Clinical parameters associated with gastric portal hypertensive polyps.

OBJECTIVES: Portal hypertensive polyps (PHPs) are incompletely characterized lesions that can be found in the distal stomach of patients with portal hypertension. We aimed to delineate clinical factors associated with the appearance of these rare polyps. MATERIAL AND METHODS: We conducted a cross-sectional study of a cohort with 513 cirrhotic patients comparing patients with and without PHP using descriptive analyses and multivariable logistic regression. To address the problem of missing values, in particular for HVPG and liver stiffness, we used multiple imputation of missing values. RESULTS: The prevalence of macroscopically diagnosed PHP was 3.3% (95% confidence interval 2.0 - 5.4%). In 53% of cases, the correct classification was missed on index gastroscopy. Patients with PHP were older at gastroscopy (65 years vs. 59), had higher hepatic venous pressure gradients (HVPG, 28 mmHg vs. 19 mmHg), higher transient elastography (TE) measurements (50.7 kPa vs. 21.8 kPa) and more often had previous rubber band ligations (RBL, 64.7% vs. 25.8%). The multivariable logistic regression on the outcome macroscopically diagnosed PHP estimated an odds ratio (OR) for HPVG of 1.13 (CI 0.95-1.34), increased liver stiffness of 1.03 (1.00 - 1.07) and previous RBL of 3.84 (1.24 - 11.88), respectively. CONCLUSION: The prevalence of PHPs in the stomach was higher than assumed in previous studies and misclassification was commonly observed. The appearance of these rare polyps is associated with previous RBL and may correlate with severity of PH. Thus, PHPs may be regarded as marker for relevant PH, but clinical significance of these polyps is still uncertain.

Diagnosis of Gastric Cancer in the Excluded Stomach After RYGB by Jejunogastrostomy Using a LAMS.

For patients after bariatric surgery, diagnosis of gastric cancer is a challenge. We present a patient after Roux-en-Y gastric bypass with upper abdominal pain and abnormal computed tomography scan with diffuse wall thickening of the gastric antrum. Various biopsy techniques have been described, with surgical (laparoscopic) exploration being the most common. We were able to successfully diagnose gastric cancer in the excluded stomach by biopsy using a jejunogastrostomy, which proved to be safe and effective.

ß6-Integrin Serves as a Potential Serum Marker for Diagnosis and Prognosis of Pancreatic Adenocarcinoma.

INTRODUCTION: Despite enormous efforts during the past decades, pancreatic adenocarcinoma (PAC) remains one of the most deleterious cancer entities. A useful biomarker for early detection or prognosis of PAC does not yet exist. The goal of our study was the characterization of ß6-integrin (ITGB6) as a novel serum tumor marker for refined diagnosis and prognosis of PAC. Serum ITGB6 levels were analyzed in 3 independent PAC cohorts consisting of retrospectively and prospectively collected serum and/or (metastatic) PAC tissue specimens. METHODS: Using 2 independent cohorts, we measured serum ITGB6 concentrations in 10 chronic pancreatitis patients, 10 controls, as well as in 27 (cohort 1) and 24 (cohort 2) patients with PAC, respectively. In these patients, we investigated whether ITGB6 serum levels correlate with known clinical and prognostic markers for PAC and whether they might differ between patients with PAC or benign inflammatory diseases of the pancreas. RESULTS: We found that elevated serum ITGB6 levels (≥0.100 ng/mL) in patients suffering from metastasizing PAC presented an unfavorable prognostic outcome. By correlating the ITGB6 tissue expression in primary and metastatic PAC with clinical parameters, we found that positive ITGB6 expression in the tumor tissue is linked to increased serum ITGB6 levels in nonmetastatic PAC and correlates with carbohydrate antigen 19-9 and clinical outcome. DISCUSSION: Our findings suggest that ITGB6 might serve as a novel serum biomarker for early diagnosis and prognosis of PAC. Given the limited specificity and sensitivity of currently used carbohydrate antigen 19-9-based assays, ITGB6 may have the potential to improve the diagnostic accuracy for PAC.

Pre-Operative Decitabine in Colon Cancer Patients: Analyses on WNT Target Methylation and Expression.

DNA hypermethylation is common in colon cancer. Previously, we have shown that methylation of WNT target genes predicts poor prognosis in stage II colon cancer. The primary objective of this study was to assess whether pre-operative treatment with decitabine can decrease methylation and increase the expression of WNT target genes APCDD1, AXIN2 and DKK1 in colon cancer patients. A clinical study was conducted, investigating these potential effects of decitabine in colon cancer patients (DECO). Patients were treated two times with 25 mg/m2 decitabine before surgery. Methylation and expression of LINE1 and WNT target genes (primary outcome) and expression of endogenous retroviral genes (secondary outcome) were analysed in pre- and post-treatment tumour samples using pyrosequencing and rt-PCR. Ten patients were treated with decitabine and eighteen patients were used as controls. Decitabine treatment only marginally decreased LINE1 methylation. More importantly, no differences in methylation or expression of WNT target or endogenous retroviral genes were observed. Due to the lack of an effect on primary and secondary outcomes, the study was prematurely closed. In conclusion, pre-operative treatment with decitabine is safe, but with the current dosing, the primary objective, increased WNT target gene expression, cannot be achieved.

