Safety and efficacy of short-course intravenous antibiotics after complicated appendicitis in selected patients.

BACKGROUND: After surgery for complicated appendicitis (CA), common practice is to treat all patients with a standardised long-course of intravenous antibiotics (IVAB) to reduce the risk of postoperative surgical infections (PSI). The aim of the current study was to evaluate the safety and efficacy of a short-course IVAB after CA in selected patients. METHODS: The Department's prospectively collected database identified CA patients treated between2015 and 2019. Baseline and treatment characteristics and postoperative outcomes were analysed. The cut-off between short- and long-course IVAB was 2 days. Outcomes of interest were PSI and 30-day unplanned readmission. RESULTS: In total, 226 patients had CA: Ninety-nine CA (43.8%) received short-course IVAB and 127 (56.2%) received long-course. PSI occurred in 6% and 10% of the short-course and long-course patients, respectively (p = 0.34). Length of IVAB after a PSI was comparable to that of patients without PSI (median 3 and 2 days of IVAB respectively; p = 0.28). 30-day unplanned readmission rates were 7% and 6%, respectively (p = 0.99). Length of IVAB for readmitted patients was similar to those who were not readmitted (median 3 days of IVAB in both; p = 0.91). Multivariable analysis showed that the intraoperative findings of the appendix (p = 0.04) was a prognostic predictor for PSI. ASA score (p = 0.02) and surgical approach (p = 0.05) were prognostic predictors for 30-day unplanned readmission. CONCLUSIONS: This study shows that when patients respond well, a short-course IVAB can safely be applied after CA without increasing risk of PSI or 30-day unplanned readmission.

A Gut-Intrinsic Melanocortin Signaling Complex Augments L-Cell Secretion in Humans.

OBJECTIVE: Hypothalamic melanocortin 4 receptors (MC4R) are a key regulator of energy homeostasis. Brain-penetrant MC4R agonists have failed, as concentrations required to suppress food intake also increase blood pressure. However, peripherally located MC4R may also mediate metabolic benefits of MC4R activation. Mc4r transcript is enriched in mouse enteroendocrine L cells and peripheral administration of the endogenous MC4R agonist, α-melanocyte stimulating hormone (α-MSH), triggers the release of the anorectic hormones Glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine (PYY) in mice. This study aimed to determine whether pathways linking MC4R and L-cell secretion exist in humans. DESIGN: GLP-1 and PYY levels were assessed in body mass index-matched individuals with or without loss-of-function MC4R mutations following an oral glucose tolerance test. Immunohistochemistry was performed on human intestinal sections to characterize the mucosal MC4R system. Static incubations with MC4R agonists were carried out on human intestinal epithelia, GLP-1 and PYY contents of secretion supernatants were assayed. RESULTS: Fasting PYY levels and oral glucose-induced GLP-1 secretion were reduced in humans carrying a total loss-of-function MC4R mutation. MC4R was localized to L cells and regulates GLP-1 and PYY secretion from ex vivo human intestine. α-MSH immunoreactivity in the human intestinal epithelia was predominantly localized to L cells. Glucose-sensitive mucosal pro-opiomelanocortin cells provide a local source of α-MSH that is essential for glucose-induced GLP-1 secretion in small intestine. CONCLUSION: Our findings describe a previously unidentified signaling nexus in the human gastrointestinal tract involving α-MSH release and MC4R activation on L cells in an autocrine and paracrine fashion. Outcomes from this study have direct implications for targeting mucosal MC4R to treat human metabolic disorders.

Circulating epigenetic biomarkers for detection of recurrent colorectal cancer.

