INTRODUCTION:The London classification provides standardization for characterization of disorders of anorectal function, although prevalences and clinical impact of these disorders are unclear. METHODS:An international research consortium was established, including 5 specialist centers. Prospective data were collected in consecutive adults referred for refractory chronic constipation (CC), fecal incontinence (FI), or coexistent CC/FI over 18 months. Patients completed a standardized clinical questionnaire and underwent anorectal physiology tests, which were performed and interpreted using uniform methodology. The prevalence of the London classification was compared between symptom groups (CC, FI, and coexistent CC/FI), equipment types, and sites. Clinical impact was assessed using Cleveland Clinic Constipation and St. Marks Incontinence Scores. RESULTS:Of 1,012 included patients (85.6% women), 30.5% had self-reported CC, 33.2% had FI, and 36.3% had coexistent CC/FI. Rectoanal areflexia was uncommon (3.1%). Disorders of anal tone/contractility (CC: 45.0%; FI: 68.5%; coexistent CC/FI: 63.8%; P < 0.0001) and disorders of rectal sensation (major findings: rectal hyposensitivity, CC: 10.0%; FI: 5.0%; coexistent CC/FI: 11.1%; P = 0.018; rectal hypersensitivity, CC: 3.8%; FI: 9.0%; coexistent CC/FI: 4.9%; P = 0.025) varied between the symptom groups and were associated with symptom severity. Most disorders of rectoanal coordination were found in similar proportions across the symptom groups and were not associated with the severity of CC (median Cleveland Clinic Constipation Score 10-14 in all groups). Prevalences of some disorders differed between equipment types (specifically balloon expulsion test). DISCUSSION:This prospective multicenter study provides information on the prevalence and clinical impact of the London classification and will guide refinement of the current London classification.

The biomarker development field within molecular medicine remains limited by the methods that are available for building predictive models. We developed an efficient method for conservatively estimating confidence intervals for the cross validation-derived prediction errors of biomarker models. This new method was investigated for its ability to improve the capacity of our previously developed method, StaVarSel, for selecting stable biomarkers. Compared with the standard cross validation method, StaVarSel markedly improved the estimated generalisable predictive capacity of serum miRNA biomarkers for the detection of disease states that are at increased risk of progressing to oesophageal adenocarcinoma. The incorporation of our new method for conservatively estimating confidence intervals into StaVarSel resulted in the selection of less complex models with increased stability and improved or similar predictive capacities. The methods developed in this study have the potential to improve progress from biomarker discovery to biomarker driven translational research.

Esophageal Cancer is the seventh commonest cancer worldwide with poor overall survival. Significant morbidity related to open esophagectomy has driven practice toward hybrid, totally minimally invasive and robotic procedures. With the increase in minimally invasive approaches, it has been suggested that there might be an increased incidence of subsequent para-conduit diaphragmatic hernia. To assess the incidence, modifiable risk factors and association with operative approach of this emerging complication, we evaluated outcomes following esophagectomy from two Australian Centers. Prospectively collected databases were examined to identify patients who developed versus did not develop a para-conduit hernia. Patient characteristics, disease factors, treatment factors, operative and post-operative factors were compared for these two groups. A total of 24 of 297 patients who underwent esophagectomy were diagnosed with a symptomatic para-conduit diaphragmatic hernia (8.1%). The significant risk factor for hernia was a minimally invasive abdominal approach (70.8% vs. 35.5%; P = 0.004, odds ratio = 12.876, 95% CI 2.214-74.89). Minimally invasive thoracic approaches were not associated with increased risk. Minimally invasive abdominal approaches to esophagectomy doubled the risk of developing a para-conduit diaphragmatic hernia. Effective operative solutions to address this complication are required.

