Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Lynch syndrome is associated with an increased risk of colorectal cancer and with a broader spectrum of cancers, especially endometrial cancer. In 2011, our group reported long-term cancer outcomes (mean follow-up 55·7 months [SD 31·4]) for participants with Lynch syndrome enrolled into a randomised trial of daily aspirin versus placebo. This report completes the planned 10-year follow-up to allow a longer-term assessment of the effect of taking regular aspirin in this high-risk population. METHODS: In the double-blind, randomised CAPP2 trial, 861 patients from 43 international centres worldwide (707 [82%] from Europe, 112 [13%] from Australasia, 38 [4%] from Africa, and four [<1%] from The Americas) with Lynch syndrome were randomly assigned to receive 600 mg aspirin daily or placebo. Cancer outcomes were monitored for at least 10 years from recruitment with English, Finnish, and Welsh participants being monitored for up to 20 years. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. The trial is registered with the ISRCTN registry, number ISRCTN59521990. FINDINGS: Between January, 1999, and March, 2005, 937 eligible patients with Lynch syndrome, mean age 45 years, commenced treatment, of whom 861 agreed to be randomly assigned to the aspirin group or placebo; 427 (50%) participants received aspirin and 434 (50%) placebo. Participants were followed for a mean of 10 years approximating 8500 person-years. 40 (9%) of 427 participants who received aspirin developed colorectal cancer compared with 58 (13%) of 434 who received placebo. Intention-to-treat Cox proportional hazards analysis revealed a significantly reduced hazard ratio (HR) of 0·65 (95% CI 0·43-0·97; p=0·035) for aspirin versus placebo. Negative binomial regression to account for multiple primary events gave an incidence rate ratio of 0·58 (0·39-0·87; p=0·0085). Per-protocol analyses restricted to 509 who achieved 2 years' intervention gave an HR of 0·56 (0·34-0·91; p=0·019) and an incidence rate ratio of 0·50 (0·31-0·82; p=0·0057). Non-colorectal Lynch syndrome cancers were reported in 36 participants who received aspirin and 36 participants who received placebo. Intention-to-treat and per-protocol analyses showed no effect. For all Lynch syndrome cancers combined, the intention-to-treat analysis did not reach significance but per-protocol analysis showed significantly reduced overall risk for the aspirin group (HR=0·63, 0·43-0·92; p=0·018). Adverse events during the intervention phase between aspirin and placebo groups were similar, and no significant difference in compliance between intervention groups was observed for participants with complete intervention phase data; details reported previously. INTERPRETATION: The case for prevention of colorectal cancer with aspirin in Lynch syndrome is supported by our results. FUNDING: Cancer Research UK, European Union, MRC, NIHR, Bayer Pharma AG, Barbour Foundation.

Parental etiological explanations and longitudinal medication use for youths with attention deficit hyperactivity disorder.

Due to the need to increase understanding of factors associated with medication usage for youth with ADHD, this study examined parental explanatory etiologies in relationship to psychotropic medication use in a sample of youth who met criteria for ADHD and utilized outpatient specialty mental health services in the previous year. When examined cross-sectionally, medication usage was positively associated with parental explanatory etiologies related to physical causes and negatively associated with those involving sociological causes. Longitudinal analyses did not show a significant effect of Time 1 parental explanatory etiologies on the slope of medication use, suggesting that the relationship between Time 1 parental explanatory etiologies and medication usage remains stable over time for those who have had past year involvement with outpatient specialty mental health services.

Study protocol for "Moving Bright, Eating Smart"- A phase 2 clinical trial on the acceptability and feasibility of a diet and physical activity intervention to prevent recurrence in colorectal cancer survivors.

BACKGROUND: Colorectal cancer is the second most common cancer and cancer-killer in Hong Kong with an alarming increasing incidence in recent years. The latest World Cancer Research Fund report concluded that foods low in fibre, and high in red and processed meat cause colorectal cancer whereas physical activity protects against colon cancer. Yet, the influence of these lifestyle factors on cancer outcome is largely unknown even though cancer survivors are eager for lifestyle modifications. Observational studies suggested that low intake of a Western-pattern diet and high physical activity level reduced colorectal cancer mortality. The Theory of Planned Behaviour and the Health Action Process Approach have guided the design of intervention models targeting a wide range of health-related behaviours. METHODS/DESIGN: We aim to demonstrate the feasibility of two behavioural interventions intended to improve colorectal cancer outcome and which are designed to increase physical activity level and reduce consumption of a Western-pattern diet. This three year study will be a multicentre, randomised controlled trial in a 2x2 factorial design comparing the "Moving Bright, Eating Smart" (physical activity and diet) programme against usual care. Subjects will be recruited over a 12-month period, undertake intervention for 12 months and followed up for a further 12 months. Baseline, interim and three post-intervention assessments will be conducted.Two hundred and twenty-two colorectal cancer patients who completed curative treatment without evidence of recurrence will be recruited into the study. Primary outcome measure will be whether physical activity and dietary targets are met at the end of the 12-month intervention. Secondary outcome measures include the magnitude and mechanism of behavioural change, the degree and determinants of compliance, and the additional health benefits and side effects of the intervention. DISCUSSION: The results of this study will establish the feasibility of targeting the two behaviours (diet and physical activity) and demonstrate the magnitude of behaviour change. The information will facilitate the design of a further larger phase III randomised controlled trial with colorectal cancer outcome as the study endpoint to determine whether this intervention model would reduce colorectal cancer recurrence and mortality. TRIAL REGISTRATION: ClinicalTrials.gov No: NCT01708824.

