Jonathan N. Lund

A randomised, prospective, double-blind, placebo-controlled trial of glyceryl trinitrate ointment in treatment of anal fissure.

BACKGROUND Anal fissure is most commonly treated surgically by internal anal sphincterotomy. However, there is some concern over the effects of this procedure on continence. Nitric oxide donors such as glyceryl trinitrate (GTN) have been shown to cause a reversible chemical sphincterotomy capable of healing fissures in a small series of cases. This study reports a prospective, randomised, double-blind, placebo-controlled trial to test the hypothesis that topical GTN is the best first-line treatment for chronic anal fissure. METHODS 80 consecutive patients were randomised to receive treatments with topical 0.2% GTN ointment or placebo. Maximum anal resting pressure (MARP) was measured with a constantly perfused side-hole catheter before and after the first application of trial ointment. Anodermal blood flow was measured during manometry by laser Doppler flowmetry. After initial treatments, patients were given a supply of ointment (either GTN or placebo) to be applied to the lower anal canal twice daily. Patients were reviewed 2-weekly. At the initial and follow up visits patients were asked to record pain experienced on defaecation on a linear analogue pain score. Endpoints were healing of the fissure or condition after 8 weeks of treatment. FINDINGS After 8 weeks, healing was observed in 26/38 (68%) patients treated with GTN and in 3/39 (8%) patients treated with placebo (p < 0.0001, chi 2 test). Linear analogue pain score fell significantly in both groups after 2 weeks of treatment. This fall was maintained in those treated with GTN but pain scores returned to pre-treatment values by 4 weeks on treatment with placebo. MARP fell significantly from a mean of 115.9 (SD 31.6) to 75.9 (30.1) cm H2O (p < 0.001, Students paired t-test) in patients treated with GTN but no change was seen in MARP after placebo. Anodermal blood flow measured by laser Doppler flowmetry significantly increased after application of GTN ointment but was unaffected by placebo. INTERPRETATION Topical GTN provides rapid, sustained relief of pain in patients with anal fissure. Over two-thirds of patients treated in this way avoided surgery which would otherwise have been required for healing. Long-term follow up is needed to assess the risk of recurrent fissure in patients with GTN.

Glyceryl trinitrate is an effective treatment for anal fissure

PURPOSE: It has been suggested that chronic anal fissure is ischemic in origin because of poor blood supply and spasm of the internal anal sphincter. Nitric oxide donors such as glyceryl trinitrate (GTN) cause a chemical sphincterotomy leading to healing of the fissure. This study addresses the hypothesis that topical GTN ointment may be an effective nonsurgical treatment for chronic anal fissure. METHODS: Thirty-nine consecutive patients (23 women; median age, 34 (range, 16–54) years) with chronic anal fissure presenting to the surgical outpatient department were treated for four to six weeks with 0.2 percent GTN ointment applied twice daily to the anoderm. Maximum anal resting pressure was measured at steady state before and after application of the ointment at the first visit. Patients were assessed at two weekly intervals. RESULTS: Previous surgery for fissure had been performed in seven patients. There were 30 posterior and 9 anterior fissures. Resting maximum anal resting pressure fell from 122.1 ± 44 to 72.5 ± 33.3 cm of water (mean ± standard deviation) by 20 minutes after application of ointment (P <0.0001; pairedt-test). Healing was complete in 14 patients at four weeks and in 33 patients at six weeks. Fissures recurred in five patients after treatment had been stopped. Four recurrences were successfully treated by further GTN ointment and one by sphincterotomy. CONCLUSIONS: This study shows that most anal fissures can be treated nonsurgically with topically applied 0.2 percent GTN ointment. Prospective, randomized controlled trials are now needed, because nonsurgical treatment of anal fissure avoids permanent division of part of the sphincter and the consequent disturbance of continence mechanisms.

Predictors for acute and chronic pouchitis following restorative proctocolectomy for ulcerative colitis

Objective This study was undertaken to evaluate the cumulative incidence, onset and risk predicting factors for acute and chronic pouchitis.

Simple psoas cross-sectional area measurement is a quick and easy method to assess sarcopenia and predicts major surgical complications

AIM Radiologically assessed muscle mass has been suggested as a surrogate marker of functional status and frailty and may predict patients at risk of postoperative complications. We hypothesize that sarcopenia negatively impacts on postoperative recovery and is predictive of complications. METHOD One hundred patients undergoing elective resection for colorectal carcinoma were included in this study. Lean muscle mass was estimated by measuring the cross-sectional area of the psoas muscle at the level of the third lumbar vertebra identified on a preoperative CT scan, normalizing for patient height. Perioperative morbidity was scored according to the Clavien-Dindo classification. All statistical data analyses were carried out using the Statistical Package for the Social Sciences (SPSS) version 20.0. RESULTS Fifteen per cent of patients were identified as sarcopenic. There were no deaths in the study group. Sarcopenia was associated with a significantly increased risk of developing major complications (Grade 3 or greater, OR = 5.41, 95% CI: 1.45-20.15, P = 0.01). Sarcopenia did not predict length of stay, critical care dependency or time to mobilization. CONCLUSION Sarcopenia, as a marker of frailty, is an important risk factor in surgical patients but difficult to estimate using bedside testing. CT scans, performed for preoperative staging, provide an opportunity to quantify lean muscle mass without additional cost or exposure to radiation and eliminate the inconvenience of further investigations.