BACKGROUND: The sensitive detection of recurrent colorectal cancer (CRC) by the measurement of circulating tumor DNA (ctDNA) might improve the chance of a cure. This study compared a quantitative methylated ctDNA test with carcinoembryonic antigen (CEA) in the setting of surveillance for recurrence. METHODS: Blood samples collected either during surveillance or within 12 months of the confirmation of recurrence were assayed for ctDNA (methylated branched-chain amino acid transaminase 1 [BCAT1]/Ikaros family zinc-finger 1 protein [IKZF1]) and CEA. The optimal ctDNA threshold was determined by receiver operating characteristic analysis, and the test performance for the detection of recurrence was compared with CEA (5 ng/mL threshold). RESULTS: The study cohort comprised 144 eligible patients and included 50 recurrence events. The sensitivity of the methylated ctDNA test for recurrence was 66.0% (95% confidence interval [CI], 57.1%-69.3%), which was significantly higher than the sensitivity of CEA (31.9%; 95% CI, 22.8%-36.6%; P < .001). The sensitivity for resectable recurrence (n = 20) was also higher (ctDNA, 60.0%; CEA, 20.0%; P = .01). The specificity did not differ between the tests (ctDNA, 97.9%; 95% CI, 93.2%-99.6%; CEA, 96.4%; 95% CI, 91.4%-99.0%). When adjustments were made for other predictors of the presence of recurrence, a positive ctDNA test was an independent predictor (odds ratio, 155.7; 95% CI, 17.9-1360.6; P < .001), whereas CEA was not (odds ratio, 2.5; 95% CI, 0.3-20.6; P = .407). CONCLUSIONS: The quantitative ctDNA test showed superior sensitivity in comparison with CEA without a difference in the specificity for detecting recurrent CRC. Longitudinal studies are warranted to further assess the utility (specifically the survival benefit) of methylated BCAT1/IKZF1 ctDNA in the surveillance of patients with CRC.

Augmented capacity for peripheral serotonin release in human obesity.

BACKGROUND/OBJECTIVES: Evidence from animal studies highlights an important role for serotonin (5-HT), derived from gut enterochromaffin (EC) cells, in regulating hepatic glucose production, lipolysis and thermogenesis, and promoting obesity and dysglycemia. Evidence in humans is limited, although elevated plasma 5-HT concentrations are linked to obesity. SUBJECTS/METHODS: We assessed (i) plasma 5-HT concentrations before and during intraduodenal glucose infusion (4 kcal/min for 30 min) in non-diabetic obese (BMI 44 ± 4 kg/m2, N = 14) and control (BMI 24 ± 1 kg/m2, N = 10) subjects, (ii) functional activation of duodenal EC cells (immunodetection of phospho-extracellular related-kinase, pERK) in response to glucose, and in separate subjects, (iii) expression of tryptophan hydroxylase-1 (TPH1) in duodenum and colon (N = 39), and (iv) 5-HT content in primary EC cells from these regions (N = 85). RESULTS: Plasma 5-HT was twofold higher in obese than control responders prior to (P = 0.025), and during (iAUC, P = 0.009), intraduodenal glucose infusion, and related positively to BMI (R2 = 0.334, P = 0.003) and HbA1c (R2 = 0.508, P = 0.009). The density of EC cells in the duodenum was twofold higher at baseline in obese subjects than controls (P = 0.023), with twofold more EC cells activated by glucose infusion in the obese (EC cells co-expressing 5-HT and pERK, P = 0.001), while the 5-HT content of EC cells in duodenum and colon was similar; TPH1 expression was 1.4-fold higher in the duodenum of obese subjects (P = 0.044), and related positively to BMI (R2 = 0.310, P = 0.031). CONCLUSIONS: Human obesity is characterized by an increased capacity to produce and release 5-HT from the proximal small intestine, which is strongly linked to higher body mass, and glycemic control. Gut-derived 5-HT is likely to be an important driver of pathogenesis in human obesity and dysglycemia.

Early follow-up colonoscopy after colorectal cancer resection detects significant pathology.

