Association between factors associated with colorectal cancer and rectal aberrant crypt foci in humans.

Aberrant crypt foci (ACF) are regarded as potential biomarkers for colorectal cancer (CRC), and have been used as such in recent early-phase chemoprevention trials. However, the associations between the presence of ACF and other factors associated with the development of CRC, such as lifestyle factors, medication use and comorbid medical conditions, remain unknown. Thus, the present retrospective, large, cross-sectional study was conducted to evaluate the potential usefulness of ACF as a surrogate biomarker of CRC. Total colonoscopy was performed and the number of rectal ACF was counted in a total of 902 subjects. A retrospective review of the medical records of the study subjects was performed, and the factors associated with the increased prevalence of ACF was investigated using univariate and multivariate logistic regression analyses. The analysis results identified older age [odds ratio (OR), 9.24; 95% confidence interval (CI), 4.80-17.8; P<0.01], smoking habit (OR, 1.78; 95% CI, 1.20-2.63; P<0.01) and use of insulin (OR, 9.97; 95% CI, 1.28-77.5; P=0.03) as significant independent risk factors associated with the increased prevalence of ACF, regardless of the presence/absence of colon tumors. In addition, it was revealed that the prevalence and number of ACF, and the Ki-67 labeling indices of the colonic epithelial cells were significantly higher in diabetic patients receiving insulin therapy than in those not receiving insulin therapy (P<0.01, P=0.03 and P=0.01, respectively). In conclusion, the potential usefulness of ACF as a surrogate biomarker of CRC was confirmed, although useful data could not be obtained on candidate chemopreventive agents. These results indicated that insulin can enhance colonic epithelial proliferative activity and induce the formation of ACF, thereby possibly triggering CRC development.

Frequency and risk factors for rebleeding events in patients with small bowel angioectasia.

BACKGROUND: Small bowel angioectasia is reported as the most common cause of bleeding in patients with obscure gastrointestinal bleeding. Although the safety and efficacy of endoscopic treatment have been demonstrated, rebleeding rates are relatively high. To establish therapeutic and follow-up guidelines, we investigated the long-term outcomes and clinical predictors of rebleeding in patients with small bowel angioectasia. METHODS: A total of 68 patients were retrospectively included in this study. All the patients had undergone CE examination, and subsequent control of bleeding, where needed, was accomplished by endoscopic argon plasma coagulation. Based on the follow-up data, the rebleeding rate was compared between patients who had/had not undergone endoscopic treatment. Multivariate analysis was performed using Cox proportional hazard regression model to identify the predictors of rebleeding. We defined the OGIB as controlled if there was no further overt bleeding within 6 months and the hemoglobin level had not fallen below 10 g/dl by the time of the final examination. RESULTS: The overall rebleeding rate over a median follow-up duration of 30.5 months (interquartile range 16.5-47.0) was 33.8% (23/68 cases). The cumulative risk of rebleeding tended to be lower in the patients who had undergone endoscopic treatment than in those who had not undergone endoscopic treatment, however, the difference did not reach statistical significance (P = 0.14). In the majority of patients with rebleeding (18/23, 78.3%), the bleeding was controlled by the end of the follow-up period. Multiple regression analysis identified presence of multiple lesions (≥3) (OR 3.82; 95% CI 1.30-11.3, P = 0.02) as the only significant independent predictor of rebleeding. CONCLUSION: In most cases, bleeding can be controlled by repeated endoscopic treatment. Careful follow-up is needed for patients with multiple lesions, presence of which is considered as a significant risk factor for rebleeding.

Risk factors for small-bowel mucosal breaks in chronic low-dose aspirin users: data from a prospective multicenter capsule endoscopy registry.

BACKGROUND: To develop appropriate management strategies for patients who take low-dose aspirin, it is important to identify the risk factors for GI injury. However, few studies have described the risk factors for small-bowel injury in these patients. OBJECTIVE: To investigate factors influencing the risk of small-bowel mucosal breaks in individuals taking continuous low-dose aspirin. DESIGN: Capsule endoscopy data were collected prospectively from 5 institutions. SETTING: Yokohama City University Hospital and 4 other hospitals. PATIENTS: A total of 205 patients receiving treatment with low-dose aspirin for over 3 months. INTERVENTIONS: Colonoscopic and upper GI endoscopy had been performed in all of the patients before the capsule endoscope evaluation. MAIN OUTCOME MEASUREMENTS: Risk factors for small-bowel mucosal breaks. RESULTS: Of the 198 patients (141 male; mean age 71.9 years) included in the final analysis, 114 (57.6%) had at least 1 mucosal break. Multivariate analysis identified protein pump inhibitor (PPI) use (OR 2.04; 95% confidence interval [CI], 1.05-3.97) and use of enteric-coated aspirin (OR 4.05; 95% CI, 1.49-11.0) as independent risk factors for the presence of mucosal breaks. LIMITATIONS: Cross-sectional study. CONCLUSION: PPI use appears to increase the risk of small-bowel injury in patients who take continuous low-dose aspirin. Clinicians should be aware of this effect of PPIs; new strategies are needed to treat aspirin-induced gastroenteropathy.

