Chemoprevention of colorectal cancer: Past, present, and future.

Chemoprevention began to be considered as a potential strategy for lowering the incidence of cancer and cancer-related deaths in the 1970s. For clinical chemoprevention trials against cancer, including colorectal cancer (CRC), well-established biomarkers are necessary for use as reliable endpoints. Difficulty in establishing validated biomarkers has delayed the start of CRC chemoprevention development. Chemoprevention trials for CRC have only recently been initiated thanks to the identification of reliable biomarkers, such as colorectal adenomas and aberrant crypt foci. Some promising agents have been developed for the prevention of CRC. The chemopreventive effect of selective cyclooxygenase 2 inhibitors has been shown, although these inhibitors are associated with cardiovascular toxicity as a crucial adverse effect. Aspirin, which is a unique agent among non-steroidal anti-inflammatory drugs (NSAIDs) showing minimal gastrointestinal toxicity and no cardiovascular risk, has prevented adenoma recurrence in some randomized controlled trials. More recently, metformin, which is a first-line oral medicine for type 2 diabetes, has been shown to be safe and to prevent adenoma recurrence. A recommendation of the United States Preventive Services Task Force published in 2016 provides a Grade B recommendation for the use of aspirin for chronic prophylaxis against diseases, including CRC, in certain select populations. However, the roles of other agents have yet to be determined, and investigations to identify novel "post-aspirin" agents are also needed. The combined use of multiple drugs, such as aspirin and metformin, is another option that may lead not only to stronger CRC prevention, but also to improvement of other obesity-related diseases.

Contrast-enhanced CT for Colonic Diverticular Bleeding before Colonoscopy: A Prospective Multicenter Study.

Purpose To demonstrate the usefulness of precolonoscopy intravenous contrast material-enhanced CT for colonic diverticular bleeding (CDB). Materials and Methods A prospective, multicenter, observational study was performed. Patients with acute-onset hematochezia who were admitted to hospital were included, and those without CDB were excluded. CT was performed before colonoscopy. A Mann-Whitney U test, χ2 test, and multivariable logistic regression analysis were performed to determine the accuracy of CT before colonoscopy. Results A total of 442 patients (mean age, 71.2 years; 302 male patients; 68.3% men) were included between January 2014 and December 2015, and 202 patients were diagnosed as having CDB. The positive extravasation rate during CT was 50 of 202 (24.7%) among all patients and five of nine (55.6%) among patients who underwent CT within 1 hour of the last hematochezia. At multivariable analysis, the interval from the last hematochezia until CT was a predictor of extravasation (beta coefficient, -.0038 ± 0.0014 [standard deviation]). Extravasation at CT had a sensitivity of 38 of 66 (57.6%; 95% confidence interval: 44.8%, 69.7%) and a specificity of 124 of 136 (91.2%; 95% confidence interval: 85.1%, 95.4%) for the prediction of stigmata of recent hemorrhage of diverticula during colonoscopy. The sensitivity was higher in patients who underwent CT examination within 4 hours of hematochezia, compared with those examined after 4 hours (64.7% [33 of 51] vs 33.3% [five of 15]; P < .01). Conclusion Extravasation findings for CT with intravenous contrast material had high specificity for the prediction of stigmata of recent hemorrhage of diverticula during colonoscopy, regardless of the timing of the CT examination. Although the sensitivity was relatively low, it was higher when the CT examination was performed within 4 hours after the last hematochezia. Therefore, urgent precolonoscopy CT may contribute to decision making regarding whether an urgent colonoscopy should be performed.

Metformin for chemoprevention of metachronous colorectal adenoma or polyps in post-polypectomy patients without diabetes: a multicentre double-blind, placebo-controlled, randomised phase 3 trial.