BACKGROUND: Colonoscopy is a key component of surveillance after colorectal cancer (CRC) resection. Surveillance intervals for colonoscopy vary across the world, with a limited evidence-base to support guidelines. OBJECTIVE: To evaluate the timing and outcome of colonoscopies after CRC resection. METHODS: Retrospective cohort study on prospectively collected data. Included adult patients under surveillance following CRC resection. Patients with organ transplant, inflammatory bowel disease or colon cancer syndromes were excluded. The outcomes of the first (up to) three follow-up colonoscopies were audited and classified for presence of advanced neoplasia (advanced adenoma or adenocarcinoma). RESULTS: 980 patients underwent at least one follow-up colonoscopy with a median time to first colonoscopy of 12.4 months. The findings included 2.7% CRC and 13.2% advanced adenoma. Older age, stage IV disease, and synchronous cancers at surgery were significantly associated with a finding of advanced neoplasia at first colonoscopy. 562 patients underwent a second colonoscopy (median of 35 months after the first surveillance colonoscopy) with findings of 1.8% CRC and 11.4% advanced adenoma. Advanced adenoma on prior colonoscopy was associated with finding advanced neoplasia at the second colonoscopy. 288 patients underwent a third colonoscopy (median of 37 months from the preceding colonoscopy), with similar outcomes of advanced neoplasia being associated with advanced adenoma at the previous colonoscopy. 43 (4.4%) patients developed CRC whilst on surveillance. CONCLUSIONS: Timely surveillance after CRC resection is important for detecting advanced neoplasia, and prolonged intervals between colonoscopies in the early years after surgery should be avoided.

Establishing a state-wide pelvic exenteration multidisciplinary team meeting in South Australia.

BACKGROUND: Pelvic exenteration surgery is complex, necessitating co-ordinated multidisciplinary input and improved referral pathways. A state-wide pelvic exenteration multidisciplinary team (MDT) meeting was established in SA and the outcomes of this were audited and compared with historical data. METHODS: All patients referred for discussion between August 2021 and July 2022 to the SA State-wide Pelvic Exenteration MDT were included in this study. MDT discussion centred around disease resectability, risk versus benefit of surgery, and need for local or interstate referral. Prospective data collection included patient demographics and MDT recommendations of surgery, palliation, or referral. Patients referred for surgery locally or interstate were compared with a retrospective patient cohort treated previously between January and December 2020. RESULTS: Over 12 months, 91 patients were discussed (including nine multiple times), by a mean of 18 meeting participants each month. Forty-eight patients (58.5%) had primary malignancy, 25 (30.5%) recurrent malignancy, and 9 (11.0%) had non-malignant disease. Colorectal cancer was the most common presentation (56.1%), followed by gynaecological (30.5%) and urological (6.1%) malignancy. Pelvic exenteration surgery was recommended to be performed locally in 53.7% of patients and the remainder for non-surgical treatment, palliation, or re-discussion. During this time, 44 patients underwent surgery locally (versus 34 in 2020) and only 4 referred interstate (versus 8 in 2020). CONCLUSION: The establishment of a dedicated state-wide pelvic exenteration MDT has resulted in better coordination of care for patients with locally advanced pelvic malignancy in SA, and significantly reduced the need for interstate referral.

Alterations in GLP-1 and PYY release with aging and body mass in the human gut.

The lining of our intestinal surface contains an array of hormone-producing cells that are collectively our bodies' largest endocrine cell reservoir. These "enteroendocrine" (EE) cells reside amongst the billions of absorptive epithelial and other cell types that line our gastrointestinal tract and can sense and respond to the ever-changing internal environment in our gut. EE cells release an array of important signalling molecules that can act as hormones, including glucagon-like peptide (GLP-1) and peptide YY (PYY) which are co-secreted from L cells. While much is known about the effects of these hormones on metabolism, insulin secretion and food intake, less is understood about their secretion from human intestinal tissue. In this study we assess whether GLP-1 and PYY release differs across human small and large intestinal tissue locations within the gastrointestinal tract, and/or by sex, body weight and the age of an individual. We identify that the release of both hormones is greater in more distal regions of the human colon, but is not different between sexes. We observe a negative correlation of GLP-1 and BMI in the small, but not large, intestine. Increased aging correlates with declining secretion of both GLP-1 and PYY in human large, but not small, intestine. When the data for large intestine is isolated by region, this relationship with age remains significant for GLP-1 in the ascending and descending colon and in the descending colon for PYY. This is the first demonstration that site-specific differences in GLP-1 and PYY release occur in human gut, as do site-specific relationships of L cell secretion with aging and body mass.

Gastrointestinal Adenocarcinoma Incidence and Survival Trends in South Australia, 1990-2017.