Long-term effect of resistant starch on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial.

BACKGROUND: Observational studies report that higher intake of dietary fibre (a heterogeneous mix including non-starch polysaccharides and resistant starches) is associated with reduced risk of colorectal cancer, but no randomised trials with prevention of colorectal cancer as a primary endpoint have been done. We assessed the effect of resistant starch on the incidence of colorectal cancer. METHODS: In the CAPP2 study, individuals with Lynch syndrome were randomly assigned in a two-by-two factorial design to receive 600 mg aspirin or aspirin placebo or 30 g resistant starch or starch placebo, for up to 4 years. Randomisation was done with a block size of 16. Post-intervention, patients entered into double-blind follow-up; participants and investigators were masked to treatment allocation. The primary endpoint for this analysis was development of colorectal cancer in participants randomly assigned to resistant starch or resistant-starch placebo with both intention-to-treat and per-protocol analyses. This study is registered, ISRCTN 59521990. FINDINGS: 463 patients were randomly assigned to receive resistant starch and 455 to receive resistant-starch placebo. At a median follow-up 52·7 months (IQR 28·9-78·4), 53 participants developed 61 primary colorectal cancers (27 of 463 participants randomly assigned to resistant starch, 26 of 455 participants assigned to resistant-starch placebo). Intention-to-treat analysis of time to first colorectal cancer showed a hazard ratio (HR) of 1·40 (95% CI 0·78-2·56; p=0·26) and Poisson regression accounting for multiple primary events gave an incidence rate ratio (IRR) of 1·15 (95% CI 0·66-2·00; p=0·61). For those completing 2 years of intervention, per-protocol analysis yielded a HR of 1·09 (0·55-2·19, p=0·80) and an IRR of 0·98 (0·51-1·88, p=0·95). No information on adverse events was gathered during post-intervention follow-up. INTERPRETATION: Resistant starch had no detectable effect on cancer development in carriers of hereditary colorectal cancer. Dietary supplementation with resistant starch does not emulate the apparently protective effect of diets rich in dietary fibre against colorectal cancer. FUNDING: European Union, Cancer Research UK, Bayer Corporation, National Starch and Chemical Co, UK Medical Research Council, Newcastle Hospitals Trustees, Cancer Council of Victoria Australia, THRIPP South Africa, The Finnish Cancer Foundation, SIAK Switzerland, and Bayer Pharma.

Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial.

BACKGROUND: Observational studies report reduced colorectal cancer in regular aspirin consumers. Randomised controlled trials have shown reduced risk of adenomas but none have employed prevention of colorectal cancer as a primary endpoint. The CAPP2 trial aimed to investigate the antineoplastic effects of aspirin and a resistant starch in carriers of Lynch syndrome, the major form of hereditary colorectal cancer; we now report long-term follow-up of participants randomly assigned to aspirin or placebo. METHODS: In the CAPP2 randomised trial, carriers of Lynch syndrome were randomly assigned in a two-by-two factorial design to 600 mg aspirin or aspirin placebo or 30 g resistant starch or starch placebo, for up to 4 years. Randomisation was in blocks of 16 with provision for optional single-agent randomisation and extended postintervention double-blind follow-up; participants and investigators were masked to treatment allocation. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. This trial is registered, ISRCTN59521990. RESULTS: 861 participants were randomly assigned to aspirin or aspirin placebo. At a mean follow-up of 55·7 months, 48 participants had developed 53 primary colorectal cancers (18 of 427 randomly assigned to aspirin, 30 of 434 to aspirin placebo). Intention-to-treat analysis of time to first colorectal cancer showed a hazard ratio (HR) of 0·63 (95% CI 0·35-1·13, p=0·12). Poisson regression taking account of multiple primary events gave an incidence rate ratio (IRR) of 0·56 (95% CI 0·32-0·99, p=0·05). For participants completing 2 years of intervention (258 aspirin, 250 aspirin placebo), per-protocol analysis yielded an HR of 0·41 (0·19-0·86, p=0·02) and an IRR of 0·37 (0·18-0·78, p=0·008). No data for adverse events were available postintervention; during the intervention, adverse events did not differ between aspirin and placebo groups. INTERPRETATION: 600 mg aspirin per day for a mean of 25 months substantially reduced cancer incidence after 55·7 months in carriers of hereditary colorectal cancer. Further studies are needed to establish the optimum dose and duration of aspirin treatment. FUNDING: European Union; Cancer Research UK; Bayer Corporation; National Starch and Chemical Co; UK Medical Research Council; Newcastle Hospitals trustees; Cancer Council of Victoria Australia; THRIPP South Africa; The Finnish Cancer Foundation; SIAK Switzerland; Bayer Pharma.