BACKGROUND: The prevalence of, and mortality from, colorectal cancer is increasing worldwide, and new strategies for prevention are needed to reduce the burden of this disease. The oral diabetes medicine metformin might have chemopreventive effects against cancer, including colorectal cancer. However, no clinical trial data exist for the use of metformin for colorectal cancer chemoprevention. Therefore, we devised a 1-year clinical trial to assess the safety and chemopreventive effects of metformin on sporadic colorectal cancer (assessed by adenoma and polyp recurrence) in patients with a high risk of adenoma recurrence. METHODS: This trial was a multicentre, double-blind, placebo-controlled, randomised phase 3 trial. Non-diabetic adult patients who had previously had single or multiple colorectal adenomas or polyps resected by endoscopy were enrolled into the study from five hospitals in Japan. Eligible patients were randomly assigned (1:1) to receive oral metformin (250 mg daily) or identical placebo tablets by a stratified computer-based randomisation method, with stratification by institute, age, sex, and body-mass index. All patients, endoscopists, doctors, and investigators were masked to drug allocation until the end of the trial. After 1 year of administration of metformin or placebo, colonoscopies were done to assess the co-primary endpoints: the number and prevalence of adenomas or polyps. Our analysis included all participants who underwent random allocation, according to the intention-to-treat principle. This trial is registered with University Hospital Medical Information Network (UMIN), number UMIN000006254. FINDINGS: Between Sept 1, 2011, and Dec 30, 2014, 498 patients who had had single or multiple colorectal adenomas resected by endoscopy were enrolled into the study. After exclusions for ineligibility, 151 patients underwent randomisation: 79 were assigned to the metformin group and 72 to the placebo group. 71 patients in the metformin group and 62 in the placebo group underwent 1-year follow-up colonoscopy. The prevalence of total polyps (hyperplastic polyps plus adenomas) and of adenomas in the metformin group was significantly lower than that in the placebo group (total polyps: metformin group 27 [38·0%; 95% CI 26·7-49·3] of 71 patients, placebo group 35 [56·5%; 95% CI 44·1-68·8] of 62; p=0·034, risk ratio [RR] 0·67 [95% CI 0·47-0·97]; adenomas: metformin group 22 [30·6%; 95% CI 19·9-41·2] of 71 patients, placebo group 32 [51·6%; 95% CI 39·2-64·1] of 62; p=0·016, RR 0·60 [95% CI 0·39-0·92]). The median number of polyps was zero (IQR 0-1) in the metformin group and one (0-1) in the placebo group (p=0·041). The median number of adenomas was zero (0-1) in the metformin group and zero (0-1) in the placebo group (p=0·037). 15 (11%) of patients had adverse events, all of which were grade 1. We recorded no serious adverse events during the 1-year trial. INTERPRETATION: The administration of low-dose metformin for 1 year to patients without diabetes was safe. Low-dose metformin reduced the prevalence and number of metachronous adenomas or polyps after polypectomy. Metformin has a potential role in the chemoprevention of colorectal cancer. However, further large, long-term trials are needed to provide definitive conclusions. FUNDING: Ministry of Health, Labour and Welfare, Japan.

Clinical value of capsule endoscopy for detecting small bowel lesions in patients with intestinal Behçet's disease.

BACKGROUND AND AIM: To evaluate the clinical value of capsule endoscopy (CE) in patients with intestinal Behçet's disease (BD). METHODS: The present study was a case-control pilot study conducted in intestinal BD patients and healthy volunteers. A total of 19 patients with intestinal BD (intestinal BD group) and 19 healthy volunteers (control group) matched for age and sex were enrolled. Frequency, number of small bowel lesions per subject, and Lewis score were comparatively evaluated between the two groups. RESULTS: Of the 19 patients with intestinal BD, 18 (94.7%) had reddened lesions, 15 (78.9%) had erosions, and nine (47.4%) had ulcers. There were significant differences in the frequency of reddened lesions (P < 0.0001), erosions (P < 0.0001) and ulcers (P = 0.0011) between the two groups. The difference in the number of small bowel lesions between the two groups was also statistically significant. The median Lewis score in the intestinal BD group was significantly higher than that in the control group (intestinal BD group 237 (0-768) vs. control group 8 (0-135); P < 0.0001). Analysis according to the location in the small bowel revealed that the frequency of ulcers tended to increase towards the distal intestine. CONCLUSION: This is the first CE study conducted to examine small bowel involvement in intestinal BD patients. Our results suggest that CE evaluation is necessary, in addition to colonoscopy, in all intestinal BD patients.