Knockdown of microRNA-21 Inhibits Proliferation and Increases Cell Death by Targeting Programmed Cell Death 4 (PDCD4) in Pancreatic Ductal Adenocarcinoma

ObjectiveThis study aims to examine the expression of a panel of five microRNAs (miRNA) in pancreatic ductal adenocarcinoma (PDAC) and the functional effect of miR-21 inhibition in PDAC cell lines.BackgroundmiRNA are short, non-coding RNA molecules, which play important roles in several cellular processes by silencing expression of their target genes through translational repression or mRNA degradation. They are often aberrantly expressed in cancer, and this dysregulation can promote carcinogenesis by altering the expression of tumour suppressor or oncogenes.MethodsmiRNA expression levels were measured in 24 PDAC tumour/matched adjacent normal tissue samples and three PDAC cell lines using reverse transcription polymerase chain reaction. Levels of cell proliferation and death and expression of programmed cell death 4 (PDCD4; tumour suppressor) were studied in PDAC cells (MIA-Pa-Ca-2) in the absence or presence of a miR-21 inhibitor.ResultsPDAC primary tissues and cell lines displayed a consistent upregulation of miR-21 (P < 0.0001) and downregulation of both miR-148a (P < 0.0001) and miR-375 (P < 0.0001) relative to adjacent normal tissue. Furthermore, miR-21 levels in the primary tumours correlated with disease stage (P < 0.0001). Inhibition of miR-21 in MIA-Pa-Ca-2 PDAC cells led to reduced cell proliferation (P < 0.01) and increased cell death (P < 0.01), with simultaneous increase in levels of the tumour suppressor, PDCD4 (P < 0.01).ConclusionmiRNA expression profiles may be used as biomarkers for detecting pancreatic cancer. Moreover, miR-21 could be a predictor of disease progression and a possible therapeutic target in part by upregulating PDCD4 in pancreatic cancer.

Risks, costs, and compliance limit colorectal adenoma surveillance: lessons from a randomised trial.

BACKGROUND AND AIMS In the USA and many other countries, endoscopic surveillance of colorectal adenoma patients is now widely practised. However, the optimal frequency and mode of such surveillance are not yet established. The aim of this trial was to compare surveillance at one, two, or five year intervals using either flexible sigmoidoscopy or colonoscopy. METHODS Analysis of a randomised trial of flexible sigmoidoscopy and colonoscopy over one, two, or five years after stratification for “high” or “low” risk of recurrent adenomas. The trial started in 1984. RESULTS A total of 776 patients were stratified into “high” (n=307) and “low” (n=469) recurrence risk groups and randomised to flexible sigmoidoscopy or colonoscopy at varying intervals. Only 81 recurrent adenomas (30/81 were >1 cm in diameter) were detected in the 2307 person years of follow up within the surveillance study. Adenoma recurrence was significantly higher in the high risk group (relative rate 1.82; 95% confidence interval 1.2–2.9) but recurrence rates per 1000 person years were low and not significantly different in those surveyed by colonoscopy or flexible sigmoidoscopy. Loss to follow up was greatest in those having an annual examination compared with two or five yearly surveillance examinations. Despite surveillance, invasive cancer developed in four patients compared with an expected value of 9.12 for the general population in England (p=0.10); of these four patients who developed cancers, only one was detected by surveillance examination. CONCLUSIONS Adenoma recurrence rates were much lower than expected in both high and low risk groups. This suggests that endoscopic surveillance should be targeted at high risk groups. A surveillance interval of five years was as effective as shorter intervals in terms of cancer prevention, and was associated with similar compliance to two yearly examinations.