BACKGROUND & AIMS: Globally, there has been a concerning rise in the incidence of young-onset cancers. The aim of this study was to provide trends in the incidence and survival of gastrointestinal adenocarcinomas (oesophagus, stomach, pancreas, and colorectal) in South Australia over a 27-year period. METHODS: This is a cross-sectional analysis of a prospective longitudinal database including all cases of gastrointestinal adenocarcinomas prospectively reported to the South Australian (State) Cancer Registry from 1990 to 2017. RESULTS: A total of 28,566 patients diagnosed with oesophageal, stomach, pancreatic, or colorectal adenocarcinoma between 1990 and 2017 were included in the study. While the overall incidence for gastrointestinal adenocarcinomas in individuals >50 years has decreased since 2000 (IRR of 0.97 (95% CI 0.94-1.00; p = 0.06)) compared to 1990-1999, the rate amongst individuals aged 18-50 has significantly increased (IRR 1.41 (95% CI 1.27-1.57; p < 0.001)) during the same reference time period. Although noted in both sexes, the rate of increase in incidence was significantly greater in males (11.5 to 19.7/100,000; p < 0.001). The overall survival from adenocarcinomas across all subsites improved in the >50-year cohort in the last decade (HR 0.89 (95% CI 0.86-0.93; p < 0.001)) compared to 1990-1999. In individuals aged 18-50 years, there has only been a significant improvement in survival for colorectal cancer (HR 0.82 (95% CI 0.68-0.99; p < 0.04)), but not the other subsites. A lower overall survival was noted for males in both age cohorts (18-50 years-HR 1.24 (95% CI 1.09-1.13; p < 0.01) and >50 years-HR 1.13 (95% CI 1.10-1.16; p < 0.001), respectively) compared to females. CONCLUSIONS: This study from South Australia demonstrates a significant increase in young-onset gastrointestinal adenocarcinomas over the last 28 years, with a greater increase in the male sex. The only significant improvement in survival in this cohort has been noted in colorectal cancer patients.

Evidence for Glucagon Secretion and Function Within the Human Gut.

Glucagon is secreted by pancreatic α cells in response to hypoglycemia and increases hepatic glucose output through hepatic glucagon receptors (GCGRs). There is evidence supporting the notion of extrapancreatic glucagon but its source and physiological functions remain elusive. Intestinal tissue samples were obtained from patients undergoing surgical resection of cancer. Mass spectrometry analysis was used to detect glucagon from mucosal lysate. Static incubations of mucosal tissue were performed to assess glucagon secretory response. Glucagon concentration was quantitated using a highly specific sandwich enzyme-linked immunosorbent assay. A cholesterol uptake assay and an isolated murine colonic motility assay were used to assess the physiological functions of intestinal GCGRs. Fully processed glucagon was detected by mass spectrometry in human intestinal mucosal lysate. High glucose evoked significant glucagon secretion from human ileal tissue independent of sodium glucose cotransporter and KATP channels, contrasting glucose-induced glucagon-like peptide 1 (GLP-1) secretion. The GLP-1 receptor agonist Exendin-4 attenuated glucose-induced glucagon secretion from the human ileum. GCGR blockade significantly increased cholesterol uptake in human ileal crypt culture and markedly slowed ex vivo colonic motility. Our findings describe the human gut as a potential source of extrapancreatic glucagon and demonstrate a novel enteric glucagon/GCGR circuit with important physiological functions beyond glycemic regulation.

Reduction in hospital admissions with an early computed tomography scan: results of an outpatient management protocol for uncomplicated acute diverticulitis.