Background Diagnostic investigations for fecal incontinence (FI) assess the structure and sensorimotor function of the anorectum. Investigations include anorectal manometry, anorectal sensory testing, pudendal nerve terminal motor latencies (PNTML), and endoanal sonography. The severity of FI and results of investigations are often discordant and the rate of symptom resolution following treatment remains <40%. High-resolution anorectal manometry (HRAM) and three-dimensional endoanal ultrasound (3D-US) have been introduced during the last decade. This study aims to assess the strength of relationships between contemporary investigation results and FI severity. Methods Adults presenting for investigation of FI were assessed using the St Mark's FI severity score (SMIS), HRAM, anorectal sensory testing, PNTML, and 3D-US. Key Results 246 patients were included. There were significant relationships between the SMIS and HRAM (resting pressurer(s)= -0.23, 95% CI = (-0.34, -0.11),P < .001; squeeze pressure (r(s)= -0.26, 95% CI = (-0.37, -0.14),P< .001) and 3D-US (anterior EAS lengthr(s)= -0.22, 95% CI = (-0.34, -0.09),P= .001). The relationships between SMIS and HRAM had a greater effect size in those with urge-predominant symptoms (resting pressure:r(s)= -0.40, 95% CI = (-0.57, -0.20),P< .001, squeeze pressure:r(s)= -0.34, 95% CI = (-0.52, -0.12),P= .003). Overall, the variance in SMIS accounted for by anorectal investigations was 8.6% (R-2= 0.098, adjustedR(2)= 0.086,P< .001). Conclusions and Inferences Anorectal investigations are not strong predictors of FI severity. These findings may reflect the multifactorial, heterogeneous pathophysiology of FI, the limitations of the SMIS and anorectal investigations, and contributing factors extrinsic to the anorectum.

Purpose Erosion of a laparoscopic adjustable gastric band (LAGB) is a devastating problem. There is no clear evidence in literature to guide the choice of revisional procedure following an eroded LAGB. The purpose of this study is to analyse the largest series of erosions following LAGB published to-date with an aim to share our experience with this rare complication and how we managed this cohort of patients following explantation of their LAGB. Materials and Methods This is a retrospective cohort study. Patient data is maintained prospectively in a surgical database. The study period was from January 1996 to January 2019. The outcomes of patients who underwent an erosion of LAGB were studied. Results Gastric band erosion was encountered in 4.7% of patients. Sixty patients opted for a revisional procedure which included 37 repeat LAGBs, 6 laparoscopic sleeve gastrectomies (LSG), 7 Roux-en-Y gastric bypasses (RYGB), 1 intragastric balloon, and 9 failed revisional procedures. Re-erosions were noted in 27% of patients who underwent a repeat gastric banding. Median %TWL at a 1-year follow-up was significantly higher in LSG and RYGB groups compared with that in LAGB ( P < 0.008 and P < 0.000, respectively). There was no significant difference between the LSG and RYGB groups. Conclusion The risk of re-erosion is increased in patients who undergo repeat AGB following a previous episode of erosion. Repeat LAGB should not be offered after a previous erosion. LSG and RYGB should be considered as appropriate revisional procedures in a patient who experience weight regain following explantation of an eroded LAGB.

Figure 1.Table 1: MEP latencies and prevalence of neuropathy.Mean ± SEM.Bold= p<0.05 vs healthy controls.Mixed FI Mixed FI + Healthy Con-FI (n=152) FI (n=152) +Constipation Constipation LAS (n=31) )LAS (n=31 trols (n=31) (n=68) (n=68) Latency (ms) Neuropathy % Latency (ms) Neuropathy % Latency (ms) Neuropathy % Latency (ms) Left-lumbar 4.1 ± 0.2 37.5% 3.8 ± 0.2 27.9% 3.7 ± 0.3 25.8% 2.9 ± 0.1 rectal Right-lumbar 4.2 ± 0.1 28.3% 4.2 ± 0.2 23.5% 3.9 ± 0.3 19.4% 3.2 ± 0.1 rectal Left-sacral rec-4.0 ± 0.1 24.3% 4.1 ± 0.2 26.5% 4.0 ± 0.3 25.8% 2.9 ± 0.2 tal Right-sacral 4.1 ± 0.1 33.6% 4.0 ± 0.2 25.0% 3.8 ± 0.3 22.6% 3.0 ± 0.2 rectal Left-lumbar 5.6 ± 0.2 57.9% 5.4 ± 0.3 60.0% 5.4 ± 0.4 58.1% 3.4 ± 0.1 anal Right-lumbar 5.8 ± 0.2 65.8% 5.3 ± 0.3 52.9% 5.3 ± 0.4 54.8% 3.4 ± 0.1 anal Left-sacral 5.1 ± 0.1 64.5% 5.3 ± 0.3 55.9% 5.4 ± 0.5 51.6% 3.0 ± 0.1 anal Right-sacral 6.1 ± 0.8 52.6% 5.3 ± 0.3 51.5% 5.1 ± 0.3 58.1% 3.1 ± 0.

