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Background and Aims: Patients with ulcerative colitis are often treated with multiple immunomodulative agents to achieve remission. In refractory disease, the next option is frequently proctocolectomy with ileal pouch–anal anastomosis. No consensus exists as to whether immunomodulatory therapy at the time of ileal pouch surgery leads to any increase in postoperative complications. Our aim was to assess, in ulcerative colitis patients with restorative proctocolectomy, the effect of preoperative anti-tumor necrosis factor therapy and corticosteroids on postoperative complications and pouch failure.Materials and Methods: A retrospective medical record review of 445 patients with ulcerative colitis who underwent proctocolectomy with ileal pouch–anal anastomosis in Helsinki University Hospital between January 2005 and June 2016.Results: Anti-tumor necrosis factor agents were not associated with postoperative complications. Only high-dose corticosteroids (prednisolone ⩾20 mg or equivalent) were associated with higher incidence of anastomotic leak (12.6% vs 2.5%, P= 0.002) and wound dehiscence (4.2% vs 0%, P= 0.019), but pouch failure rate was no higher (2.1% vs 0%, P= 0.141) than in patients without corticosteroid treatment. A lower dosage of corticosteroids had no effect on early postoperative complications, but pouch failure rate was increased (4.4% vs 0%, P= 0.015).Conclusion: Corticosteroids, but not anti-tumor necrosis factor therapy, were associated with postoperative complications. Preoperative use of corticosteroids may increase pouch failure rate, but the risk is still minor in high-volume centers performing ileal pouch surgery.

Background and Aims: Several studies and guidelines are questioning routine preoperative laboratory tests in surgical and endoscopic procedures. Their effect in endoscopic retrograde cholangiopancreatography is not currently known. This study was carried out to evaluate the risk of adverse effects in endoscopic retrograde cholangiopancreatography and their association with preoperative lab tests.Materials and Methods: A single-center, prospective observational study on all 956 patients undergoing 1196 endoscopic retrograde cholangiopancreatographies in the Endoscopy Unit of Helsinki University Central Hospital from 1 March 2012 to 28 February 2013. Routine preoperative laboratory test results (basic blood count, creatinine, potassium, sodium, international normalized ratio/thromboplastin time, and amylase), health status, medication, and demographic information of all patients were analyzed in relation to adverse effects related to endoscopic retrograde cholangiopancreatography and procedural sedation.Results: Multivariate analysis showed post–endoscopic retrograde cholangiopancreatography pancreatitis (43 cases, 3.6%) to have no association with abnormal routine preoperative laboratory tests. Respiratory depression caused by sedation (128 cases, 11%) was not associated with abnormal routine preoperative laboratory tests, and anemia was found to be a slightly protecting factor. Cardiovascular depression caused by sedation was associated with thrombocytopenia (odds ratio = 1.87, p = 0.025) and, in male patients, hyponatremia (odds ratio = 3.66, p < 0.001). Incidence of other adverse effects was too low for statistical analysis.Conclusion: Routine universal preoperative lab testing was not found to be successful in predicting adverse effects in endoscopic retrograde cholangiopancreatography procedures. Laboratory testing should be done focusing on each patient’s individual needs.

Objectives: Since the early 1990s, low long-term survival rates following pancreatic surgery for pancreatic ductal adenocarcinoma have challenged us to improve treatment. In this series, we aim to show improved survival from pancreatic ductal adenocarcinoma during the era of centralized pancreatic surgery.Methods: Analysis of all pancreatic resections performed at Helsinki University Hospital and survival of pancreatic ductal adenocarcinoma patients during 2000–2013 were included. Post-operative complications such as fistulas, reoperations, and mortality rates were recorded. Patient and tumor characteristics were compared with survival data.Results: Of the 853 patients undergoing pancreatic surgery, 581 (68%) were pancreaticoduodenectomies, 195 (21%) distal resections, 28 (3%) total pancreatectomies, and 49 (6%) other procedures. Mortality after pancreaticoduodenectomy was 2.1%. The clinically relevant B/C fistula rate was 7% after pancreaticoduodenectomy and 13% after distal resection, and the re-operation rate was 5%. The 5- and 10-year survival rates for pancreatic ductal adenocarcinoma were 22% and 14%; for T1-2, N0 and R0 tumors, the corresponding survival rates were 49% and 31%. Carbohydrate antigen 19-9 >75?kU/L, carcinoembryonic antigen >5?µg/L, N1, lymph-node ratio >20%, R1, and lack of adjuvant therapy were independent risk factors for decreased survival.Conclusion: After centralization of pancreatic surgery in southern Finland, we have managed to enable pancreatic ductal adenocarcinoma patients to survive markedly longer than in the early 1990s. Based on a 1.7-million population in our clinic, mortality rates are equal to those of other high-volume centers and long-term survival rates for pancreatic ductal adenocarcinoma have now risen to some of the highest reported.