Is it worthwhile to perform capsule endoscopy for asymptomatic patients with positive immunochemical faecal occult blood test?

BACKGROUND: The immunochemical faecal occult blood test (IFOBT) is widely performed for colorectal cancer screening, but the usefulness of IFOBT in the detection of disorders of the small intestine is unknown. The objective of this study was to investigate what proportion of IFOBT-positive subjects with negative colonoscopy and oesophagogastroduodenoscopy has pathologies of the small intestine detected by capsule endoscopy (CE). METHODS: Between October 2008 and June 2010, asymptomatic IFOBT-positive patients with negative total colonoscopy and oesophagogastroduodenoscopy underwent CE. CE findings were classified into three categories: P0 (no abnormalities, or findings without potential for bleeding), P1 (findings with uncertain potential for bleeding), P2 and (findings with high potential for bleeding). RESULTS: Fifty-three patients (37 males, 16 females; 52.1 ± 13.0 years) were included. There were no cases with P2, 19 cases with P1, and 34 cases with P0 (there were no abnormalities in 25 of 34 cases). As a result, lesions in the small intestine were detected in 28 cases. Additional examination was considered necessary for five patients after CE, but no abnormality was detected, and therapeutic intervention was not undertaken in any case. Caecal completion rate was 92.5%. CONCLUSIONS: No significant pathologies of the small intestine were detected in asymptomatic IFOBT-positive cases with negative colonoscopy and oesophagogastroduodenoscopy. CE is of limited use in asymptomatic patients with positive IFOBT.

[Diagnosis of small bowel carcinoma by capsule endoscopy].

Now in Japan, the use of capsule endoscopy for small bowel is approved only for the diagnosis of obscure gastrointestinal bleeding. Since the small bowel is anatomically difficult to approach, and small bowel carcinomas are often asymptomatic at early stages, they were usually diagnosed only after symptoms such as intestinal stenosis have developed. The advent of capsule endoscopy, however, enabled us to diagnose small bowel carcinoma at an early stage. However, we must be careful of the risk of capsule retention. The combination of capsule endoscopy, double balloon endoscopy, and traditional examination modalities including radiography or computed tomography will make it possible to diagnose and treat small bowel carcinoma at an early stage, and further progress is expected in this field.

A nationwide, multi-center, retrospective study of symptomatic small bowel stricture in patients with Crohn's disease.

BACKGROUND: Small bowel stricture is one of the most common complications in patients with Crohn's disease (CD). Endoscopic balloon dilatation (EBD) is a minimally invasive treatment intended to avoid surgery; however, whether EBD prevents subsequent surgery remains unclear. We aimed to reveal the factors contributing to surgery in patients with small bowel stricture and the factors associated with subsequent surgery after initial EBD. METHODS: Data were retrospectively collected from surgically untreated CD patients who developed symptomatic small bowel stricture after 2008 when the use of balloon-assisted enteroscopy and maintenance therapy with anti-tumor necrosis factor (TNF) became available. RESULTS: A total of 305 cases from 32 tertiary referral centers were enrolled. Cumulative surgery-free survival was 74.0% at 1 year, 54.4% at 5 years, and 44.3% at 10 years. The factors associated with avoiding surgery were non-stricturing, non-penetrating disease at onset, mild severity of symptoms, successful EBD, stricture length < 2 cm, and immunomodulator or anti-TNF added after onset of obstructive symptoms. In 95 cases with successful initial EBD, longer EBD interval was associated with lower risk of surgery. Receiver operating characteristic analysis revealed that an EBD interval of ≤ 446 days predicted subsequent surgery, and the proportion of smokers was significantly high in patients who required frequent dilatation. CONCLUSIONS: In CD patients with symptomatic small bowel stricture, addition of immunomodulator or anti-TNF and smoking cessation may improve the outcome of symptomatic small bowel stricture, by avoiding frequent EBD and subsequent surgery after initial EBD.