Cancer Prevention with Resistant Starch in Lynch Syndrome Patients in the CAPP2-Randomized Placebo Controlled Trial: Planned 10-Year Follow-up.

ABSTRACT: The CAPP2 trial investigated the long-term effects of aspirin and resistant starch on cancer incidence in patients with Lynch syndrome (LS). Participants with LS were randomized double-blind to 30 g resistant starch (RS) daily or placebo for up to 4 years. We present long-term cancer outcomes based on the planned 10-year follow-up from recruitment, supplemented by National Cancer Registry data to 20 years in England, Wales, and Finland. Overall, 463 participants received RS and 455 participants received placebo. After up to 20 years follow-up, there was no difference in colorectal cancer incidence (n = 52 diagnosed with colorectal cancer among those randomized to RS against n = 53 on placebo) but fewer participants had non-colorectal LS cancers in those randomized to RS (n = 27) compared with placebo (n = 48); intention-to-treat (ITT) analysis [HR, 0.54; 95% confidence interval (CI), 0.33-0.86; P = 0.010]. In ITT analysis, allowing for multiple primary cancer diagnoses among participants by calculating incidence rate ratios (IRR) confirmed the protective effect of RS against non-colorectal cancer LS cancers (IRR, 0.52; 95% CI, 0.32-0.84; P = 0.0075). These effects are particularly pronounced for cancers of the upper GI tract; 5 diagnoses in those on RS versus 21 diagnoses on placebo. The reduction in non-colorectal cancer LS cancers was detectable in the first 10 years and continued in the next decade. For colorectal cancer, ITT analysis showed no effect of RS on colorectal cancer risk (HR, 0.92; 95% CI, 0.62-1.34; P = 0.63). There was no interaction between aspirin and RS treatments. In conclusion, 30 g daily RS appears to have a substantial protective effect against non-colorectal cancer cancers for patients with LS. PREVENTION RELEVANCE: Regular bowel screening and aspirin reduce colorectal cancer among patients with LS but extracolonic cancers are difficult to detect and manage. This study suggests that RS reduces morbidity associated with extracolonic cancers. See related Spotlight, p. 557.

Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome.

BACKGROUND: Observational and epidemiologic data indicate that the use of aspirin reduces the risk of colorectal neoplasia; however, the effects of aspirin in the Lynch syndrome (hereditary nonpolyposis colon cancer) are not known. Resistant starch has been associated with an antineoplastic effect on the colon. METHODS: In a randomized, placebo-controlled trial, we used a two-by-two design to investigate the effects of aspirin, at a dose of 600 mg per day, and resistant starch (Novelose), at a dose of 30 g per day, in reducing the risk of adenoma and carcinoma among persons with the Lynch syndrome. RESULTS: Among 1071 persons in 43 centers, 62 were ineligible to participate in the study, 72 did not enter the study, and 191 withdrew from the study. These three categories were equally distributed across the study groups. Over a mean period of 29 months (range, 7 to 74), colonic adenoma or carcinoma developed in 141 participants. Of 693 participants randomly assigned to receive aspirin or placebo, neoplasia developed in 66 participants receiving aspirin (18.9%), as compared with 65 receiving placebo (19.0%) (relative risk, 1.0; 95% confidence interval [CI], 0.7 to 1.4). There were no significant differences between the two groups with respect to the development of advanced neoplasia (7.4% and 9.9%, respectively; P=0.33). Among the 727 participants receiving resistant starch or placebo, neoplasia developed in 67 participants receiving starch (18.7%), as compared with 68 receiving placebo (18.4%) (relative risk, 1.0; 95% CI, 0.7 to 1.4). Advanced adenomas and colorectal cancers were evenly distributed in the two groups. The prevalence of serious adverse events was low, and the events were evenly distributed. CONCLUSIONS: The use of aspirin, resistant starch, or both for up to 4 years has no effect on the incidence of colorectal adenoma or carcinoma among carriers of the Lynch syndrome. (Current Controlled Trials number, ISRCTN59521990.)