Background and Aims: The rainage (PBD) prior to pancreaticoduodenectomy (PD) is controversial. If PBD is required, large bore self-expandable metallic stents (SEMS) are thought to maintain better drainage and have fewer postoperative complications than plastic stents. The confirming evidence is scarce. The aim of the study was to compare outcomes of surgery in patients who underwent PBD with SEMS or plastic stents deployed at endoscopic retrograde cholangiopancreatography (ERCP).Material and Methods: This is a retrospective study of 366 patients having had PD during 2000–2009. Preceding endoscopic PBD was performed in 191 patients and nine had had percutaneous transhepatic drainage (PTD). At the time of operation, 163 patients had a plastic stent and 28 had SEMS. Due to stent exchanges, 176 plastic stents and 29 SEMS were placed in all.Results and Conclusions: The stent failure rate was 7.4% for plastic stents and 3.4% for SEMS (p= 0.697). A bilirubin level under 50 µmol/L was reached by 80% of the patients with plastic stents and by 61% of the patients with SEMS (p= 0.058). A postoperative infection complication and/or a pancreatic fistula was found in 26% while using plastic stents and in 25% using SEMS (p= 1.000). In unstented patients with biliary obstruction, the bile juice was sterile significantly more often than in endoscopically stented patients (100% vs 1%, p< 0.001). When the stented and unstented patients were compared regarding postoperative infection complications, there was no significant difference between the groups (p= 0.365). Plastic stents did not differ from SEMS regarding the stent failure rate, bilirubin level decrease, amount of bacteria in the bile juice, or postoperative complications when used for PBD. The significantly higher price of SEMS suggests their use in selected cases only.

Background and Aims: In a randomized trial the effect of short-term preoperative radio therapy and postoperative chemotherapy was studied in patients undergoing total mesorectal excision (TME) for clinically resectable rectal cancer. The primary endpoint was overall survival. The secondary endpoints published herein were the incidence of postoperative complications and adverse events with perioperative adjuvant therapy.Material and Methods: In 1995–2002, 278 eligible patients with stage II and stage III rectal cancer were randomly assigned to TME alone (surgery group) or to preoperative 25Gy radiotherapy in 5 fractions and postoperative 5-fluorouracil and leucovorin chemotherapy in addition (RT+CTgroup).Results: Anastomotic leakage rate did not significantly differ between the surgery and the RT + CT group, 20.6% vs. 27.4%. Postoperative infections (15.5 vs. 26.2%, p = 0.037) and perineal wound dehiscence (15.9 vs. 38.5%, p = 0.045) were more common after radiotherapy. Grade 3–5 adverse events were uncommon with preoperative radiotherapy (one, 0.7% with reversible lumbar plexopathy) and postoperative chemotherapy (hematologic in 10.8%, with one septic death, and gastrointestinal in 4.8%).Conclusions: Perioperative adjuvant therapy was generally well tolerated and did not lead to an increase in serious surgical complications. Wound infections and perineal wound dehiscence were more common in irradiated patients.

Background & Aims: Identification of the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome enables prevention of colorectal cancer (CRC) by means of colonoscopy and polypectomies. We evaluated the efficacy of screening in a controlled trial over 15 years. Methods: Incidence of CRC and survival were compared in 2 cohorts of at-risk members of 22 families with HNPCC. Colonic screening at 3-year intervals was arranged for 133 subjects; 119 control subjects had no screening. Genetic testing was offered to subjects in whose families the causative mutation was known. Results: CRC developed in 8 screened subjects (6%) compared with 19 control subjects (16 %; P = 0.014). The CRC rate was reduced by 62%. In mutation-positive subjects alone, the CRC rates were 18% in screened subjects and 41% in controls (P = 0.02). The decrease resulted from the removal of adenomas in 13 mutation-positive individuals (30%) and in 6 subjects with unknown mutation status (40%). All CRCs in the study group were local, causing no deaths, compared with 9 deaths caused by CRC in the controls. The overall death rates were 10 vs. 26 subjects in the study and control groups (P = 0.003), 4 vs. 12 in mutation-positive subjects (P = 0.05). Conclusions: Colonoscopic screening at 3-year intervals more than halves the risk of CRC, prevents CRC deaths, and decreases overall mortality by about 65% in HNPCC families. GASTROENTEROLOGY 2000;118:829-834