The purpose of this study is to determine whether the reason for gastric band explantation would influence percentage excess weight loss (%EWL) following revisional Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG).

Endoscopic surveillance of Barrett’s esophagus (BE) is probably not cost-effective. A sub-population with BE at increased risk of high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) who could be targeted for cost-effective surveillance was sought.

Background. The precise etiology of fecal incontinence (FI), which occurs frequently following external beam radiotherapy (EBRT) for prostate carcinoma is unknown. It is possibly related to pelvic nerve injury. The aim of this study was to assess the incidence of pudendal nerve dysfunction in men with FI after EBRT for prostate cancer compared to men with FI but no history of EBRT.Material and methods. Data were evaluated from 74 men with intact anal sphincters on endo-anal ultrasound (17 post-EBRT) who had been investigated for FI at a tertiary center. Wexner incontinence scores, pudendal nerve function, anorectal manometry, and rectal sensitivity were compared between the two patient groups.Results. Post-radiotherapy patients were older (77 +/- 6 vs. 62 +/- 17 years, p < 0.005) and had worse incontinence than those with no history of radiotherapy (Wexner score; 13 +/- 3 vs. 8 +/- 4; p < 0.005). Bilateral pudendal nerve terminal motor latency (PNTML) was abnormal in 87% of radiotherapy versus 22% of non-radiotherapy patients (p < 0.001) and the significant difference persisted even after correction for age differences. Anal sphincter pressures and rectal sensitivity for both groups were similar.Conclusion. There is a markedly higher incidence of pudendal nerve dysfunction in men with FI after EBRT for prostate cancer compared with men with FI from other etiologies. The increased severity of incontinence in radiotherapy patients is not matched by alterations in either anal sphincter pressures or rectal sensitivity compared to FI in non-ERBT patients.

Carcinoma of the prostate is a significant cause of mortality and morbidity worldwide and is the most common non-cutaneous malignancy in American men. External beam radiotherapy (EBRT) for locally advanced prostate carcinoma is associated with a halving of the 10-year prostate cancer mortality. A frequent complication of EBRT is fecal incontinence, which significantly impairs quality of life for patients. Pelvic nerve damage as a result of the radiotherapy has been implicated as a possible cause of fecal incontinence. The aim of this study was to determine if fecal incontinence severity and pudendal nerve dysfunction were more commonly associated with men that had undergone EBRT for prostate cancer than in men with fecal incontinence with no history of prostate cancer or pelvic floor radiotherapy. Methods: At Flinders Medical Centre 1305 patients underwent anorectal physiology testing between January 1998 andNovember 2013. 114men were investigated for fecal incontinence with pudendal nerve terminal motor latency (PNTML) testing and anal manometry. Men with evidence of sphincter injury on endoanal ultrasound (EUS) (n=34), a missing EUS result (n=2) or who had received radiotherapy for causes other than prostate cancer (n=4) were excluded. Of the remaining 74 men, 17 had previously undergone radiotherapy for prostate carcinoma (presenting for anorectal testing on average 8.8 years post EBRT) and 57 had no reported prostate cancer. Pudendal nerve function, mean resting pressures (MRP), squeeze pressures (MSP) and Wexner incontinence scores, were compared between the two groups. Results The non-radiotherapy group (62±17 yrs; range 18-85) and a mean Wexner incontinence score of 8 ± 4 which was significantly less (p<0.005) than the mean score of 13 ± 3 in the radiotherapy group (77 ± 6 yrs; range 67-86). In the non-radiotherapy group, 21.7% had abnormal bilateral PNTML compared to 87.5% in the radiotherapy group (p<0.001, Chi-Square). 15.2% in the non-radiotherapy group had delayed bilateral or unilateral PNTML compared to 25.1% in the radiotherapy group (p<0.001). 6.5% of patients in the non-radiotherapy group had no unilateral or bilateral pudendal nerve response (no sphincter contraction in response to stimulus) compared to 62.6% in the radiotherapy group (p<0.001). MRP was 83 ± 40 cmH20 (normal range 54-124 cmH20) in the nonradiotherapy group compared to 55 ± 29 cm H20 in the radiotherapy group (p<0.05). MSP was 246 ± 74 cm H20 (normal range 179-317 cmH20) in the non-radiotherapy group compared to 190 ± 90 cm H20 in the radiotherapy group (p<0.05). Conclusions. Abnormal pudendal nerve function is associated with incontinent males who have received radiotherapy for prostate cancer. This study suggests that pelvic nerve damage as a result of radiotherapy may play a role in the fecal functional disorders experienced by many post-EBRT men.