Lived experience of dietary change among Chinese colorectal cancer survivors in Hong Kong: A qualitative study.

OBJECTIVES: This is a qualitative study which aims to understand the lived experience of dietary changes among Chinese survivors of colorectal cancer who participated in a dietary intervention. SETTING: The surgical and oncological departments of four public hospitals in Hong Kong. PARTICIPANTS: Fifty-five Chinese colorectal cancer survivors who were aged 18 years or above and had received potentially curative treatment in the surgical and oncological departments in Hong Kong were examined. Participants' mean age was 64 years, with 29 (53%) males. INTERVENTION: A 12-month dietary intervention delivered via face-to-face motivational interviews, fortnightly motivational phone calls, monthly electronic pamphlets, quarterly newsletters and quarterly group meeting. OUTCOME MEASURE: We adopted the qualitative approach to capture participants' perspectives and to apply the understanding pragmatically in everyday life. Content analysis was conducted. RESULTS: We identified themes of motives to changes of dietary practices including (1) individual commitment to dietary change; (2) adaptive strategies in interpersonal contexts and (3) working with healthcare professionals during the journey. CONCLUSIONS: The findings demonstrated how Chinese custom and culture posing unique challenges to colorectal cancer survivors and the need of having dietary advice from healthcare professionals. Participants were motivated to change their eating habits by support from family, friends and healthcare professionals. Our findings could help healthcare professionals provide specific dietary advice and guidance to Chinese colorectal cancer survivors. TRIAL REGISTRATION NUMBER: NCT01708824.

Refinement of the basis and impact of common 11q23.1 variation to the risk of developing colorectal cancer.

The common single-nucleotide polymorphism (SNP) rs3802842 at 11q23.1 has recently been reported to be associated with risk of colorectal cancer (CRC). To examine this association in detail we genotyped rs3802842 in eight independent case-control series comprising a total of 10 638 cases and 10 457 healthy individuals. A significant association between the C allele of rs3802842 and CRC risk was found (per allele OR = 1.17; 95% confidence interval [CI]: 1.12-1.22; P = 1.08 x 10(-12)) with the risk allele more frequent in rectal than colonic disease (P = 0.02). In combination with 8q21, 8q24, 10p14, 11q, 15q13.3 and 18q21 variants, the risk of CRC increases with an increasing numbers of variant alleles for the six loci (OR(per allele) = 1.19; 95% CI: 1.15-1.23; P(trend) = 7.4 x 10(-24)). Using the data from our genome-wide association study of CRC, LD mapping and imputation, we were able to refine the location of the causal locus to a 60 kb region and screened for coding changes. The absence of exonic mutations in any of the transcripts (FLJ45803, LOC120376, C11orf53 and POU2AF1) mapping to this region makes the association likely to be a consequence of non-coding effects on gene expression.

Hopefulness predicts resilience after hereditary colorectal cancer genetic testing: a prospective outcome trajectories study.

BACKGROUND: Genetic testing for hereditary colorectal cancer (HCRC) had significant psychological consequences for test recipients. This prospective longitudinal study investigated the factors that predict psychological resilience in adults undergoing genetic testing for HCRC. METHODS: A longitudinal study was carried out from April 2003 to August 2006 on Hong Kong Chinese HCRC family members who were recruited and offered genetic testing by the Hereditary Gastrointestinal Cancer Registry to determine psychological outcomes after genetic testing. Self-completed questionnaires were administered immediately before (pre-disclosure baseline) and 2 weeks, 4 months and 1 year after result disclosure. Using validated psychological inventories, the cognitive style of hope was measured at baseline, and the psychological distress of depression and anxiety was measured at all time points. RESULTS: Of the 76 participating subjects, 71 individuals (43 men and 28 women; mean age 38.9 +/- 9.2 years) from nine FAP and 24 HNPCC families completed the study, including 39 mutated gene carriers. Four patterns of outcome trajectories were created using established norms for the specified outcome measures of depression and anxiety. These included chronic dysfunction (13% and 8.7%), recovery (0% and 4.3%), delayed dysfunction (13% and 15.9%) and resilience (76.8% and 66.7%). Two logistic regression analyses were conducted using hope at baseline to predict resilience, with depression and anxiety employed as outcome indicators. Because of the small number of participants, the chronic dysfunction and delayed dysfunction groups were combined into a non-resilient group for comparison with the resilient group in all subsequent analysis. Because of low frequencies, participants exhibiting a recovery trajectory (n = 3 for anxiety and n = 0 for depression) were excluded from further analysis. Both regression equations were significant. Baseline hope was a significant predictor of a resilience outcome trajectory for depression (B = -0.24, p < 0.01 for depression); and anxiety (B = -0.11, p = 0.05 for anxiety). CONCLUSIONS: The current findings suggest that hopefulness may predict resilience after HCRC genetic testing in Hong Kong Chinese. Interventions to increase the level of hope may be beneficial to the psychological adjustment of CRC genetic testing recipients.