A Patient with KL-6 Elevation with Anti-TNFα Who Could Receive Long-Term Use without Interstitial Pneumonia after Class Switch of Anti-TNFα.

A 40-year-old man with refractory ulcerative colitis (UC) was treated with tumor necrosis factor α inhibitor (anti-TNFα), infliximab. One month later, the chest computed tomography and laboratory test showed noninfectious interstitial lung disease (ILD) and elevation of serum Krebs von den Lungen-6 (KL-6). Fortunately, ILD disappeared after the discontinuation with anti-TNFα. Two and a half years after his first UC treatment, he was treated again with another anti-TNFα, adalimumab, for relapse and he had a second ILD. This course suggested anti-TNFα induced ILD. The characteristics of anti-TNFα-induced ILD in inflammatory bowel disease (IBD) are not well understood. We summarized and investigated the characteristics of such patients based on a literature review including 15 cases. It suggested that anti-TNFα-induced ILD in IBD might be rare and tends to have a better outcome compared with ILD in rheumatoid arthritis.

AMPK: Therapeutic Target for Diabetes and Cancer Prevention.

BACKGROUND: AMP-activated protein kinase (AMPK) is a protein kinase that maintains homeostasis in cells and organs. As a master regulator of metabolism, AMPK coordinates many metabolic reactions. AMPK is a key factor in diabetes and metabolic syndrome associated with dysregulation of the metabolic status. Recently, AMPK has also attracted attention as a tumor suppressor. The aim of this article is to discuss about the role of AMPK in diabetes as well as cancer and to evaluate its effectiveness in treatment and prevention of these diseases. METHOD: We reviewed studies of signaling mechanism involving AMPK and research on the role of AMPK in human disease including diabetes and cancer. In particular, we focused our attention on clinical trials about cancer treatment and prevention targeting AMPK. RESULTS: Many experimental studies reported the relation of AMPK and various metabolic reactions, mainly regulating energy homeostasis. Recent studies showed effect of AMPK on arrest of cell cycle as well as suppression of inflammation, which are important factors for carcinogenesis. Although some clinical studies investigated cancer treatment and prevention targeting AMPK, the effective yields in clinical trial have been limited. CONCLUSION: AMPK activation as represented by metformin showed to improve disorders associated with diabetes and metabolic syndrome and became a well-established treatment strategy for these diseases. The increasing evidence suggests that AMPK is a promising target in the treatment and prevention of cancer. Further investigation including long-term clinical trials with large sample size is needed.

Small bowel injury in low-dose aspirin users.

The use of low-dose aspirin (LDA) is well known to be associated with an increased risk of serious upper gastrointestinal complications, such as peptic ulceration and bleeding. Until recently, attention was mainly focused on aspirin-induced damage of the stomach and duodenum. However, recently, there has been growing interest among gastroenterologists on the adverse effects of aspirin on the small bowel, especially as new endoscopic techniques, such as capsule endoscopy (CE) and balloon-assisted endoscopy, have become available for the evaluation of small bowel lesions. Preliminary CE studies conducted in healthy subjects have shown that short-term administration of LDA can induce mild mucosal inflammation of the small bowel. Furthermore, chronic use of LDA results in a variety of lesions in the small bowel, including multiple petechiae, loss of villi, erosions, and round, irregular, or punched-out ulcers. Some patients develop circumferential ulcers with stricture. In addition, to reduce the incidence of gastrointestinal lesions in LDA users, it is important for clinicians to confirm the differences in the gastrointestinal toxicity between different types of aspirin formulations in clinical use. Some studies suggest that enteric-coated aspirin may be more injurious to the small bowel mucosa than buffered aspirin. The ideal treatment for small bowel injury in patients taking LDA would be withdrawal of aspirin, however, LDA is used as an antiplatelet agent in the majority of patients, and its withdrawal could increase the risk of cardiovascular/cerebrovascular morbidity and mortality. Thus, novel means for the treatment of aspirin-induced enteropathy are urgently needed.