The tolerance of the duodenal mucosa to luminal acid was investigated by measuring with a liquid sensor pH microelectrode technique the epithelial surface pH (pHs) and subepithelial tissue pH (pHt) in rat proximal (duodenal bulb, Brunner gland area) and distal duodenum exposed to luminal acid. Under basal conditions, pHs was roughly equal in both parts of the duodenum; proximal duodenum, 7.40 ± 0.14 (mean ± sem) at the villus tip and 7.54 ± 0.16 at the depth of crypt; distal duodenum, 7.46 ± 0.19 and 7.55 ± 0.09, respectively. Yet, exposure of the mucosa to luminal acid (10 mM HCl) provoked a significantly lesser decrease of pHs (0.25 ± 0.13 vs 0.42 ± 0.12 pH units) in the proximal duodenum, suggesting that the response of epithelial HCO3 secretion to luminal acid is stronger in that part of the duodenum. Further, the initial acidification of pHs was followed in the proximal duodenum by a secondary alkalinization of pHs, leading to normalization of pHs, which may suggest activation of compensatory protective mechanisms. pHt at the villus tip was likewise roughly equal in both parts of duodenum (7.29 ± 0.05 vs 7.17 ± 0.04), but, again, acidification of the luminal perfusate progressively from 10 to 100 mM HCl induced a much earlier and significantly more profound acidification in the distal than in the proximal duodenum. The possible contribution of Brunner glands to the greater mucosal tolerance to acid in the proximal duodenum was assessed by investigating whether stimulation or inhibition of Brunner gland secretion modulates the response of the duodenal mucosa to acid. It appeared that even though stimulation of Brunner gland secretion by secretin increased slightly but significantly pHs (0.10 ± 0.03 pH units), it did not alleviate intramucosal acidosis during exposure to luminal acid. In contrast, inhibition of Brunner gland secretion by somatostatin had no influence on pHs but markedly enhanced the susceptibility of the mucosa to tissue acidosis during acid exposure. This suggests that Brunner glands may, indeed, have a role in the mucosal defense against acid but that this protective action is mediated by some other mechanisms than stimulation of alkaline secretion. The data indicate that the proximal duodenum has a greater tolerance against luminal acid than distal duodenum, presumably due to a stronger stimulatory response of HCO3 secretion to luminal acid. In addition, the action of the Brunner glands may contribute to the enhanced capacity of the proximal duodenum to withstand luminal acid.

Abstract: Systemic metabolic alkalosis and topical prostaglandins protect the gastric mucosa against luminal acid. This study investigates whether this protection is mediated by increased epithelial HCO 3– secretion with resultant alkalization of the preepithelial mucus-HCO 3– buffer layer. Surface pH of chamberedex vivo rat gastric epithelium was measured with liquid sensor pH microelectrodes during luminal perfusion of increasing acidities (0, 10, 30, 50, 100 mM HCl). The experimental groups were: (1) control, (2) topical 16,16-dimethyl-PGE2 treatment, (3) high-HCO 3– metabolic alkalosis, and (4) low-HCO 3– respiratory alkalosis. The gastric mucosa of PGE2-treated and high-HCO 3– alkalotic rats tolerated significantly better luminal acid than that of controls, but the tolerance of low-HCO 3– alkalotic rats was significantly impaired. There was a significant correlation between arterial HCO 3– concentration (but not arterial pH) and surface pH (r=0.81,P<0.01). This suggests that the protective actions of systemic high-HCO 3– alkalosis and topical-PGE2 treatment in the gastric mucosa against luminal acid are, at least in part, mediated by enhanced buffer capacity of the preepithelial mucus-HCO 3– layer.

Abstract:  Previously 2D cable analysis has been performed with two microelectrodes, one for passing intraepithelial current and the other for measuring the voltage response in multiple cells along the distance scale. This requires that the epithelium must be in a stable state for a considerably long period because of the multiple impalements. To follow changes of intraepithelial resistances in chambered Necturus antral mucosa with good temporal resolution, four/five electrodes were used to impale cells in the same preparation and the intraepithelial current (6.5–20 nA) was conducted sequentially to three/four of the electrodes, one at a time, to obtain six/ten independent voltage response measurements along the distance scale. The solution to the 2D cable equations was fitted to results and apical, basolateral and shunt resistances were calculated. It was found that an incorrect distance configuration can ruin the precision of the measurement. The distance configuration can, however, be optimized. The resistance values calculated with the 2D cable analysis were very close to those obtained by the amiloride exposure technique in the same tissues. The improvement gained with this work is better temporal resolution (even <10 s) when measuring epithelial resistances.

