62 patients with CRC and 29 control patients without colorectal neoplasia. RNA was isolated from routinely collected fecal samples. The expression levels of COX-2 and MMP-7 mRNAs were determined by nested reverse transcription-PCR. PCR conditions were optimized where the specificity of fecal COX-2 and MMP-7 mRNA assay result in 100%. The sensitivity of each fecal assay was 87% [95% confidence interval (95% CI), 76-94%] and 65% (95% CI, 51-76%) for CRC, respectively. The sensitivity of fecal RNA test (either marker being positive) was high for CRC (90%; 95% CI, 80-96%). The sensitivity of the fecal RNA test was also high (93%; 95% CI, 80-98%) in patients with stage I or II who are often cured by surgical resection. The fecal RNA test using COX-2 and MMP-7 mRNAs improved the sensitivity to detect CRC without decreasing the specificity. These results suggest that the fecal RNA test would be a promising approach for CRC screening, although larger clinical investigations are indicated. (Cancer Epidemiol Biomarkers Prev 2009;18(6):1888–93)

SummaryBackground Acid inhibitory effects of proton pump inhibitors (PPIs) are influenced by CYP2C19 genotype. In contrast, the potent acid inhibition of vonoprazan is not influenced by CYP2C19 genotype. Aim To compare the acid inhibitory effects of vonoprazan and esomeprazole in relation to CYP2C19 genotype. Methods Twenty-eight healthy Japanese volunteers [7 CYP2C19 poor metabolisers (PMs), 11 intermediate metabolisers (IMs) and 10 rapid metabolisers (RMs)] received four different regimens in a randomised crossover manner: (i) vonoprazan 20 mg twice daily (b.d.), (ii) vonoprazan 20 mg daily, (iii) esomeprazole 20 mg b.d. and (iv) esomeprazole 20 mg daily. The timing of each dosing was 1 h before a meal. Twenty-four-hour intragastric pH monitoring was performed on day 7 on each regimen. Results In the overall genotype group, pH ≥4 holding time ratios (pH 4 HTRs) with vonoprazan b.d., vonoprazan daily, esomeprazole b.d. and esomeprazole daily were 100%, 95%, 91%, and 68% respectively. pH 5 HTRs were 99%, 91%, 84% and 54% respectively. Vonoprazan b.d. potently suppressed acid for 24 h, and was significantly superior to other regimens irrespective of CYP2C19 genotype. Vonoprazan daily was equivalent to esomeprazole b.d. in IMs and PMs, but superior in RMs. CYP2C19 genotype-dependent differences were observed in esomeprazole daily but not in vonoprazan b.d. or daily. Conclusion Vonoprazan 20 mg b.d. inhibits acid irrespective of CYP2C19 genotype, more potently than esomeprazole 20 mg b.d., pH 4 and 5 holding time ratios reached 100% and 99%, respectively.

Background & Aims Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is the most common DNA mismatch repair defect in colorectal cancers, observed in approximately 60% of specimens. This acquired genotype correlates with metastasis and poor outcomes for patients, and is associated with intra-epithelial inflammation and heterogeneous nuclear levels of the mismatch repair protein hMSH3. Inflammation and accompanying oxidative stress can cause hMSH3 to change its intracellular location, but little is known about the source of oxidative stress in cancer cells. We investigated whether cytokines mediate this process. Methods We analyzed levels of interleukin 6 (IL6) and its receptor (IL6R) in human colon and lung cancer cell lines by flow cytometry and enzyme-linked immunosorbent assay; proteins were localized by immunofluorescence and immunoblot analyses. IL6 signaling was blocked with antibodies against IL6, soluble glycoprotein 130 Fc fragments, and the signal transducers and activators of transcription 3 inhibitor NSC74859; a constitutively active form of STAT3 was expressed in colon and lung cancer cell lines to replicate IL6R signaling. EMAST was detected by DNA fragment analysis. Immunohistochemistry was used to examine levels of IL6 in 20 colorectal tumor and adjacent nontumor tissues. Results Incubation of colon and lung cancer cell lines with IL6, but not other cytokines, caused hMSH3, but no other mismatch repair proteins, to move from the nucleus to the cytosol after generation of oxidative stress; inhibition of IL6 signaling prevented this shift. Expression of constitutively active STAT3 also caused hMSH3 to translocate from the nucleus to the cytoplasm in cancer cell lines. Incubation of cells with IL6 led to tetranucleotide frameshifts, the signature for EMAST. EMAST-positive colorectal tumors had significantly higher levels of IL6 than EMAST-negative tumors. Conclusions IL6 signaling disrupts the nuclear localization of hMSH3 and DNA repair, leading to EMAST in cancer cell lines. Inflammatory cytokines might therefore promote genetic alterations in human cancer cells.