Visual distraction alone for the improvement of colonoscopy-related pain and satisfaction.

AIM: To evaluate the effect of a relaxing visual distraction alone on patient pain, anxiety, and satisfaction during colonoscopy. METHODS: This study was designed as an endoscopist-blinded randomized controlled trial with 60 consecutively enrolled patients who underwent elective colonoscopy at Yokohama City University Hospital, Japan. Patients were randomly assigned to two groups: group 1 watched a silent movie using a head-mounted display, while group 2 only wore the display. All of the colonoscopies were performed without sedation. We examined pain, anxiety, and the satisfaction of patients before and after the procedure using questionnaires that included the Visual Analog Scale. Patients were also asked whether they would be willing to use the same method for a repeat procedure. RESULTS: A total of 60 patients were allocated to two groups. Two patients assigned to group 1 and one patient assigned to group 2 were excluded after the randomization. Twenty-eight patients in group 1 and 29 patients in group 2 were entered into the final analysis. The groups were similar in terms of gender, age, history of prior colonoscopy, and pre-procedural anxiety score. The two groups were comparable in terms of the cecal insertion rate, the time to reach the cecum, the time needed for the total procedure, and vital signs. The median anxiety score during the colonoscopy did not differ significantly between the two groups (median scores, 20 vs 24). The median pain score during the procedure was lower in group 1, but the difference was not significant (median scores, 24.5 vs 42). The patients in group 1 reported significantly higher median post-procedural satisfaction levels, compared with the patients in group 2 (median scores, 89 vs 72, P = 0.04). Nearly three-quarters of the patients in group 1 wished to use the same method for repeat procedures, and the difference in rates between the two groups was statistically significant (75.0% vs 48.3%, P = 0.04). Patients with greater levels of anxiety before the procedure tended to feel a painful sensation. Among patients with a pre-procedural anxiety score of 50 or higher, the anxiety score during the procedure was significantly lower in the group that received the visual distraction (median scores, 20 vs 68, P = 0.05); the pain score during the colonoscopy was also lower (median scores, 23 vs 57, P = 0.04). No adverse effects arising from the visual distraction were recognized. CONCLUSION: Visual distraction alone improves satisfaction in patients undergoing colonoscopy and decreases anxiety and pain during the procedure among patients with a high pre-procedural anxiety score.

Lubiprostone decreases the small bowel transit time by capsule endoscopy: an exploratory, randomised, double-blind, placebo-controlled 3-way crossover study.

The aim of this study was to investigate the usefulness of lubiprostone for bowel preparation and as a propulsive agent in small bowel endoscopy. Six healthy male volunteers participated in this randomized, 3-way crossover study. The subjects received a 24 µg tablet of lubiprostone 60 minutes prior to the capsule ingestion for capsule endoscopy (CE) and a placebo tablet 30 minutes before the capsule ingestion (L-P regimen), a placebo tablet 60 minutes prior to CE and a 24 µg tablet of lubiprostone 30 minutes prior to CE (P-L regimen), or a placebo tablet 60 minutes prior to r CE and a placebo tablet again 30 minutes prior to CE (P-P regimen). The quality of the capsule endoscopic images and the amount of water in the small bowel were assessed on 5-point scale. The median SBTT was 178.5 (117-407) minutes in the P-P regimen, 122.5 (27-282) minutes in the L-P regimen, and 110.5 (11-331) minutes in the P-L regimen (P = 0.042). This study showed that the use of lubiprostone significantly decreased the SBTT. We also confirmed that lubiprostone was effective for inducing water secretion into the small bowel during CE.