BACKGROUND: There is increasing evidence that uncomplicated acute diverticulitis (UAD) can be safely and effectively managed as an outpatient. The aim of the current study was to evaluate if an early computed tomography (CT) scan in the emergency department (ED) can reduce the number of hospital admissions when UAD is diagnosed, without compromising patient safety. METHODS: A protocol was introduced in 2015, whereby patients with suspected diverticulitis receive a CT scan on presentation to the ED and be considered for discharge home on oral antibiotics if UAD is confirmed. A retrospective analysis of a prospectively collected database was conducted for all patients presenting to the ED with acute diverticulitis over a 4-year period: 2 years prior (May 2013-April 2015; pre-protocol) and 2 years after implementation of the protocol (May 2015-April 2017; post-protocol). RESULTS: A total of 1147 patients presented to the ED, who were diagnosed with diverticulitis, and UAD was confirmed in 552 patients. There was a significant decrease in hospital admissions for UAD in the post-protocol group from 93% to 39% (P < 0.0001) and in the total number of hospital admission days from 602 to 370 (P < 0.0001). There was no increase in representations between both periods (7% versus 6%; P = 0.49). CONCLUSION: Definitive diagnosis by early CT scan in the ED decreased the admission rate for UAD by more than 50%, and significantly reduced the total number of hospital days without resulting in an increase in representations. UAD can safely and effectively be treated in an outpatient setting leading to a reduction in the burden on the health system.

The Use of Circulating Tumor DNA to Monitor and Predict Response to Treatment in Colorectal Cancer.

Background: Colorectal cancer is one of the most common cancers worldwide and has a high mortality rate following disease recurrence. Treatment efficacy is maximized by providing tailored cancer treatment, ideally involving surgical resection and personalized neoadjuvant and adjuvant therapies, including chemotherapy, radiotherapy and increasingly, targeted therapy. Early detection of recurrence or disease progression results in more treatable disease and is essential to improving survival outcomes. Recent advances in the understanding of tumor genetics have resulted in the discovery of circulating tumor DNA (ctDNA). A growing body of evidence supports the use of these sensitive biomarkers in detecting residual disease and diagnosing recurrence as well as enabling targeted and tumor-specific adjuvant therapies. Methods: A literature search in Pubmed was performed to identify all original articles preceding April 2019 that utilize ctDNA for the purpose of monitoring response to colorectal cancer treatment. Results: Ninety-two clinical studies were included. These studies demonstrate that ctDNA is a reliable measure of tumor burden. Studies show the utility of ctDNA in assessing the adequacy of surgical tumor clearance and changes in ctDNA levels reflect response to systemic treatments. ctDNA can be used in the selection of targeted treatments. The reappearance or increase in ctDNA, as well as the emergence of new mutations, correlates with disease recurrence, progression, and resistance to therapy, with ctDNA measurement allowing more sensitive monitoring than currently used clinical tools. Conclusions: ctDNA shows enormous promise as a sensitive biomarker for monitoring response to many treatment modalities and for targeting therapy. Thus, it is emerging as a new way for guiding treatment decisions-initiating, altering, and ceasing treatments, or prompting investigation into the potential for residual disease. However, many potentially useful ctDNA markers are available and more work is needed to determine which are best suited for specific purposes and for improving specific outcomes.

Metformin Triggers PYY Secretion in Human Gut Mucosa.

CONTEXT: The antidiabetic drug metformin causes weight loss, but the underlying mechanisms are unclear. Recent clinical studies show that metformin increases plasma levels of the anorectic gut hormone, peptide YY (PYY), but whether this is through a direct effect on the gut is unknown. OBJECTIVE: We hypothesized that exposure of human gut mucosal tissue to metformin would acutely trigger PYY secretion. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS: Mucosal tissue was prepared from 46 human colonic and 9 ileal samples obtained after surgical resection and ex vivo secretion assays were performed. Tissue was exposed to metformin, as well as a series of other compounds as part of our mechanistic studies, in static incubations. Supernatant was sampled after 15 minutes. MAIN OUTCOME MEASURES: PYY levels in supernatant, measured using ELISA. RESULTS: Metformin increased PYY secretion from both ileal (P < 0.05) and colonic (P < 0.001) epithelia. Both basal and metformin-induced PYY secretion were unchanged across body mass index or in tissues obtained from individuals with type 2 diabetes. Metformin-dependent PYY secretion was blocked by inhibitors of the plasma membrane monoamine transporter (PMAT) and the serotonin reuptake transporter (SERT), as well as by an inhibitor of AMP kinase (AMPK). CONCLUSIONS: This is a report of a direct action of metformin on the gut epithelium to trigger PYY secretion in humans, occurring via cell internalization through PMAT and SERT and intracellular activation of AMPK. Our results provide further support that the role of metformin in the treatment of metabolic syndrome has a gut-based component.