Identification of clinical outcome measures for recovery of gastrointestinal motility in postoperative ileus.

OBJECTIVE: To identify clinical hallmarks associated with recovery of gastrointestinal transit. BACKGROUND: Impaired gastrointestinal transit or postoperative ileus largely determines clinical recovery after abdominal surgery. However, validated clinical hallmarks of gastrointestinal recovery to evaluate new treatments and readiness for discharge from the hospital are lacking. METHODS: Gastric emptying and colonic transit were scintigraphically assessed from postoperative day 1 to 3 in 84 patients requiring elective colonic surgery and were compared with clinical parameters. The clinical hallmark that best reflected recovery of gastrointestinal transit was validated using data from a multicenter trial of 320 segmental colectomy patients. RESULTS: Seven of 84 patients developed a major complication with paralytic ileus characterized by total inhibition of gastrointestinal motility and were excluded from further analysis. In the remaining patients, recovery of colonic transit (defined as geometric center of radioactivity ≥2 on day 3), but not gastric emptying, was significantly correlated with clinical recovery (ρ = -0.59, P < 0.001). Conversely, the combined outcome measure of tolerance of solid food and having had defecation (SF + D) (area under the curve = 0.9, SE = 0.04, 95% CI = 0.79-0.95, P < 0.001), but not time to first flatus, best indicated recovery of gastrointestinal transit with a positive predictive value of 93% (95% CI = 78-99). Also in the main clinical trial, multiple regression analysis revealed that SF + D best predicted the duration of hospital stay. CONCLUSIONS: Our data indicate that the time to SF + D best reflects recovery of gastrointestinal transit and therefore should be considered as primary outcome measure in future clinical trials on postoperative ileus.(Netherlands National Trial Register, number NTR1884 and NTR222).

Faster recovery of gastrointestinal transit after laparoscopy and fast-track care in patients undergoing colonic surgery.

BACKGROUND & AIMS: Postoperative ileus is characterized by delayed gastrointestinal (GI) transit and is a major determinant of recovery after colorectal surgery. Both laparoscopic surgery and fast-track multimodal perioperative care have been reported to improve clinical recovery. However, objective measures supporting faster GI recovery are lacking. Therefore, GI transit was measured following open and laparoscopic colorectal surgery with or without fast-track care. METHODS: Patients (n = 93) requiring elective colonic surgery were randomized to laparoscopic or conventional surgery with fast-track multimodal management or standard care, resulting in 4 treatment arms. Gastric emptying and colonic transit were scintigraphically assessed from days 1 to 3 in 78 patients and compared with clinical parameters such as time to tolerance of solid food and/or bowel movement and time until (ready for) discharge. RESULTS: A total of 71 patients without mechanical bowel obstructions or surgical complications requiring intervention were available for analysis. No differences in gastric emptying 24 hours after surgery between the different groups were observed (P = .61). However, the median colonic transit of patients undergoing laparoscopic/fast-track care was significantly faster compared with the laparoscopic/standard, open/fast-track, and open/standard care groups. Multiple linear regression analysis showed that both laparoscopic surgery and fast-track care were significant independent predictive factors of improved colonic transit. Both were associated with significantly faster clinical recovery and shorter time until tolerance of solid food and first bowel movement. CONCLUSIONS: Colonic transit recovers significantly faster after laparoscopic surgery and the fast-track program; laparoscopy and fast-track care lead to faster recovery of GI motility and improve clinical recovery.

The role of mast cell stabilization in treatment of postoperative ileus: a pilot study.

