Michael P. Lewis

Review of guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen: prepared on behalf of the British Committee for Standards in Haematology by a working party of the Haemato-Oncology task force.

Guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen were first published by the British Committee for Standards in Haematology (BCSH) in 1996 and formally reviewed in 2002. Although the guidelines originated from discussion within the BCSH, the intended readership is wide given the multidisciplinary nature of the management of hyposplenism.

Prospective randomized trial of laparoscopic gastrojejunostomy versus duodenal stenting for malignant gastric outflow obstruction

BackgroundWe prospectively compared laparoscopic gastrojejunostomy with duodenal stenting as a means of palliating malignant gastric outflow obstruction.MethodsA total of 27 patients with malignant gastric outflow obstruction were randomized to either laparoscopic gastrojejunostomy (LGJ) or duodenal stenting (DS) over a 3-year period.ResultsThirteen patients underwent successful LGJ and 10 had successful DS. Eight patients had complications after LGJ, but none had complications after DS. Patients who underwent LGJ had a significant increase in visual analog pain score at day 1 (p = 0.05), and also had a longer hospital stay compared to those who underwent DS (11.4 vs. 5.2 days, p = 0.02). After DS, patients experienced an improvement in physical health at 1 month as measured using the Short Form-36 (SF-36) questionnaire (p < 0.01). There was no change following LGJ.ConclusionDuodenal stenting is a safe means of palliating malignant gastric outflow obstruction. It offers significant advantages for patients compared with minimal-access surgery.

Attendance at a pain clinic with severe chronic pain after open and laparoscopic inguinal hernia repairs

The aim was to compare the frequency of severe chronic pain that required attendance at a pain clinic after open and laparoscopic inguinal hernia repairs.

Dynamic and differential regulation of NKCC1 by calcium and cAMP in the native human colonic epithelium

The capacity of the intestine to secrete fluid is dependent on the basolateral Na+–K+–2Cl− co‐transporter (NKCC1). Given that cAMP and Ca2+ signals promote sustained and transient episodes of fluid secretion, respectively, this study investigated the differential regulation of functional NKCC1 membrane expression in the native human colonic epithelium. Tissue sections and colonic crypts were obtained from sigmoid rectal biopsy tissue samples. Cellular location of NKCC1, Na+–K+‐ATPase, M3 muscarinic acetylcholine receptor (M3AChR) and lysosomes was examined by immunolabelling techniques. NKCC1 activity (i.e. bumetanide‐sensitive uptake), intracellular Ca2+ and cell volume were assessed by 2′,7′‐bis(2‐carboxyethyl)‐5‐(and‐6)‐carboxyfluorescein (BCECF), Fura‐2 and differential interference contrast/calcein imaging. Unstimulated NKCC1 was expressed on basolateral membranes and exhibited a topological expression gradient, predominant at the crypt base. Cholinergic Ca2+ signals initiated at the crypt base and spread along the crypt axis. In response, NKCC1 underwent a Ca2+‐dependent 4 h cycle of recruitment to basolateral membranes, activation, internalization, degradation and re‐expression. Internalization was prevented by the epidermal growth factor receptor kinase inhibitor tyrphostin‐AG1478, and re‐expression was prohibited by the protein synthesis inhibitor cylcoheximide; the lysosome inhibitor chloroquine promoted accumulation of NKCC1 vesicles. NKCC1 internalization and re‐expression were accompanied by secretory volume decrease and bumetanide‐sensitive regulatory volume increase, respectively. In contrast, forskolin (i.e. cAMP elevation)‐stimulated NKCC1 activity was sustained, and membrane expression and cell volume remained constant. Co‐stimulation with forskolin and acetylcholine promoted dramatic recruitment of NKCC1 to basolateral membranes and prolonged the cycle of co‐transporter activation, internalization and re‐expression. In conclusion, persistent NKCC1 activation by cAMP is constrained by a Ca2+‐dependent cycle of co‐transporter internalization, degradation and re‐expression; this is a novel mechanism to limit intestinal fluid loss.