Sugar Responses of Human Enterochromaffin Cells Depend on Gut Region, Sex, and Body Mass.

Gut-derived serotonin (5-HT) is released from enterochromaffin (EC) cells in response to nutrient cues, and acts to slow gastric emptying and modulate gastric motility. Rodent studies also evidence a role for gut-derived 5-HT in the control of hepatic glucose production, lipolysis and thermogenesis, and in mediating diet-induced obesity. EC cell number and 5-HT content is increased in the small intestine of obese rodents and human, however, it is unknown whether EC cells respond directly to glucose in humans, and whether their capacity to release 5-HT is perturbed in obesity. We therefore investigated 5-HT release from human duodenal and colonic EC cells in response to glucose, sucrose, fructose and α-glucoside (αMG) in relation to body mass index (BMI). EC cells released 5-HT only in response to 100 and 300 mM glucose (duodenum) and 300 mM glucose (colon), independently of osmolarity. Duodenal, but not colonic, EC cells also released 5-HT in response to sucrose and αMG, but did not respond to fructose. 5-HT content was similar in all EC cells in males, and colonic EC cells in females, but 3 to 4-fold higher in duodenal EC cells from overweight females (p < 0.05 compared to lean, obese). Glucose-evoked 5-HT release was 3-fold higher in the duodenum of overweight females (p < 0.05, compared to obese), but absent here in overweight males. Our data demonstrate that primary human EC cells respond directly to dietary glucose cues, with regional differences in selectivity for other sugars. Augmented glucose-evoked 5-HT release from duodenal EC is a feature of overweight females, and may be an early determinant of obesity.

Findings at surveillance colonoscopy following surgery for colorectal cancer.

BACKGROUND: Colonoscopic surveillance following potentially curative surgery for colorectal cancer aims to detect treatable metachronous neoplasia. The timing and findings of colonoscopies for patients enrolled in an endoscopic surveillance programme were examined in this study. METHODS: A retrospective clinical audit was undertaken of 174 consecutive patients undergoing surgery for first-presentation colorectal cancer, looking at the findings of subsequent surveillance colonoscopies. RESULTS: Sixty-nine patients were fit for ongoing surveillance, with the median time to first colonoscopy being 14 months, and significant metachronous pathology was identified in 25%, comprising low-risk adenomas, high-risk adenomas, sessile serrated adenomas and one Dukes A carcinoma. Twenty-seven patients underwent a second colonoscopy, with a median interval of 34 months between the investigations, and adenomas were identified in 30% of patients at the second surveillance colonoscopy. All polyps were colonoscopically resectable. CONCLUSION: Colonoscopy at 1 and 4 years following bowel cancer resection may detect treatable pathology in a significant proportion of those patients fit for ongoing surveillance.

Observation of "complete clinical response" in rectal cancer after neoadjuvant chemoradiation: The Flinders experience.

AIM: Observation with close follow-up ("watch and wait") is a recognized treatment option in patients who achieve a complete clinical response to long course chemoradiotherapy. This review of a prospective database aims to evaluate the clinical outcomes among patients with a complete clinical response managed with observation. METHODS: A prospective study of 32 patients who achieved a complete clinical response was undertaken. The primary outcomes measured were overall and recurrence-free survival, and rate of organ preservation in patients who deferred immediate surgery. RESULTS: Seven patients developed local regrowth over a median follow-up period of 38 months (range, 9-91 months). Median time to detection was 12 months. All seven underwent salvage surgery with complete surgical clearance. One patient developed combined local and systemic recurrence following a low anterior resection. Organ preservation was possible in 25 (78%) patients who sustained a complete clinical response with no evidence of local regrowth or disease recurrence. Among the patients who sustained a complete response, two developed isolated systemic disease. Overall and recurrence-free survival was 95.7% and 87.0%, respectively. CONCLUSION: The majority of patients with rectal cancer who achieved a complete clinical response after chemoradiotherapy and managed with a "watch and wait" approach preserved their rectum and did not develop cancer relapse. Salvage surgery was achieved in all patients who developed local regrowth. The study supports a period of observation in rectal cancer patients who achieve a complete clinical response.