Guggulsterone, a plant polyphenol guggulipid, has several antitumour effects and acts as an antagonist for the farnesoid X receptor. Although bile acids induce caudal-related homeobox 2 (CdX2), a transcription factor essential for intestinal development and gut tumourigenesis, the effects of guggulsterone on regulation of CdX2 in the gut are unknown.Regulation of CdX2 expression by treatment with bile acids and/or guggulsterone was analysed by immunoblot analysis in human gut-derived adenocarcinoma, Bic-1 cells. Nuclear factor-kappaB (NF-kappaB) activity and the cell cycle distribution were also examined.Chenodeoxycholic acid and deoxycholic acid increased CdX2 expression in Bic-1 cells. Guggulsterone reduced bile acid-induced and constitutive CdX2 expression at 5 microM. Guggulsterone (up to 5 microM) did not affect cell viability or the cell cycle and did not attenuate bile acid-induced or constitutive NF-kappaB activation.Guggulsterone may be used as a novel drug to target CdX2 expression in certain gut adenocarcinomas.

Colorectal cancer (CRC) is one of the most common causes of cancer-related mortality worldwide. Effective screening to detect cancer is expected to reduce the mortality rate of CRC (Mandel et al, 1993; Hardcastle et al, 1996; Scholefield et al, 2002; Lindholm et al, 2008). Faecal occult blood test (FOBT) is a non-invasive and simple test reported to reduce the morbidity and mortality associated with CRC (Mandel et al, 1993; Hardcastle et al, 1996; Scholefield et al, 2002; Lindholm et al, 2008). However, the efficacy of FOBT is limited because of the common occurrence of occult bleeding from non-neoplastic sources (Osborn and Ahlquist, 2005) and less sensitivity for proximal CRC (Morikawa et al, 2005). Novel methods are now under development for detection of CRC, including those based on the detection of mutated DNA, DNA integrity (Imperiale et al, 2004; Ahlquist et al, 2008), cancer-related methylation (Chen et al, 2005; Glockner et al, 2009), and upregulation of cancer-related gene expression in faecal samples (Kanaoka et al, 2004; Koga et al, 2008; Yu et al, 2008; Takai et al, 2009). We previously reported that faecal cyclooxygenase-2 (COX-2) mRNA assay is a sensitive and specific method to detect CRC and adenoma (Kanaoka et al, 2004, 2007; Takai et al, 2009). However, factors that contribute to faecal COX-2 mRNA expression were not well evaluated. COX-2 mRNA expression levels in faeces may be affected by both the number of exfoliated cells that express COX-2 mRNA and the mRNA degradation in faecal samples. Colonocytes and inflammatory cells are reported to be abundant in the mucocellular layer covering CRC tissue (Ahlquist et al, 2000). Some of the colonocytes in this mucocellular layer in CRC were reported to retain tumour-associated antigen (Ahlquist et al, 2000), suggesting that some of them may express COX-2 mRNA. Inflammatory cells are known to express COX-2 mRNA (Sano et al, 1995). Inflammatory cell infiltrates are commonly seen surrounding and/or infiltrating primary tumours. Therefore, it is possible that the degree of inflammatory cell infiltration influences COX-2 mRNA expression in faeces. The increase in faecal COX-2 mRNA expression may be caused by the increased number of exfoliated cells. Cell exfoliation from colonic epithelium was known to be dramatically increased in neoplasia (Ahlquist et al, 2000; Loktionov, 2007). It is well known that COX-2 is overexpressed in >80% of CRCs (Kawasaki et al, 2008). The difference in COX-2 mRNA expression among colorectal tumours may affect COX-2 mRNA expression in faeces. Tumour size can be another factor that affects faecal COX-2 mRNA expression through the increase in exfoliated cells and through modification of COX-2 mRNA expression in CRC (Fujita et al, 1998). Faecal COX-2 mRNA expression may be affected by the location of tumour, if the degradation of COX-2 mRNA in the colon is affected by the transit time of stool in the colon. All these factors, including the number of exfoliating cells, inflammatory cell infiltration, the expression of COX-2 mRNA in cancer tissue, and the size and location of the tumour, may contribute to the expression of faecal COX-2 mRNA in CRC. In this study, we evaluated the number of exfoliated cells by measuring the faecal expression of β-2-microglobulin (B2M) mRNA that is expressed at similar levels in both normal and cancer cells (Dydensborg et al, 2006), and carcinoembryonic antigen (CEA) and E-cadherin (E-cad) mRNAs that are expressed in normal and CRC colonic epithelium (Benchimol et al, 1989; Dorudi et al, 1993). CD45 mRNA, as a marker of the number of exfoliated inflammatory cells (Charbonneau et al, 1988), and the expression of COX-2 mRNA in tumour were also evaluated.

We report an elderly patient with esophageal adenocarcinoma in whom a complete response (CR) was obtained by chemoradiotherapy using daily low-dose nedaplatin (CDGP) and continuous infusion of 5-FU. A 86-year-old man who had non-tuberculous mycobacterial infection was admitted for dysphagia, and diagnosed with Stage II A (T2N0M0) esophageal adenocarcinoma of the lower esophagus according to the TNM classification (sixth edition) of the International Union against Cancer (UICC). Chemoradiotherapy using daily low-dose CDGP and continuous infusion of 5- FU was performed, and thereafter one cycle of chemotherapy using CDGP and 5-FU was added. As the side effects of treatment, grade 3 leucopenia was observed while he was receiving chemoradiotherapy. A year later, he presented with grade 2 pericardial and pleural effusion and recovered with conservative treatment. CR was obtained and has been continued for two years. Definitive chemoradiotherapy using daily low-dose CDGP and continuous infusion of 5-FU is an effective choice for elderly and high-risk patients with esophageal adenocarcinoma.