OBJECTIVES: Although postoperative ileus (POI) is considered multifactorial, intestinal inflammation resulting from manipulation-induced mast cell activation is recognized as an important pathophysiological mechanism. Therefore, mast cell stabilization may represent a new therapeutic approach to shortening POI. The aim of this paper was to study the effect of ketotifen, a mast cell stabilizer, on postoperative gastrointestinal transit in patients who underwent abdominal surgery. METHODS: In this pilot study, 60 patients undergoing major abdominal surgery for gynecological malignancy with standardized anesthesia were randomized to treatment with ketotifen (4 or 12 mg) or placebo. Patients were treated for 6 days, starting 3 days before surgery. Gastric emptying of liquids, selected as a primary outcome parameter, was measured 24 h after surgery using scintigraphy. Secondary end points were (scintigraphically assessed) colonic transit, represented as geometrical center of activity (segment 1(cecum) to 7(stool)) and clinical parameters. RESULTS: Gastric retention 1 h after liquid intake was significantly reduced by 12 mg (median 3% (1-7), P=0.01), but not by 4 mg ketotifen (18% (3-45), P=0.6) compared with placebo (16% (5-75)). Twenty-four hour colonic transit in placebo was 0.8 (0.0-1.1) vs. 1.2 (0.2-1.4) colon segments in the 12 mg ketotifen group (P=0.07). Abdominal cramps were significantly relieved in patients treated with 12 mg ketotifen, whereas other clinical parameters were not affected. CONCLUSIONS: Ketotifen significantly improves gastric emptying after abdominal surgery and warrants further exploration of mast cell stabilizers as putative therapy for POI.

Activation of the cholinergic anti-inflammatory pathway ameliorates postoperative ileus in mice.

BACKGROUND & AIMS: We previously showed that intestinal inflammation is reduced by electrical stimulation of the efferent vagus nerve, which prevents postoperative ileus in mice. We propose that this cholinergic anti-inflammatory pathway is mediated via alpha7 nicotinic acetylcholine receptors expressed on macrophages. The aim of this study was to evaluate pharmacologic activation of the cholinergic anti-inflammatory pathway in a mouse model for postoperative ileus using the alpha7 nicotinic acetylcholine receptor-agonist AR-R17779. METHODS: Mice were pretreated with vehicle, nicotine, or AR-R17779 20 minutes before a laparotomy (L) or intestinal manipulation (IM). Twenty-four hours thereafter gastric emptying was determined using scintigraphy and intestinal muscle inflammation was quantified. Nuclear factor-kappaB transcriptional activity and cytokine production was assayed in peritoneal macrophages. RESULTS: Twenty-four hours after surgery IM led to a delayed gastric emptying compared with L (gastric retention: L(saline) 14% +/- 4% vs IM(saline) 38% +/- 10%, P = .04). Pretreatment with AR-R17779 prevented delayed gastric emptying (IM(AR-R17779) 15% +/- 4%, P = .03). IM elicited inflammatory cell recruitment (L(saline) 50 +/- 8 vs IM(saline) 434 +/- 71 cells/mm(2), P = .001) which was reduced by AR-R17779 pretreatment (IM(AR-R17779) 231 +/- 32 cells/mm(2), P = .04). An equimolar dose of nicotine was not tolerated. Subdiaphragmal vagotomy did not affect the anti-inflammatory properties of AR-R17779. In peritoneal macrophages, both nicotinic agonists reduced nuclear factor kappaB transcriptional activity and proinflammatory cytokine production, with nicotine being more effective than AR-R17779. CONCLUSIONS: AR-R17779 treatment potently prevents postoperative ileus, whereas toxicity limits nicotine administration to ineffective doses. Our data further imply that nicotinic inhibition of macrophage activation may involve other receptors in addition to alpha7 nicotinic acetylcholine receptor.

Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway.

Acetylcholine released by efferent vagus nerves inhibits macrophage activation. Here we show that the anti-inflammatory action of nicotinic receptor activation in peritoneal macrophages was associated with activation of the transcription factor STAT3. STAT3 was phosphorylated by the tyrosine kinase Jak2 that was recruited to the alpha7 subunit of the nicotinic acetylcholine receptor. The anti-inflammatory effect of nicotine required the ability of phosphorylated STAT3 to bind and transactivate its DNA response elements. In a mouse model of intestinal manipulation, stimulation of the vagus nerve ameliorated surgery-induced inflammation and postoperative ileus by activating STAT3 in intestinal macrophages. We conclude that the vagal anti-inflammatory pathway acts by alpha7 subunit-mediated Jak2-STAT3 activation.

The ICAM-1 antisense oligonucleotide ISIS-3082 prevents the development of postoperative ileus in mice.