Laparoscopic resection of gastric gastrointestinal stromal tumors

BackgroundGastrointestinal stromal tumors (GISTs) are neoplasms with low malignant potential. They occur most commonly in the stomach, where they are amenable to laparoscopic resection.MethodsA case note review of all patients undergoing laparoscopic resection of a presumed gastric GIST at the Norfolk and Norwich University Hospital, United Kingdom, was conducted.ResultsSince September 1995, 30 patients have undergone this procedure. The patients had a mean age of 64.2 years (range, 31–87 years) and a mean weight of 74.1 kg (range, 44–104 kg). A presumptive diagnosis of GIST was made in all the cases based on the endoscopic and radiologic appearance of the lesion. Laparoscopic resection was completed successfully in 23 patients with a mean operating time of 73.8 min (range, 26–160 min). Seven procedures were converted to open surgery: three because the tumor was deemed too large for laparoscopic resection, two because the tumor could not be identified, one because of dense peritoneal adhesions, and one because of bleeding. The mean estimated blood loss was 196 ml (range, 0–1,000 ml), and the mean hospital stay was 5 days (ranges, 1–11 days). Pathologic analysis of the resected specimens showed 22 GISTs, 3 inflammatory fibroids, 2 submucosal lipomas, 1 submucosal varix, and 1 nest of heterotopic pancreatic tissue. During a median follow-up period of 18 months (range, 2–101 months) there have been two cases of recurrence. In both cases, the tumor was catagorized as high risk for aggressive behavior after primary resection.ConclusionStapled laparoscopic resection is a safe and effective treatment option for nonmetastatic primary gastric GIST.

Statin Use Is Associated With Reduced Risk of Histologic Subtypes of Esophageal Cancer: A Nested Case-Control Analysis

BACKGROUND & AIMS Most patients with esophageal adenocarcinoma (EAC) or squamous cell cancer (ESCC) present with advanced, incurable disease. Statins have reported anti-carcinogenic effects and may be chemoprotective. We investigated the association between regular use of statins and the main histologic subtypes of esophageal malignancy (EAC, esophagogastric junctional adenocarcinoma, and ESCC) in the UK general population. METHODS We identified all individuals in the UK General Practice Research Database diagnosed with esophageal cancer from 2000 through 2009. Patients were linked to the National Cancer Registry to confirm histologic subtypes. Each patient was matched with up to 4 controls for age, sex, and practice. We performed a nested case-control analysis using conditional logistic regression to estimate the risk of each subtype with regular statin use, adjusted for body mass index, smoking, alcohol intake, and concomitant use of medications. RESULTS In total, 581 participants with EAC, 213 with esophagogastric junctional adenocarcinoma, and 332 with ESCC were matched to 2167, 783, and 1242 controls, respectively. Regular statin use was inversely associated with development of EAC (odds ratio = 0.58; 95% confidence interval: 0.39-0.87) (with significant dose and duration responses) and esophagogastric junctional adenocarcinoma (odds ratio = 0.29; 95% confidence interval: 0.09-0.92) (with high-dose use only). Statin use for 1-4 years was inversely associated with ESCC (odds ratio = 0.51; 95% confidence interval: 0.27-0.98). CONCLUSIONS In a nested case-control analysis of a UK population-based cohort, statin use was inversely associated with histologic subtypes of esophageal cancer. Randomized controlled trials are warranted to determine whether statins have chemopreventive effects in high-risk groups.

Canonical Wnt signals combined with suppressed TGFβ/BMP pathways promote renewal of the native human colonic epithelium

Background A defining characteristic of the human intestinal epithelium is that it is the most rapidly renewing tissue in the body. However, the processes underlying tissue renewal and the mechanisms that govern their coordination have proved difficult to study in the human gut. Objective To investigate the regulation of stem cell-driven tissue renewal by canonical Wnt and TGFβ/bone morphogenetic protein (BMP) pathways in the native human colonic epithelium. Design Intact human colonic crypts were isolated from mucosal tissue samples and placed into 3D culture conditions optimised for steady-state tissue renewal. High affinity mRNA in situ hybridisation and immunohistochemistry were complemented by functional genomic and bioimaging techniques. The effects of signalling pathway modulators on the status of intestinal stem cell biology, crypt cell proliferation, migration, differentiation and shedding were determined. Results Native human colonic crypts exhibited distinct activation profiles for canonical Wnt, TGFβ and BMP pathways. A population of intestinal LGR5/OLFM4-positive stem/progenitor cells were interspersed between goblet-like cells within the crypt-base. Exogenous and crypt cell-autonomous canonical Wnt signals supported homeostatic intestinal stem/progenitor cell proliferation and were antagonised by TGFβ or BMP pathway activation. Reduced Wnt stimulation impeded crypt cell proliferation, but crypt cell migration and shedding from the crypt surface were unaffected and resulted in diminished crypts. Conclusions Steady-state tissue renewal in the native human colonic epithelium is dependent on canonical Wnt signals combined with suppressed TGFβ/BMP pathways. Stem/progenitor cell proliferation is uncoupled from crypt cell migration and shedding, and is required to constantly replenish the crypt cell population.