An inverted Meckel’s diverticulum is a rare gastrointestinal congenital anomaly that is difficult to diagnose prior to surgery and presents with anemia, abdominal pain, or intussusception. Here, we report the case of 57-year-old men with an inverted Meckel’s diverticulum, who was preoperatively diagnosed using double-balloon enteroscopy. He had repeatedly experienced epigastric pain for 2 mo. Ultrasonography and computed tomography showed intestinal wall thickening in the pelvis. Double-balloon enteroscopy via the anal route was performed for further examination, which demonstrated an approximately 8-cm, sausage-shaped, submucosal tumor located approximately 80 cm proximal to the ileocecal valve. A small depressed erosion was observed at the tip of this lesion. Forceps biopsy revealed heterotopic gastric mucosa. Thus, the patient was diagnosed with an inverted Meckel’s diverticulum, and single-incision laparoscopic surgery was performed. This case suggests that an inverted Meckel’s diverticulum should be considered as a differential diagnosis for a submucosal tumor in the ileum. Balloon-assisted enteroscopy with forceps biopsy facilitate a precise diagnosis of this condition.

Elevated Microsatellite Alterations at Selected Tetranucleotide repeats (EMAST) is a genetic signature found in up to 60% of colorectal cancers (CRCs) that is caused by somatic dysfunction of the DNA mismatch repair (MMR) protein hMSH3. We have previously shown in vitro that recognition of 5-fluorouracil (5-FU) within DNA and subsequent cytotoxicity was most effective when both hMutSα (hMSH2-hMSH6 heterodimer) and hMutSβ (hMSH2-hMSH3 heterodimer) MMR complexes were present, compared to hMutSα > hMutSβ alone. We tested if patients with EMAST CRCs (hMutSβ defective) had diminished response to adjuvant 5-FU chemotherapy, paralleling in vitro findings. We analyzed 230 patients with stage II/III sporadic colorectal cancers for which we had 5-FU treatment and survival data. Archival DNA was analyzed for EMAST (>2 of 5 markers mutated among UT5037, D8S321, D9S242, D20S82, D20S85 tetranucleotide loci). Kaplan-Meier survival curves were generated and multivariate analysis was used to determine contribution to risk. We identified 102 (44%) EMAST cancers. Ninety-four patients (41%) received adjuvant 5-FU chemotherapy, and median follow-up for all patients was 51 months. Patients with EMAST CRCs demonstrated improved survival with adjuvant 5FU to the same extent as patients with non-EMAST CRCs (P

Background Protracted low-dose concurrent chemotherapy combined with radiation has been proposed for enhanced treatment results for esophageal cancer. We evaluated the efficacy and the toxicity of a novel regimen of daily low-dose nedaplatin (cis-diammine-glycolatoplatinum) and continuous infusion of 5-fluorouracil (5-FU) with radiation in patients with esophageal squamous cell carcinoma. Methods Between January 2003 and June 2008, 33 patients with clinical stage I to IVB esophageal squamous cell carcinoma were enrolled. Nedaplatin (10 mg/body/day) was administered daily and 5-FU (500 mg/body/day) was administered continuously for 20 days. Fractionated radiotherapy for a total dose of 50.4-66 Gy was administered together with chemotherapy. Additional chemotherapy with nedaplatin and 5-FU was optionally performed for a maximum of 5 courses after chemoradiotherapy. The primary end-point of this study was to evaluate the tumor response, and the secondary end-points were to evaluate the toxicity and the overall survival. Results Twenty-two patients (72.7%) completed the regimen of chemoradiotherapy. Twenty patients (60.6%) achieved a complete response, 10 patients (30.3%) a partial response. One patient (3.0%) had a stable disease, and 2 (6.1%) a progressive disease. The overall response rate was 90.9% (95% confidence interval: 75.7%-98.1%). For grade 3-4 toxicity, leukopenia was observed in 75.8% of the cases, thrombocytopenia in 24.2%, anemia in 9.1%, and esophagitis in 36.4%, while late grade 3-4 cardiac toxicity occurred in 6.1%. Additional chemotherapy was performed for 26 patients (78.8%) and the median number of courses was 3 (range, 1-5). The 1-, 2- and 3-year survival rates were 83.9%, 76.0% and 58.8%, respectively. The 1- and 2-year survival rates were 94.7% and 88.4% in patients with T1-3 M0 disease, and 66.2% and 55.2% in patients with T4/M1 disease. Conclusion The treatment used in our study may yield a high complete response rate and better survival for each stage of esophageal squamous cell carcinoma. Trial registration ClinicalTrials.gov Identifier: NCT00197444