Sensory information from the viscera to the brain is conducted by vagal and spinal afferent neurons (1). The pancreatobiliary system is innervated by both vagal and splanchnic afferents however there are few reports describing their functional electrophysiological properties. Under pathological conditions such as pancreatitis and pancreatic cancer, these sensory inputs are believed to be essential to the perception of the pain associated with these conditions and additional symptoms e.g. nausea. The pancreatic mechanosensitive afferents have been poorly investigated. Some information has been generated using anesthetized animal studies (2, 3). Due to the limited access to the pancreas in such preparations, the extent and distribution of mechanosensitive nerve endings has not been fully described.

BACKGROUND:We have previously shown that galantide, a non-specific galanin receptor antagonist, ameliorates acute pancreatitis (AP) induced in mice. Octreotide, a somatostatin analogue, has been used in the treatment of AP with inconsistent outcomes. This study set out to compare the efficacy of a combined treatment of galantide and octreotide with the efficacy of each agent individually in experimental AP.METHODS:Acute pancreatitis was induced in mice with 7-hourly caerulein injections. Galantide and/or octreotide were co-administered with each caerulein injection commencing with the first injection. Control animals received galantide, octreotide or saline alone. Pancreata were harvested for histological examination and estimation of myeloperoxidase (MPO) activity. Plasma amylase and lipase activities were measured.RESULTS:Galantide significantly reduced AP-induced hyperenzymaemia by 39-45%. Octreotide alone, or in combination with galantide, did not significantly alter AP-induced hyperenzymaemia. Plasma enzyme activity in the control groups was comparable with pre-treatment activity. Galantide and octreotide administered individually reduced MPO activity by 79% and 50%, respectively; however their combination was without effect. Galantide, octreotide and their combination significantly reduced the percentage of abnormal acinar cells by 28-45%.CONCLUSIONS:Treatment with galantide alone ameliorated most of the indices of AP studied, whereas treatment with octreotide reduced pancreatic MPO activity and acinar cell damage. Combining the two peptides appears to negate their individual benefits, which suggests an interaction in their mechanism of action.

OBJECTIVES:Acute pancreatitis (AP) is characterized by pancreatic microcirculatory and secretory disturbances. As galanin can modulate pancreatic vascular perfusion, we sought to determine if galanin plays a role in AP.METHODS:Acute pancreatitis was induced in wild-type and galanin gene knockout mice by intraperitoneal injections of cerulein. The severity of AP was evaluated (plasma amylase and lipase, myeloperoxidase activity, and acinar cell necrosis) with and without treatment with galanin or the antagonist galantide. Galanin receptor messenger RNA expression in mouse pancreas was measured by reverse transcription-polymerase chain reaction and Western blot analysis.RESULTS:Galantide ameliorated AP, reducing all indices by 25% to 40%, whereas galanin was without effect. In galanin knockout mice, all indices of AP were reduced 25% to 50% compared with wild-type littermates. Galanin administration to the knockout mice exacerbated AP such that it was comparable with the AP induced in the wild-type mice. Conversely, administration of galantide to the galanin knockout mice did not affect the AP, whereas AP was ameliorated in the wild-type mice. The 3 galanin receptor subtypes are expressed in mouse pancreas, with receptor subtype 3 expression predominating.CONCLUSIONS:These data implicate a role for galanin in AP and suggest a potential clinical application for galanin antagonists in treatment.