Clinical pharmacokinetic drug interaction studies of gabapentin enacarbil, a novel transported prodrug of gabapentin, with naproxen and cimetidine.

AIM: Gabapentin enacarbil, a transported prodrug of gabapentin, provides sustained, dose-proportional exposure to gabapentin. Unlike gabapentin, the prodrug is absorbed throughout the intestinal tract by high-capacity nutrient transporters, including mono-carboxylate transporter-1 (MCT-1). Once absorbed, gabapentin enacarbil is rapidly hydrolyzed to gabapentin, which is subsequently excreted by renal elimination via organic cation transporters (OCT2). To examine the potential for drug-drug interactions at these two transporters, the pharmacokinetics of gabapentin enacarbil were evaluated in healthy adults after administration alone or in combination with either naproxen (an MCT-1 substrate) or cimetidine (an OCT2 substrate). METHODS: Subjects (n= 12 in each study) received doses of study drug until steady state was achieved; 1200 mg gabapentin enacarbil each day, followed by either naproxen (500 mg twice daily) or cimetidine (400 mg four times daily) followed by the combination. RESULTS: When gabapentin enacarbil was co-administered with naproxen, gabapentin C(ss,max) increased by, on average, 8% and AUC by, on average, 13%. When gabapentin enacarbil was co-administered with cimetidine, gabapentin AUC(ss) increased by 24% and renal clearance of gabapentin decreased. Co-administration with gabapentin enacarbil did not affect naproxen or cimetidine exposure. Gabapentin enacarbil was generally well tolerated. CONCLUSIONS: No gabapentin enacarbil dose adjustment is needed with co-administration of naproxen or cimetidine.

A comprehensive training programme for nurse endoscopist performing flexible sigmoidoscopy in Hong Kong.

AIMS: To describe the process and explore the feasibility of training a colorectal nurse in Hong Kong to perform flexible sigmoidoscopy. BACKGROUND: Given the shortage and high turnover rate of medical staff, a pilot programme was designed to train and expand the role of colorectal nurse clinicians. It was hoped that such nurses could share some of the clinical duties of the medical staff. An advanced practice nurse was selected for the programme. One of the training components was the performance of flexible sigmoidoscopy. DESIGN: This was a descriptive, case review study. METHOD: A one-year-structured endoscopic training programme was designed for the nurse clinician. Weekly sessions were conducted by one of the trainers. The training process included the following: (1) procedural observation; (2) supervised withdrawal, advancement and manipulation of the sigmoidoscope and (3) a final assessment of the nurse's competency in performing sigmoidoscopy independently. RESULTS: In total, 119 outpatients (58 male and 61 female) with a mean age of 57·02 years (SD 14·6 years; range: 18-83 years) underwent flexible sigmoidoscopy by the nurse over 11 months. The mean procedural time was 9·38 minutes (SD 3·5 minutes; range 3-26 minutes). The procedure was terminated prematurely if it could not be tolerated by the patient or if the bowel preparation was inadequate. The mean depth of insertion was 53·5 cm (SD 12·2 cm; range 6-60 cm). In total, 82 patients had a normal exam, 32 patients had abnormalities. There were no procedural complications, and no patient required an unplanned hospital admission after the procedure. CONCLUSION: In Queen Mary Hospital, nurses can be trained to perform flexible sigmoidoscopy in a safe and effective manner. RELEVANCE TO CLINICAL PRACTICE: Nurse endoscopists could increase the use of flexible sigmoidoscopy in colorectal cancer screening and can also enhance the professional development of colorectal nurses.

Effects of dietary and physical activity interventions on generic and cancer-specific health-related quality of life, anxiety, and depression in colorectal cancer survivors: a randomized controlled trial.

