Development of upper gastrointestinal cancer in patients with symptomatic gallstones, cholecystectomy, and sphincterotomy: A nationwide cohort study.

BACKGROUND AND OBJECTIVE: Exposures of gallstones and treatments thereof in relation to development of cancer have not been explored before in long-term follow-up studies. Our objective was to determine whether symptomatic gallstones, cholecystectomy, or sphincterotomy were associated with development of upper gastrointestinal cancers. METHODS: This is a nationwide cohort study of persons born in Denmark 1930-1984 included from age 30 years with long-term follow-up (1977-2014). Exposures were hospital admissions with gallstones, cholecystectomy, and sphincterotomy. Time-varying covariates were included in analyses to allow the impact of exposures to change with time. Follow-up periods were 2-5 and > 5 years. Hazard ratios (HR) with 95% confidence intervals (CI) were reported. RESULTS: A total of 4,465,962 persons were followed. We found positive associations between sphincterotomy and biliary (>5 years HR 4.34, CI [2.17-8.70]), gallbladder (2-5 years HR 20.7, CI [8.55-50.1]), and pancreatic cancer (2-5 years HR 3.68, CI [2.09-6.49]). Cholecystectomy was positively associated with duodenal (2-5 years HR 2.94, CI [1.31-6.58]) and small bowel cancer (2-5 years HR 2.75, CI [1.56-4.87]). Inverse associations were seen for cholecystectomy and biliary (>5 years HR 0.60, CI [0.41-0.87]), pancreatic (>5 years HR 0.45 CI [0.35-0.57]), esophageal (>5 years HR 0.57, CI [0.43-0.74]), and gastric cancer (>5 years HR 0.68, CI [0.55-0.86]) and for gallstones and pancreatic cancer (>5 years HR 0.66, CI [0.47-0.93]). Gallstones were positively associated with gallbladder (>5 years HR 3.51, CI [2.02-6.10]) and small bowel cancer (2-5 years HR 3.21, CI [1.60-6.45]). CONCLUSIONS: A positive association between sphincterotomy and biliary cancer was identified. Cholecystectomy seems to be inversely associated with biliary, pancreatic, esophageal, and gastric cancer. Associations should be explored in similar large cohorts.

Current clinical algorithms for predicting common bile duct stones have only moderate accuracy.

BACKGROUND AND AIM: A risk-stratified approach for selecting patients likely to harbor common bile duct (CBD) stones to proceed directly to endoscopic or surgical stone clearance, rather than undergo less invasive testing, has been proposed. We assessed the performance of three clinical algorithms used to predict CBD stones. METHODS: All patients undergoing first-time endoscopic retrograde cholangiopancreatography (ERCP) in 2011-2012 as a result of suspected CBD stones were enrolled prospectively in a clinical database. Data such as imaging test findings and liver function tests (LFTs) were collected 48 h prior to and on the day of ERCP. Patients were stratified into different risk groups for harboring CBD stones according to three clinical algorithms using imaging and laboratory data. Findings on ERCP were used as gold standard. Performance characteristics of each algorithm were separately calculated for each time point of LFT assessment. RESULTS: Overall, 186 patients were analyzed, 75% of whom presented CBD stones on ERCP. Proportion of patients categorized as high-risk for harboring CBD stones varied among the three algorithms (67% vs 73% vs 56%). Also, the algorithms showed only moderate, albeit comparable, accuracy for predicting the presence of CBD stones (0.65, 95% confidence interval [CI] 0.62-0.68 vs 0.68, 95% CI 0.63-0.67 vs 0.59, 95% CI 0.57-0.61). Similar results were obtained when performance characteristics were recalculated using LFT from 48 h prior to ERCP (data not shown). CONCLUSION: Three diagnostic algorithms commonly used for predicting CBD stones have comparable but only moderate accuracy. Further research is warranted to improve risk stratification of patients with suspected CBD stones.

The collagen turnover profile is altered in patients with inguinal and incisional hernia.