We have previously shown that galantide ameliorates mild acute pancreatitis (AP), and the salivary tripeptide analogue, feG, ameliorates severe AP in mice. In this study, we compared the efficacy of combining galantide and feG with that of the individual agents in treating mild AP induced in mice with 7-hourly caerulein injections. Galantide was co-administered with each caerulein injection commencing with the first injection. feG was co-administered with the first injection of caerulein as a single intraperitoneal injection. Combination of the agents was also administered. Control animals received galantide, feG, or saline alone. Pancreata were harvested for histological examination and estimation of myeloperoxidase (MPO) activity. Plasma enzyme activities were measured. Galantide significantly reduced AP-induced hyperenzymemia by 41–49%. The combination of galantide and feG significantly reduced AP-induced hyperenzymemia by 39–40%, whereas feG alone was without effect. Plasma enzyme activity in the control groups was comparable with pre-treatment activity. Galantide, feG, and their combination significantly reduced MPO activity by 83, 44 and 74% respectively, and % abnormal acinar cells by 32, 29 and 36% respectively. This study demonstrates for the first time the beneficial effect of feG in mild caerulein-induced AP. Moreover the data indicate that the hyperenzymemia in mild caerulein-induced AP at 12h possibly reflect a larger secretory component as compared to enzyme release due to neutrophil-mediated acinar cell damage. The effects of the treatment with both peptides indicate a possible role for galantide in modulating neutrophil chemotaxis/activation and supports the hypothesis that galantide may influence neurogenic inflammation in AP.

Pancreatic exocrine secretion is affected by galanin, but the mechanisms involved are unclear. We aimed to determine the effect and elucidate the mechanism of action of exogenous galanin on basal and stimulated pancreatic amylase secretion in vitro. The effect of galanin on basal-, carbachol-, and caerulein-stimulated amylase secretion from isolated murine pancreatic lobules was measured. Carbachol and caerulein concentration-response relationships were established. Lobules were coincubated with galanin (10(-12) M to 10(-7) M), carbachol (10(-6) M), or caerulein (10(-10) M). Lobules were preincubated with atropine (10(-5) M), tetrodotoxin (10(-5) M), hexamethonium (10(-5) M), or diazoxide (10(-7) M and 10(-4) M) for 30 min followed by incubation with caerulein (10(-10) M) alone or combined with galanin (10(-12) M). Amylase secretion was expressed as percent of total lobular amylase. Immunohistochemical studies used the antigen retrieval technique and antisera for galanin receptor (GALR) 1, 2, and 3. Carbachol and caerulein stimulated amylase secretion in a concentration-dependent manner with maximal responses of two- and 1.7-fold over control evoked at 10(-6) M and 10(-10) M, respectively. Galanin (10(-12) M) completely inhibited caerulein-stimulated amylase secretion but had no effect on carbachol-stimulated or basal secretion. Atropine and tetrodotoxin pretreatment abolished the caerulein-stimulated amylase secretion, whereas hexamethonium had no significant effect. Diazoxide significantly reduced caerulein-stimulated amylase secretion by approximately 80%. Galanin did not affect caerulein-stimulated amylase secretion in the presence of hexamethonium or diazoxide. Glucose-stimulated amylase secretion was also inhibited by galanin. Immunohistochemistry revealed islet cells labeled for GALR2. These data suggest that galanin may modulate caerulein-stimulated amylase secretion by acting on cholinergic nerves and/or islet cells possibly via GALR2 to regulate insulin release.