PURPOSE: To assess the effects of dietary and physical activity (PA) interventions on generic and cancer-specific quality of life (QoL), anxiety, and depression levels among adult Chinese colorectal cancer (CRC) survivors. METHODS: Two-hundred twenty-three adult CRC survivors within 1 year of completion of primary cancer treatment were randomized to receive dietary, PA or combined intervention, or usual care for a 12 monthduration, under a 2 (diet vs usual care) × 2 (PA vs usual care) factorial design. Generic and cancer-specific QoL was assessed using a Chinese version 12-Item Short Form Health Survey (SF-12) and the Functional Assessment of Cancer Therapy-Colorectal (FACT-C) scale, respectively. Anxiety and depression was assessed using the Hospital Anxiety and Depression Scale at baseline, 6, 12, 18, and 24 months. Linear mixed models were used for examining the intervention effects. RESULTS: Participants receiving dietary intervention experienced a significant improvement in the generic measure of QoL (SF-6D utility scores, mean difference 0.042, 95%CI 0.03 to 0.081) at 12 months, the cancer-specific QoL scores (mean difference 3.09, 95%CI 0.13 to 6.04), and levels of depression (P = 0.015) at both 12 and 24 months follow-up. Participants receiving PA intervention only demonstrated a significant improvement in SF-6D utility index (mean difference 0.039, 95%CI 0.002 to 0.077) and physical functioning (mean difference 2.85, 95%CI 1.00 to 4.70) at 6 months. CONCLUSIONS: Dietary intervention improved the generic and cancer-specific QoL and depression in CRC survivors. TRIAL REGISTRATION: The study was prospectively registered on 17 October 2012 at ClinicalTrials.gov (NCT01708824). IMPLICATIONS FOR CANCER SURVIVORS: CRC survivors can benefit from dietary interventions in alleviating depression and improving overall health-related QoL.

Dietary and Physical Activity Interventions for Colorectal Cancer Survivors: A Randomized Controlled Trial.

There has been evidence on the protective effects of diets high in fiber and low in red and processed meat (RPM), and physical activity (PA) against colorectal cancer (CRC) development, but that against CRC recurrence has been limited. This study evaluated the efficacy of a behavioral program comprising dietary and PA interventions in improving Chinese CRC survivors' lifestyle. A 2 × 2 factorial randomized controlled trial of 223 CRC patients (82 females, mean age 65), randomly assigned to receive dietary, PA or both interventions, or usual care for 12 months, and assessed every 6 months for 24 months. Primary outcomes included two dietary and two PA targets. Secondary outcomes included changes in dietary consumptions and PA levels. Dietary interventions significantly increased the odds of achieving the targets of consuming less RPM at all time-points (OR 3.22-4.57, all p < 0.01) and refined grain (RG) at months 6 (OR 3.13, p = 0.002) and 24 (OR 2.19, p = 0.039), and reduced RPM (2.49-3.48 servings/week, all p < 0.01) and RG (0.31-0.5 servings/day, all p < 0.01) consumptions. Patients receiving PA interventions potentially spent more time on moderate-to-vigorous PA. This study demonstrated the efficacy of a behavioral program in improving dietary habits of Chinese CRC survivors.

Anastomotic leakage is associated with poor long-term outcome in patients after curative colorectal resection for malignancy.

The impact of anastomotic leakage on long-term outcomes after curative surgery for colorectal cancer has not been well documented. This study aimed to investigate the effect of anastomotic leakage on survival and tumor recurrence in patients who underwent curative resection for colorectal cancer. Prospectively collected data of the 1,580 patients (904 men) of a median age of 70 years (range: 24-94), who underwent potentially curative resection for colorectal cancer between 1996 and 2004, were reviewed. Cancer-specific survival and disease recurrence were analyzed using Kaplan Meier method, and variables were compared with log rank test. Cox regression model was used in multivariate analysis. The cancer was situated in the colon and the rectum in 933 and 647 patients, respectively. Anastomotic leakage occurred in 60 patients (clinical leakage: n = 48; radiological leak: n = 12). The leakage rate was significantly higher in patients with surgery for rectal cancer (6.3 vs 2.0%, p < 0.001). The 5-year cancer-specific survivals were 56.9% in those with leakage and 75.9% in those without leakage (p = 0.012). The 5-year systemic recurrence rates were 48.4 and 22.6% in patients with and without anastomotic leak, respectively (p = 0.001), whereas the 5-year local recurrence rates were 12.9 and 5.7%, respectively (p = 0.009). Anastomotic leakage remained an independent factor associated with a worse cancer-specific survival (p = 0.043, hazard ratio: 1.63, 95% CI: 1.02-2.60) and a higher systemic recurrence rate (hazard ratio: 1.94, 95% CI: 1.23-3.06, p = 0.004) on multivariate analysis. In rectal cancer, anastomotic leakage was an independent factor for a higher local recurrence rate (hazard ratio: 2.55, 95% CI: 1.07-6.06, p = 0.034). In conclusion, anastomotic leakage is associated with a poor survival and a higher tumor recurrence rate after curative resection of colorectal cancer. Efforts should be undertaken to avoid this complication to improve the long-term outcome.

Self-expanding metallic stent as a bridge to surgery versus emergency resection for obstructing left-sided colorectal cancer: a case-matched study.