Characteristics of the small bowel lesions detected by capsule endoscopy in patients with chronic kidney disease.

Obscure gastrointestinal bleeding (OGIB) is one of the common complications in patients with chronic kidney disease (CKD), especially those who are on maintenance hemodialysis (HD). However, little is known about the characteristics of the small-bowel lesions in these patients, or of the factors that could predict the presence of such lesions. Therefore we enrolled a total of 42 CKD patients (including 19 HD patients and 23 non-HD patients), and compared the incidence of the small-bowel lesions among two groups. Furthermore, to identify predictive factors for the presence of small-bowel lesions, we performed multivariate logistic-regression-analyses. The incidence of small-bowel vascular lesions was significantly higher in CKD patients than in age-and-sex matched non-CKD patients (P < 0.001). On the other hand, there was any significant difference of the incidence of small-bowel lesions between HD and non-HD patients. In CKD patients, past history of blood transfusion (OR 5.66; 95% CI 1.10-29.1, P = 0.04) was identified as an independent predictor of the presence of vascular lesions, and history of low-dose aspirin use (OR 6.00; 95% CI 1.13-31.9, P = 0.04) was identified as that of erosive/ulcerated lesions. This indicated that proactive CE examination would be clinically meaningful for these patients.

Improvement of pneumatosis cystoides intestinalis after steroid tapering in a patient with bronchial asthma: a case report.

INTRODUCTION: We report the case of a patient who was diagnosed as having pneumatosis cystoides intestinalis while being treated with prednisolone for bronchial asthma. Even before we had experienced a case of this, the relationship between pneumatosis cystoides intestinalis and prednisolone was unclear. In this case, pneumatosis cystoides intestinalis was improved with the reduction of prednisolone, and therefore we thought a direct relationship between pneumatosis cystoides intestinalis and prednisolone might become clear, such as whether it is dose dependent. CASE PRESENTATION: A 62-year-old Japanese woman had been treated for bronchial asthma for approximately 40 years. She presented with abdominal distension, and a radiographic examination showed intraperitoneal free gas and intramural gas, suggestive of pneumatosis cystoides intestinalis. However, when her prednisolone dose was decreased from 30 mg to 0 mg for approximately a year because of improvement in her asthma symptoms, her abdominal symptom resolved, and the frequency of her bowel movements returned to normal. CONCLUSION: Amelioration of pneumatosis cystoides intestinalis was observed with tapering of the prednisolone, suggesting that prednisolone may have been involved in the pathogenesis of pneumatosis cystoides intestinalis in this patient.

Factors predicting the presence of small bowel lesions in patients with obscure gastrointestinal bleeding.

AIM: To identify the predictive factors for the presence of small bowel lesions in patients with obscure gastrointestinal bleeding (OGIB). METHODS: A total of 242 patients with OGIB (overt 149: occult 93) were retrospectively included in the present study. Capsule endoscopy (CE) was carried out to investigate the small bowel, and detected lesions were classified according to the P0-P2 system. Only P2 lesions were defined as significant lesions. Univariate and multivariate logistic regression analyses were carried out to define the predictive factors for the presence of small bowel lesions. RESULTS: In patients with overt OGIB, chronic kidney disease (CKD) ≥stage 4 (odds ratio [OR] 4.03; 95% confidence interval [CI] 1.45-11.1, P = 0.007) was identified as an independent predictor of the presence of vascular lesions, and a history of non-steroidalanti-inflammatory drug (NSAID) use as that of erosive/ulcerated lesions (OR 4.73; 95% CI 1.47-15.2, P = 0.009). However, in patients with occult OGIB, no significant predictors of the presence of vascular lesions were identified, whereas a history of low-dose aspirin (LDA) (OR 3.57; 95% CI 1.21-10.5, P = 0.02) and proton pump inhibitor (PPI) use (OR 3.18; 95% CI 1.02-9.92, P = 0.05) were identified as independent predictors of the presence of erosive/ulcerated lesions. CONCLUSIONS: Our results indicated that bleeding pattern and clinical characteristics could contribute to predicting the origin of OGIB.