Features of “H+back-diffusion” after disruption of the gastric mucosal barrier were investigated by assessing, with a microelectrode technique, the influence of three barrier-breaking agents, taurocholate (10 mM), ethanol (20% vol/vol), and acetylsalicylic acid (10 mM) on intracellular pH and epithelial membrane potentials and resistances in isolated Necturusantral mucosa exposed to luminal acid (pH 3). Exposure of the mucosa to each of the three agents induced intracellular acidification of surface epithelial cells, but the pattern of pHibehavior was different for each agent: taurocholate induced immediate acidification of pHi, ethanol acidified pHiafter a delay of 4–6 min, whereas acetylsalicyclic acid initially alkalinized pHi, whereafter a rapid acidification of pHioccurred. Assessment of intraepithelial membrane resistances indicated that taurocholate primarily increases cellular conductance, decreasing in particular Ra. In contrast, ethanol mainly increased paracellular conductance, but also decreased cellular resistance, in particular Ra. Acetylsalicylic acid initially increased cell membrane resistances and Ra/Rbwhereafter a rapid decrease of Ra/Rband Rtoccurred. In each instance, the decrease of Ra/Rbpreceded acidification of pHi. The data suggest that all three agents induce intracellular acidification by increasing the conductance of the apical cell membrane to H+, but in ethanol-treated tissues paracellular conductance primarily contributes to H+backdiffusion.

BACKGROUND & AIMS: The gastric mucosa must have efficient protective mechanisms to maintain physiological intracellular pH. The aim of this study was to investigate the effect of low luminal pH on apical membrane permeability. METHODS: Chambered Necturus antral mucosa was perfused with Ringer's/95% O2-5% CO2 at pH 7.25. The mucosal side was exposed to pH 4.0-2.0 with four microelectrodes placed in surface cells. Two-dimensional cable analysis was used to measure apical, basolateral, and shunt resistances. In some experiments, liquid sensor pH or Na(+)-selective microelectrodes were used. RESULTS: Luminal acidification hyperpolarized apical cell membrane potential and increased apical cell membrane resistance from 21.3 +/- 2.6 (pH 7.25) to 38.0 +/- 2.3 k omega.cm2 (pH 3.0; n = 8). The increase in apical cell membrane resistance was preceded by transient intracellular acidosis from 7.32 +/- 0.07 (pH 4.0) to 7.23 +/- 0.06 (pH 3.0; n = 6). Similar intracellular acidosis (provoked by NH4+ prepulse) failed to cause the effects observed with luminal acid. The increase in apical cell membrane resistance caused by luminal acid was eliminated when N- methyl-D-glucamine+, but not Na+, was substituted for all cations in the luminal solution. CONCLUSIONS: Luminal acidification (pH 3.0-2.0) closes apical amiloride-blockable Na+ channels. Protons are probably able to pass and even block these channels, but their effect in closing the channels does not occur intracellularly. (Gastroenterology 1997 Sep;113(3):875-83)

Abstract. Acute gastric ulceration induced by haemorrhagic shock is associated with profound intramucosal acidification due to diffusion of luminal H+into the mucosa. High‐HCO3−metabolic alkalosis protects the mucosa against this ulceration, whereas low‐HCO3−respiratory alkalosis does not, suggesting that lack of systemic and intramucosal HCO3−. rather than tissue acidosis per se, renders the mucosa susceptible to ulceration. In normal mucosa, disruption of the mucosal barrier by taurocholate, ethanol or acetylsalicylic acid leads to efflux of alkali (HCO3−) from the mucosa, with generation of an alkaline buffer layer at the epithelial surface to protect the mucosa from further damage. In ischaemic mucosa no such protective alkaline layer is formed, and exposure to luminal acid leads to severe acidification of and damage to the mucosa. The efflux of alkali may be driven by capillary hydrostatic pressure, since no such protective alkaline efflux occurs in vitro, but rather exposure to luminal acid and barrier‐breaking agents results in intracellular acidification. The potential pathogenetic role of a disrupted intramucosal acid‐base balance, as well as the protective effect of systemic and intramucosal HCO3−in acute gastric stress ulceration is further substantiated by the in vitrofindings that perfusion conditions simulating in vivoulcerogenic conditions provoke intracellular acidosis, and serosal HCO3−significantly contributes to the maintenance of normal intracellular pH in surface epithelial cells exposed to luminal acid.