This study aimed to compare the outcomes of patients who suffered from obstructing left-sided colorectal cancer, treated with self-expanding metallic stent (SEMS) as a bridge to surgery, with those who underwent emergency operation. Twenty patients who had acute obstruction due to left-sided colorectal cancer underwent surgical resection after insertion of SEMS (group I) were matched to 40 patients with emergency colonic resection (group II). The two groups were compared for the incidence of primary anastomosis, stoma rate, hospital stay, duration of intensive care, postoperative morbidity, and mortality. Both groups had similar preoperative comorbidity and stage of disease, but the tumors in group I were more distally located (P < 0.001). In group I, one patient developed colon perforation and required Hartmann's operation. All the other patients underwent elective operation with primary anastomosis. In group II, primary anastomosis was performed in 29 patients (72.5%; P = 0.047). The operative mortality of group I and group II was 5% and 12.5%, respectively (P = 0.653). Significantly shorter median postoperative hospital stay and median stay in the intensive care unit (ICU) were observed in group I (9 days [range, 5-39 days] vs. 12 days [range, 8-49 days], P = 0.015 and 0 day [range, 0-17 days] vs. 0.5 day [range, 0-18 days], P = 0.022, respectively). There were no differences in hospital mortality (P = 0.653) or 30-day mortality (P = 0.653). Both groups had similar reoperation rates, surgical complications, and medical complications. When compared with emergency resection, insertion of SEMS as a bridge to surgery for obstructing left-sided colorectal cancer is associated with a higher rate of primary anastomosis as well as a better outcome in terms of hospital stay and stay in the ICU. The wider application of this treatment option for obstructing colorectal cancer warranted further studies.

Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia.

Activation of the RAS/RAF/extracellular signal-regulated kinase-mitogen-activated protein kinase/extracellular signal-regulated kinase/mitogen-activated protein kinase pathway by RAS mutations is commonly found in human cancers. Recently, we reported that mutation of BRAF provides an alternative route for activation of this signaling pathway and can be found in melanomas, colorectal cancers, and ovarian tumors. Here we perform an extensive characterization of BRAF mutations in a large series of colorectal tumors in various stages of neoplastic transformation. BRAF mutations were found in 11 of 215 (5.1%) colorectal adenocarcinomas, 3 of 108 (2.8%) sporadic adenomas, 1 of 63 (1.6%) adenomas from familial adenomatous polyposis (FAP) patients, and 1 of 3 (33%) hyperplastic polyps. KRAS mutations were detected in 34% of carcinomas, 31% of sporadic adenomas, 9% of FAP adenomas, and no hyperplastic polyps. Eight of 16 BRAF mutations were V599E, the previously described hotspot, and none of these was associated with a KRAS mutation in the same lesion. The remaining eight mutations involve other conserved amino acids in the kinase domain, and 62.5% have a KRAS mutation in the same tumor. Our data suggest that BRAF mutations are, to some extent, biologically similar to RAS mutations in colorectal cancer because both occur at approximately the same stage of the adenoma-carcinoma sequence, both are associated with villous morphology, and both are less common in adenomas from FAP cases. By contrast, colorectal adenocarcinomas with BRAF mutations are associated with early Dukes' tumor stages (P = 0.006) and no such relationship was observed for KRAS mutations. The presence in some colorectal neoplasms of mutations in both BRAF and KRAS suggests that modulation of the RAS-RAF-extracellular signal-regulated kinase-mitogen-activated protein kinase/extracellular signal-regulated kinase/mitogen-activated protein kinase signaling pathway may occur by mutation of multiple components.

Epidemiology of Inflammatory Bowel Disease from 1981 to 2014: Results from a Territory-Wide Population-Based Registry in Hong Kong.

BACKGROUND: Incidence of inflammatory bowel disease (IBD) is increasing in Asia, but population-based prevalence data are limited. This study examined IBD incidence and prevalence based on results of a territory-wide IBD registry in Hong Kong. METHODS: We collected data on 2575 patients with IBD (1541 ulcerative colitis [UC], 983 Crohn's disease [CD], 51 IBD unclassified) from 1981 to 2014 using hospital and territory-wide administrative coding system. Prevalence and incidence, disease phenotype, surgery, and mortality were analyzed. RESULTS: Adjusted prevalence of IBD, UC, CD, and IBD unclassified per 100,000 individuals in 2014 were 44.0, 24.5, 18.6, and 0.9, respectively. Age-adjusted incidence of IBD per 100,000 individuals increased from 0.10 (95% confidence interval, 0.06-0.16) in 1985 to 3.12 (95% confidence interval, 2.88-3.38) in 2014. UC:CD incidence ratio reduced from 8.9 to 1.0 over 30 years (P < 0.001). A family history of IBD was reported in 3.0% of patients. Stricturing or penetrating disease was found in 41% and perianal disease in 25% of patients with CD. 5-aminosalicylate use was common in UC (96%) and CD (89%). Cumulative rates of surgery for CD were 20.3% at 1 year and 25.7% at 5 years, and the corresponding rates for UC were 1.8% and 2.1%, respectively. Mortality for CD and UC was not significantly different from the general population. CONCLUSIONS: In a population-based study in Hong Kong, prevalence of IBD is lower than in the west although comparable to that of other East Asian countries. Complicated CD is common. Overall mortality remains low in Asians with IBD.