BACKGROUND: Disturbed metabolism in the extracellular matrix (ECM) contributes to formation of abdominal wall hernias. The aim of this study was to gain deeper insight into the ECM turnover in hernia patients by analyzing serum biomarkers specifically reflecting collagen synthesis and breakdown in the interstitial matrix (types I, III, and V collagens) and in the basement membrane (type IV collagen). MATERIAL AND METHODS: Patients with 3 different types of hernias were included: Primary unilateral inguinal hernia (n = 17), multiple hernias defined as ≥3 hernias (n = 21), and incisional hernia (n = 25). Patients without hernias scheduled to undergo elective operation for gallstones (n = 18) served as controls. Whole venous blood was collected preoperatively. Biomarkers for synthesis of interstitial matrix (PINP, Pro-C3, P5CP) and basement membrane (P4NP) as well as corresponding degradation (C1M, C3M, C5M, and C4M) were measured in serum by validated, solid-phase competitive assays. RESULTS: In inguinal hernia patients, the turnover of the interstitial matrix collagens type III (P < .042) and V (P < .001) was decreased compared with controls, whereas the turnover of the basement membrane collagen type IV was increased (P < .001). In incisional hernia patients, the turnover of type V collagen was decreased (P = .048) and the turnover of type IV collagen was increased compared with the hernia-free controls (P < .001). CONCLUSION: Hernia patients demonstrated systemically altered collagen metabolism. The serologic turnover profile of type IV collagens may predict the presence of inguinal and incisional hernia. Regulation of type IV collagen turnover may be crucial for hernia development.

Circulating levels of matrix metalloproteinases and tissue inhibitors of metalloproteinases in patients with incisional hernia.

Incisional hernia formation is a common complication to laparotomy and possibly associated with alterations in connective tissue metabolism. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are closely involved in the metabolism of the extracellular matrix. Our aim was to study serum levels of multiple MMPs and TIMPs in patients with and without incisional hernia. Out of 305 patients who underwent laparotomy, 79 (25.9%) developed incisional hernia over a median follow-up period of 3.7 years. Pooled sera from a subset (n = 72) of these patients were screened for MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-12, MMP-13, TIMP-1, TIMP-2, and TIMP-4 using a multiplex sandwich fluorescent immunoassay supplemented with gelatin zymography. The screening indicated differences in serum MMP-9 and TIMP-1 levels. Consequently, MMP-9 and TIMP-1 levels were measured in serum in the whole patient cohort with enzyme-linked immunosorbent assay. There were no significant differences in either MMP-9 (p = 0.411) or TIMP-1 (p = 0.679) levels between hernia and hernia-free patients. MMP-9 was significantly increased in smokers compared with nonsmokers (p = 0.016). In conclusion, a possible involvement of MMPs and TIMPs in the pathogenesis of incisional hernia formation was not reflected systemically.

Tissue inhibitor of metalloproteinases-1 as a biological marker in colorectal cancer: influence of smoking on plasma levels?

BACKGROUND: At present plasma tissue inhibitor of metalloproteinases-1 (TIMP-1) is undergoing validation as a biological marker in colorectal cancer (CRC). The clinical implementation of plasma TIMP-1 in prognosis, prediction, screening and monitoring CRC requires robust information as to the influence of preanalytical factors, including inter- and intrapersonal biological variations. The aim of the present study was to evaluate the possible effects of smoking on the level of TIMP-1 in plasma from healthy subjects. MATERIALS AND METHODS: Forty-six never-smokers and 48 daily smokers participated in the 13-week study. Smokers were randomized into 3 groups of 16 subjects each: one group continued to smoke, a second group refrained from smoking and used a transdermal nicotine patch, and a third group refrained from smoking and used placebo patches. Plasma TIMP-1 levels were determined using ELISA. RESULTS: No significant differences in TIMP-1 levels could be shown between the smoking group, the 2 different abstinent smoking groups and the never-smoking group. CONCLUSION: Smoking does not appear to have any influence on TIMP-1 levels in plasma collected from healthy subjects.

Direct and recurrent inguinal hernias are associated with ventral hernia repair: a database study.