Eicosapentaenoic acid (EPA) efficacy for colorectal aberrant crypt foci (ACF): a double-blind randomized controlled trial.

BACKGROUND: Colorectal cancer (CRC) is one of the most commonly occurring neoplasms and a leading cause of cancer death worldwide, and new preventive strategies are needed to lower the burden of this disease. Eicosapentaenoic acid (EPA), the omega-3 polyunsaturated fatty acid that is widely used in the treatment of hyperlipidemia and prevention of cardiovascular disease, has recently been suggested to have a suppressive effect on tumorigenesis and cancer cell growth. In CRC chemoprevention trials, in general, the incidence of polyps or of the cancer itself is set as the study endpoint. Although the incidence rate of CRC would be the most reliable endpoint, use of this endpoint would be unsuitable for chemoprevention trials, because of the relatively low occurrence rate of CRC in the general population and the long-term observation period that it would necessitate. Moreover, there is an ethical problem in conducting long-term trials to determine whether a test drug might be effective or harmful. Aberrant crypt foci (ACF), defined as lesions containing crypts that are larger in diameter and stain more darkly with methylene blue than normal crypts, are considered as a reliable surrogate biomarker of CRC. Thus, we devised a prospective randomized controlled trial as a preliminary study prior to a CRC chemoprevention trial to evaluate the chemopreventive effect of EPA against colorectal ACF formation and the safety of this drug, in patients scheduled for polypectomy. METHODS: This study is a multicenter, double-blind, placebo-controlled, randomized controlled trial to be conducted in patients with both colorectal ACF and colorectal polyps scheduled for polypectomy. Eligible patients shall be recruited for the study and the number of ACF in the rectum counted at the baseline colonoscopy. Then, the participants shall be allocated randomly to either one of two groups, the EPA group and the placebo group. Patients in the EPA group shall receive oral 900-mg EPA capsules thrice daily (total daily dose, 2.7 g per day), and those in the placebo group shall receive oral placebo capsules thrice daily. After one month's treatment with EPA/placebo, colonoscopic examination and polypectomy will be performed to evaluate the formation of ACF, and the cell-proliferative activity and cell-apoptotic activity in normal colorectal mucosa and colorectal polyps. DISCUSSION: This is the first study proposed to explore the effect of EPA against colorectal ACF formation in humans.This trial has been registered in the University hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000008172.

Metformin efficacy and safety for colorectal polyps: a double-blind randomized controlled trial.

BACKGROUND: Colorectal cancer is one of the major neoplasms and a leading cause of cancer death worldwide, and new preventive strategies are needed to lower the burden of this disease. Metformin, a biguanide, which is widely used for treating diabetes mellitus, has recently been suggestive to have a suppressive effect on tumorigenesis and cancer cell growth. In a previous study conducted in non-diabetic subjects, we showed that oral short-term low-dose metformin suppressed the development of colorectal aberrant crypt foci (ACF). ACF have been considered as a useful surrogate biomarker of CRC, although the biological significance of these lesions remains controversial. We devised a prospective randomized controlled trial to evaluate the chemopreventive effect of metformin against metachronous colorectal polyps and the safety of this drug in non-diabetic post-polypectomy patients. METHODS/DESIGN: This study is a multi-center, double-blind, placebo-controlled, randomized controlled trial to be conducted in non-diabetic patients with a recent history of undergoing colorectal polypectomy. All adult patients visiting the Yokohama City University hospital or affiliated hospitals for polypectomy shall be recruited for the study. Eligible patients will then be allocated randomly into either one of two groups: the metformin group and the placebo group. Patients in the metformin group shall receive oral metformin at 250 mg per day, and those in the placebo group shall receive an oral placebo tablet. At the end of 1 year of administration of metformin/placebo, colonoscopy will be performed to evaluate the polyp formation. DISCUSSION: This is the first study proposed to explore the effect of metformin against colorectal polyp formation. Metformin activates AMPK, which inhibits the mammalian target of rapamycin (mTOR) pathway. The mTOR pathway plays an important role in the cellular protein translational machinery and cell proliferation. Patients with type 2 diabetes taking under treatment with metformin have been reported to be at a lower risk of cancer development than those not taking under treatment with metformin. We showed in a previous study that metformin suppressed the formation of human colorectal ACF. We therefore decided to conduct a study to determine whether metformin might suppress the formation of human colorectal polyps. TRIAL REGISTRATION: This trial has been registered in the University hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000006254.