The colon-selective spasmolytic otilonium bromide inhibits muscarinic M 3 receptor-coupled calcium signals in isolated human colonic crypts

Otilonium bromide (OB) is a smooth muscle relaxant used in the treatment of irritable bowel syndrome. Otilonium bromide has been shown to interfere with the mobilization of calcium in intestinal smooth muscle, but the effects on other intestinal tissues have not been investigated. We identified the muscarinic receptor subtype coupled to calcium signals in colonic crypt derived from the human colonic epithelium and evaluated the inhibitory effects of OB. Calcium signals were monitored by fluorescence imaging of isolated human colonic crypts and Chinese hamster ovary cells stably expressing the cloned human muscarinic M3 receptor subtype (CHO‐M3). Colonic crypt receptor expression was investigated by pharmacological and immunohistochemical techniques. The secretagogue acetylcholine (ACh) stimulated calcium mobilization from intracellular calcium stores at the base of human colonic crypts with an EC50 of 14 μM. The muscarinic receptor antagonists 4‐DAMP, AF‐DX 384, pirenzepine and methroctamine inhibited the ACh‐induced calcium signal with the following respective IC50 (pKb) values: 0.78 nM (9.1), 69 nM (7.2), 128 nM (7.1), and 2510 nM (5.8). Immunohistochemical analyses of muscarinic receptor expression demonstrated the presence of M3 receptor subtype expression at the crypt‐base. Otilonium bromide inhibited the generation of ACh‐induced calcium signals in a dose dependent manner (IC50=880 nM). In CHO‐M3 cells, OB inhibited calcium signals induced by ACh, but not ATP. In addition, OB did not inhibit histamine‐induced colonic crypt calcium signals. The present studies have demonstrated that OB inhibited M3 receptor‐coupled calcium signals in human colonic crypts and CHO‐M3 cells, but not those induced by stimulation of other endogenous receptor types. We propose that the M3 receptor‐coupled calcium signalling pathway is directly targeted by OB at the level of the colonic epithelium, suggestive of an anti‐secretory action in IBS patients suffering with diarrhoea.

Stapled laparoscopic cystgastrostomy: a series with 15 cases.

BackgroundThe goal of this study was to assess the clinical outcome of patients undergoing laparoscopic stapled cystgastrostomy for pancreatic pseudocysts in contact with the posterior wall of the stomach.MethodsWe performed a case note review of all patients who have undergone stapled laparoscopic cystgastrostomy in Norwich, UK. The cystgastrostomy was fashioned through an anterior gastrotomy using a vascular ETS stapling device in all cases.ResultsFifteen patients have undergone stapled laparoscopic cystgastrostomy. The procedure was completed successfully in 12 patients. Three procedures were converted to open surgery for technical reasons. There were no complications due to bleeding from the cystgastrostomy. Early complications included systemic sepsis (one), bleeding gastric ulcer (one) and pseudocyst recurrence due to partial closure of the cystgastrostomy (two). No late recurrences or other complications have been found at a median follow-up of 37 months.ConclusionStapled laparoscopic cystgastrostomy is a safe and effective procedure for draining pancreatic pseudocysts in contact with the posterior wall of the stomach. The use of a hemostatic stapling device to fashion the cystgastrostomy may reduce the risk of catastrophic hemorrhage from the pseudocyst wall.

Systematic review:potential preventive effects of statins against oesophageal adenocarcinoma

The incidence of oesophageal adenocarcinoma (OAC) has risen dramatically in recent decades, and its prognosis remains extremely poor. There is emerging evidence that statins may prevent OAC.