Skeletal muscle hypertrophy adaptations predominate in the early stages of resistance exercise training, matching deuterium oxide-derived measures of muscle protein synthesis and mechanistic target of rapamycin complex 1 signaling

Resistance exercise training (RET) is widely used to increase muscle mass in athletes and also aged/cachectic populations. However, the time course and metabolic and molecular control of hypertrophy remain poorly defined. Using newly developed deuterium oxide (D2O)‐tracer techniques, we investigated the relationship between long‐term muscle protein synthesis (MPS) and hypertrophic responses to RET. A total of 10 men (23 ± 1 yr) undertook 6 wk of unilateral (1‐legged) RET [6 × 8 repetitions, 75% 1 repetition maximum (1‐RM) 3/wk], rendering 1 leg untrained (UT) and the contralateral, trained (T). After baseline bilateral vastus lateralis (VL) muscle biopsies, subjects consumed 150 ml D2O (70 atom percentage; thereafter 50 ml/wk) with regular body water monitoring in saliva via high‐temperature conversion elemental analyzer:isotope ratio mass spectrometer. Further bilateral VL muscle biopsies were taken at 3 and 6 wk to temporally quantify MPS via gas chromatography:pyrolysis:isotope ratio mass spectrometer. Expectedly, only the T leg exhibited marked increases in function [i.e., 1‐RM/maximal voluntary contraction (60°)] and VL thickness (peaking at 3 wk). Critically, whereas MPS remained unchanged in the UT leg (e.g., ∼1.35 ± 0.08%/d), the T leg exhibited increased MPS at 0‐3 wk (1.6 ± 0.01%/d), but not at 3‐6 wk (1.29 ± 0.11%/d); this was reflected by dampened acute mechanistic target of rapamycin complex 1 signaling responses to RET, beyond 3 wk. Therefore, hypertrophic remodeling is most active during the early stages of RET, reflecting longer‐term MPS. Moreover, D2O heralds promise for coupling MPS and muscle mass and providing insight into the control of hypertrophy and efficacy of anabolic interventions.—Brook, M. S., Wilkinson, D. J., Mitchell, W. K., Lund, J. N., Szewczyk, N. J., Greenhaff, P. L., Smith, K., Atherton, P. J. Skeletal muscle hypertrophy adaptations predominate in the early stages of resistance exercise training, matching deuterium oxide‐derived measures of muscle protein synthesis and mechanistic target of rapamycin complex 1 signaling. FASEB J. 29, 4485‐4496 (2015). www.fasebj.org

Effect of tumor burden and subsequent surgical resection on skeletal muscle mass and protein turnover in colorectal cancer patients

BACKGROUND Cachexia is a consequence of tumor burden caused by ill-defined catabolic alterations in muscle protein turnover. OBJECTIVE We aimed to explore the effect of tumor burden and resection on muscle protein turnover in patients with nonmetastatic colorectal cancer (CRC), which is a surgically curable tumor that induces cachexia. DESIGN We recruited the following 2 groups: patients with CRC [n = 13; mean ± SEM age: 66 ± 3 y; BMI (in kg/m(2)): 27.6 ± 1.1] and matched healthy controls (n = 8; age: 71 ± 2 y; BMI: 26.2 ± 1). Control subjects underwent a single study, whereas CRC patients were studied twice before and ~6 wk after surgical resection to assess muscle protein synthesis (MPS), muscle protein breakdown (MPB), and muscle mass by using dual-energy X-ray absorptiometry. RESULTS Leg muscle mass was lower in CRC patients than in control subjects (6290 ± 456 compared with 7839 ± 617 g; P < 0.05) and had an additional decline after surgery (5840 ± 456 g; P < 0.001). Although postabsorptive MPS was unaffected, catabolic changes with tumor burden included the complete blunting of postprandial MPS (0.038 ± 0.004%/h in the CRC group compared with 0.065 ± 0.006%/h in the control group; P < 0.01) and a trend toward increased MPB under postabsorptive conditions (P = 0.09). Although surgical resection exacerbated muscle atrophy (-7.2%), catabolic changes in protein metabolism had normalized 6 wk after surgery. The recovery in postprandial MPS after surgery was inversely related to the degree of muscle atrophy (r = 0.65, P < 0.01). CONCLUSIONS CRC patients display reduced postprandial MPS and a trend toward increased MPB, and tumor resection reverses these derangements. With no effective treatment of cancer cachexia, future therapies directed at preserving muscle mass should concentrate on alleviating proteolysis and enhancing anabolic responses to nutrition before surgery while augmenting muscle anabolism after resection.

E-learning vs lecture: which is the best approach to surgical teaching?

Aim  Most medical teaching is still delivered by traditional face‐to‐face interaction. E‐learning has the potential benefit of instilling deeper learning of topics by virtue of repeated and convenient access to content presented in a range of media. We aimed to evaluate objectively the benefit of educating medical students on a common surgical topic (haemorrhoids), through a website and podcast package vs a traditional lecture.

Rifaximin‐ciprofloxacin combination therapy is effective in chronic active refractory pouchitis

Objective  Treatment of chronic refractory pouchitis is often difficult and disappointing and some of the affected pouches subsequently fail. This study was conducted to evaluate the efficacy and tolerability of treatment with rifaximin, a nonabsorbable oral antibiotic with immunomdulatory functions, in combination with ciprofloxacin for chronic active refractory pouchitis.