Metformin-induced glucagon-like peptide-1 secretion contributes to the actions of metformin in type 2 diabetes.

BACKGROUND: Metformin reduces plasma glucose and has been shown to increase glucagon-like peptide 1 (GLP-1) secretion. Whether this is a direct action of metformin on GLP-1 release, and whether some of the glucose-lowering effect of metformin occurs due to GLP-1 release, is unknown. The current study investigated metformin-induced GLP-1 secretion and its contribution to the overall glucose-lowering effect of metformin and underlying mechanisms in patients with type 2 diabetes. METHODS: Twelve patients with type 2 diabetes were included in this placebo-controlled, double-blinded study. On 4 separate days, the patients received metformin (1,500 mg) or placebo suspended in a liquid meal, with subsequent i.v. infusion of the GLP-1 receptor antagonist exendin9-39 (Ex9-39) or saline. During 240 minutes, blood was sampled. The direct effect of metformin on GLP-1 secretion was tested ex vivo in human ileal and colonic tissue with and without dorsomorphin-induced inhibiting of the AMPK activity. RESULTS: Metformin increased postprandial GLP-1 secretion compared with placebo (P = 0.014), and the postprandial glucose excursions were significantly smaller after metformin + saline compared with metformin + Ex9-39 (P = 0.004). Ex vivo metformin acutely increased GLP-1 secretion (colonic tissue, P < 0.01; ileal tissue, P < 0.05), but the effect was abolished by inhibition of AMPK activity. CONCLUSIONS: Metformin has a direct and AMPK-dependent effect on GLP-1-secreting L cells and increases postprandial GLP-1 secretion, which seems to contribute to metformin's glucose-lowering effect and mode of action. TRIAL REGISTRATION: NCT02050074 (https://clinicaltrials.gov/ct2/show/NCT02050074). FUNDING: This study received grants from the A.P. Møller Foundation, the Novo Nordisk Foundation, the Danish Medical Association research grant, the Australian Research Council, the National Health and Medical Research Council, and Pfizer Inc.

Surveillance of patients following surgery with curative intent for colorectal cancer.

Surveillance after resection of colorectal cancer with curative intent is an important component of post-operative care. Clinical review, imaging, colonoscopy, and cost to the community are among significant issues to consider in planning a surveillance regime. This review aims to identify the available evidence for the use of surveillance and its individual components. The literature pertaining to follow-up of patients following potentially curative surgery for colorectal cancer was reviewed in order to formulate a summary of the wide range of clinical practice. There is evidence of improved survival of patients undergoing more intense follow-up compared with those having minimal surveillance, with an estimated overall 5-year gain of up to 10%. The efficacy of individual components of follow-up regimes remains unclear, but an overall package of 'intensive' follow-up including clinical review, liver imaging, and colonoscopy appears to be of benefit. It is cost-effective and can be specialist or community-based.

Chemoprevention of colorectal neoplasia.

BACKGROUND: Colorectal cancer is a common and often fatal malignancy. Currently, the modifications that alter disease outcome include early symptom recognition, population screening as well as improved surgical and adjuvant treatments. Preventative strategies have been limited with little evidence that lifestyle changes significantly alter risk. There is however a growing awareness of a potential role for chemoprevention in some patient groups. This study aimed to review the literature associated with chemoprevention in colorectal cancer. METHODS: An electronic literature search of MEDLINE and Embase databases was performed on PubMed for studies detailing the use of chemoprevention agents in colon and rectal cancer. The search was limited to clinical trials on adult humans (>16 years of age) published in English since 1990. RESULTS: The strongest evidence is for non-steroidal anti-inflammatory drugs slowing polyp progression, notably Sulindac and aspirin in patients with familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer, respectively. There is also increasing evidence that continuing use of low-dose aspirin reduces long-term incidence of colorectal cancers. Cyclooxygenase 2 inhibitors also have a potential role but cardiac toxicity currently limits their use. Folic acid, statins, antioxidants, calcium and 5-aminosalicylic acid lack evidence to support their use at present. CONCLUSIONS: Currently, there is not enough evidence to support the implementation of a chemopreventative agent for general use. However, there appears to be a role for aspirin in selected subgroups.