Germline, somatic and epigenetic events underlying mismatch repair deficiency in colorectal and HNPCC-related cancers.

High-frequency microsatellite instability (MSI-H) results from deficiency in nucleotide mismatch repair. It contributes significantly to carcinogenesis in the human colorectal mucosa. Here we study 41 colorectal and three other HNPCC-related cancers with MSI-H to provide comprehensive information on the mechanisms of inactivation of the two major proteins involved, hMLH1 and hMSH2. Seventeen of the patients had family histories meeting the criteria for Bethesda grades 1, 2 or 3. Of these familial cases, 14 (83%) had early-onset disease, defined on the basis of diagnosis prior to the age of 50, but in three the disease was of late onset (>50 years). A second subset of 20 patients had early onset disease without family history. The remaining seven patients were selected to allow comparisons with sporadic, late-onset disease, the molecular basis of which has been extensively reported elsewhere. We stratified the tumours initially on the basis of hMLH1 or hMSH2 protein deficiency, detected by immunohistochemistry, and then by analysis of germline and somatic mutation, mRNA transcription, loss of heterozygosity (LOH) at the hMLH1 and hMSH2 loci, and methylation status in two regions of the hMLH1 promoter. The functional significance of several of these changes in the MSI-H tumours was confirmed by comparisons with 16 tumours with low-frequency microsatellite instability and 56 tumours with stable microsatellites. As anticipated, patients with family histories usually showed germline mutation of hMSH2 or hMLH1. In many cases the residual normal allele was silenced in their tumours by loss of heterozygosity (LOH). The small subset of late-onset, sporadic cases confirmed the preponderance in this group of biallelic hMLH1 promoter methylation. In the early-onset, apparently sporadic subset there were 11 tumours with hMLH1 deficiency, five with hMSH2 deficiency and four with no detectable abnormality in expression of either protein. These showed a complex mixture of lesions, including germline and somatic mutations, promoter methylation, LOH, suppression of wild-type RNA by as yet undiscovered mechanisms, or no detectable abnormality in any of these parameters. Evidence is presented to indicate that methylation in proximal region of the hMLH1 promoter is a more reliable correlate of transcriptional silencing in colorectal cancers than methylation in upstream region. These observations have significant implications for management of patients with MSI-H tumours.

Value of gastrografin in adhesive small bowel obstruction after unsuccessful conservative treatment: a prospective evaluation.

AIM: Gastrografin is a hyperosmolar water-soluble contrast medium. Besides its predictive value for the need for operative treatment, a potential therapeutic role of this agent in adhesive small bowel obstruction has been suggested. This study aimed at evaluating the effectiveness of gastrografin in adhesive small bowel obstruction when conservative treatment failed. METHODS: Patients with adhesive small bowel obstruction were given trial conservative treatment unless there was fear of bowel strangulation. Those responded in the initial 48 h had conservative treatment continued. Patients who showed no improvement in the initial 48 h were given 100 mL of gastrografin through nasogastric tube followed by serial abdominal radiographs. Patients with the contrast appeared in large bowel within 24 h were regarded as having partial obstruction and conservative treatment was continued. Patients in which the contrast failed to reach large bowel within 24 h were considered to have complete obstruction and laparotomy was performed. RESULTS: Two hundred and twelve patients with 245 episodes of adhesive obstruction were included. Fifteen patients were operated on soon after admission due to fear of strangulation. One hundred and eighty-six episodes of obstruction showed improvement in the initial 48 h and conservative treatment was continued. Two patients had subsequent operations because of persistent obstruction. Forty-four episodes of obstruction showed no improvement within 48 h and gastrografin was administered. Seven patients underwent complete obstruction surgery. Partial obstruction was demonstrated in 37 other cases, obstruction resolved subsequently in all of them except one patient who required laparotomy because of persistent obstruction. The overall operative rate in this study was 10%. There was no complication that could be attributed to the use of gastrografin. CONCLUSION: The use of gastrografin in adhesive small bowel obstruction after unsuccessful conservative treatment is safe and reduces the need for surgical intervention.