Intestinal manipulation (IM) during abdominal surgery triggers the influx of inflammatory cells, leading to postoperative ileus. Prevention of this local muscle inflammation, using intercellular adhesion molecule-1 (ICAM-1) and leukocyte function-associated antigen-1-specific antibodies, has been shown to shorten postoperative ileus. However, the therapeutic use of antibodies has considerable disadvantages. The aim of the current study was to evaluate the effect of ISIS-3082, a mouse-specific ICAM-1 antisense oligonucleotide, on postoperative ileus in mice. Mice underwent a laparotomy or a laparotomy combined with IM after treatment with ICAM-1 antibodies, 0.1-10 mg kg(-1) ISIS-3082, saline or ISIS-8997 (scrambled control antisense oligonucleotides, 1 and 3 mg kg(-1)). At 24 h after surgery, gastric emptying of a 99mTC labelled semi-liquid meal was determined using scintigraphy. Intestinal inflammation was assessed by myeloperoxidase (MPO) activity in ileal muscle whole mounts. IM significantly reduced gastric emptying compared to laparotomy. Pretreatment with ISIS-3082 (0.1-1 mg kg(-1)) as well as ICAM-1 antibodies (10 mg kg(-1)), but not ISIS-8997 or saline, improved gastric emptying in a dose-dependent manner. This effect diminished with higher doses of ISIS-3082 (3-10 mg kg(-1)). Similarly, ISIS-3082 (0.1-1 mg kg(-1)) and ICAM-1 antibodies, but not ISIS-8997 or higher doses of ISIS-3082 (3-10 mg kg(-1)), reduced manipulation-induced inflammation. Immunohistochemistry showed reduction of ICAM-1 expression with ISIS-3082 only. ISIS-3082 pretreatment prevents postoperative ileus in mice by reduction of manipulation-induced local intestinal muscle inflammation. Our data suggest that targeting ICAM-1 using antisense oligonucleotides may represent a new therapeutic approach to the prevention of postoperative ileus.

Mast cell degranulation during abdominal surgery initiates postoperative ileus in mice.

BACKGROUND & AIMS: Inflammation of the intestinal muscularis following manipulation during surgery plays a crucial role in the pathogenesis of postoperative ileus. Here, we evaluate the role of mast cell activation in the recruitment of infiltrates in a murine model. METHODS: Twenty-four hours after control laparotomy or intestinal manipulation, gastric emptying was determined. Mast cell degranulation was determined by measurement of mast cell protease-I in peritoneal fluid. Intestinal inflammation was assessed by determination of tissue myeloperoxidase activity and histochemical staining. RESULTS: Intestinal manipulation elicited a significant increase in mast cell protease-I levels in peritoneal fluid and resulted in recruitment of inflammatory infiltrates to the intestinal muscularis. This infiltrate was associated with a delay in gastric emptying 24 hours after surgery. Pretreatment with mast cell stabilizers ketotifen (1 mg/kg, p.o.) or doxantrazole (5 mg/kg, i.p.) prevented both manipulation-induced inflammation and gastroparesis. Reciprocally, in vivo exposure of an ileal loop to the mast cell secretagogue compound 48/80 (0.2 mg/mL for 1 minute) induced muscular inflammation and delayed gastric emptying. The manipulation-induced inflammation was dependent on the presence of mast cells because intestinal manipulation in mast cell-deficient Kit/Kitv mice did not elicit significant leukocyte recruitment. Reconstitution of Kit/Kitv mice with cultured bone marrow-derived mast cells from congenic wild types restored the manipulation-induced inflammation. CONCLUSIONS: Our results show that degranulation of connective tissue mast cells is a key event for the establishment of the intestinal infiltrate that mediates postoperative ileus following abdominal surgery.

Postoperative ileus is maintained by intestinal immune infiltrates that activate inhibitory neural pathways in mice.

BACKGROUND AND AIMS: Postoperative ileus after abdominal surgery largely contributes to patient morbidity and prolongs hospitalization. We aimed to study its pathophysiology in a murine model by determining gastric emptying after manipulation of the small intestine. METHODS: Gastric emptying was determined at 6, 12, 24, and 48 hours after abdominal surgery by using scintigraphic imaging. Intestinal or gastric inflammation was assessed by immune-histochemical staining and measurement of tissue myeloperoxidase activity. Neuromuscular function of gastric and intestinal muscle strips was determined in organ baths. RESULTS: Intestinal manipulation resulted in delayed gastric emptying up to 48 hours after surgery; gastric half-emptying time 24 hours after surgery increased from 16.0 +/- 4.4 minutes after control laparotomy to 35.6 +/- 5.4 minutes after intestinal manipulation. The sustained delay in gastric emptying was associated with the appearance of leukocyte infiltrates in the muscularis of the manipulated intestine, but not in untouched stomach or colon. The delay in postoperative gastric emptying was prevented by inhibition of intestinal leukocyte recruitment. In addition, postoperative neural blockade with hexamethonium (1 mg/kg intraperitoneally) or guanethidine (50 mg/kg intraperitoneally) normalized gastric emptying without affecting small-intestinal transit. The appearance of intestinal infiltrates after intestinal manipulation was associated with increased c-fos protein expression in sensory neurons in the lumbar spinal cord. CONCLUSIONS: Sustained postoperative gastroparesis after intestinal manipulation is mediated by an inhibitory enterogastric neural pathway that is triggered by inflammatory infiltrates recruited to the intestinal muscularis. These findings show new targets to shorten the duration of postoperative ileus pharmacologically.