BACKGROUND: A systemically altered connective tissue metabolism has been demonstrated in patients with abdominal wall hernias. The most pronounced connective tissue changes are found in patients with direct or recurrent inguinal hernias as opposed to patients with indirect inguinal hernias. The aim of the present study was to assess whether direct or recurrent inguinal hernias are associated with an elevated rate of ventral hernia surgery. METHODS: In the nationwide Danish Hernia Database, a cohort of 92,457 patients operated on for inguinal hernias was recorded from January 1998 until June 2010. Eight-hundred forty-three (0.91 %) of these patients underwent a ventral hernia operation between January 2007 and June 2010. A multivariate logistic regression analysis was applied to assess an association between inguinal and ventral hernia repair. RESULTS: Direct (Odds Ratio [OR] = 1.28 [95 % CI, 1.08-1.51]) and recurrent (OR = 1.76, [95 % CI, 1.39-2.23]) inguinal hernias were significantly associated with ventral hernia repair after adjustment for age, gender, and surgical approach (open or laparoscopic). CONCLUSIONS: Patients with direct and recurrent inguinal herniation are more prone to ventral hernia repair than patients with indirect inguinal herniation. This is the first study to show that herniogenesis is associated with type of inguinal hernia.

Laparoscopic surgery compared with open surgery decreases surgical site infection in obese patients: a systematic review and meta-analysis.

OBJECTIVE: To compare surgical site infections rate in obese patients after laparoscopic surgery with open general abdominal surgery. BACKGROUND: In mixed surgical populations, surgical site infections are fewer in laparoscopic surgery than in open surgery. It is not clear if this is also the case for obese patients, who have a higher risk of surgical site infections than nonobese patients. METHODS: MEDLINE, Embase, and The Cochrane library (CENTRAL) were searched systematically for studies on laparoscopic surgery compared with open abdominal surgery. Randomized controlled trials (RCTs) and observational studies reporting surgical site infection in groups of obese patients (body mass index ≥ 30) were included. Separate meta-analyses with a fixed effects model for RCTs and a random effects model for observational studies were performed. Methodological quality of the included studies was assessed according to the Cochrane method and the Newcastle-Ottawa Scale. RESULTS: Eight RCTs and 36 observational studies on bariatric and nonbariatric surgery were identified. Meta-analyses of RCTs and observational studies showed a significantly lower surgical site infection rate after laparoscopic surgery (OR = 0.19; 95% CI [0.08-0.45]; P = 0.0002 and OR = 0.33; 95% CI [0.26-0.42]; P = 0.00001). Sensitivity analyses to assess the impact of selection and detection bias confirmed the significant estimates with acceptable heterogeneity. No publication bias was present for the observational studies. CONCLUSIONS: Laparoscopic surgery in obese patients reduces surgical site infection rate by 70%-80% compared with open surgery across general abdominal surgical procedures. Future efforts should be focused on further development of laparoscopic surgery for the growing obese population.

Gene expression profiles in stages II and III colon cancers: application of a 128-gene signature.

PURPOSE: A 128-gene signature has been proposed to predict outcome in patients with stages II and III colorectal cancers. In the present study, we aimed to reproduce and validate the 128-gene signature in external and independent material. METHODS: Gene expression data from the original material were retrieved from the Gene Expression Omnibus (GEO) (n = 111) in addition to a Danish data set (n = 37). All patients had stages II and III colon cancers. A Prediction Analysis of Microarray classifier, based on the 128-gene signature and the original training set of stage I (n = 65) and stage IV (n = 76) colon cancers, was reproduced. The stages II and III colon cancers were subsequently classified as either stage I-like (good prognosis) or stage IV-like (poor prognosis) and assessed by the 36 months cumulative incidence of relapse. RESULTS: In the GEO data set, results were reproducible in stage III, as patients predicted to be stage I-like had a significant lower risk of relapse than patients predicted as stage IV-like (P = 0.04, Gray test). Results were not reproducible in stage II patients (P > 0.05, Gray test). In the Danish data set, two of four stage III patients with relapse were correctly predicted as stage IV-like, and the remaining patients were predicted as stage I-like and unclassifiable, respectively. Stage II patients could not be stratified. CONCLUSIONS: The 128-gene signature showed reproducibility in stage III colon cancer, but could not predict recurrence in stage II. Individual patient predictions in an independent Danish material were unsatisfactory. Additional validation in larger cohorts is warranted.

Risk factors for morbidity and mortality following gastroenterostomy.

BACKGROUND: Morbidity and mortality following traditional surgical treatment of gastric outlet obstruction is high. The aim of this work was to identify risk factors predictive of postoperative complications and mortality following gastroenterostomy. METHODS: One-hundred sixty-five consecutive patients subjected to open gastroenterostomy from January 1996 through July 2003 were included. Data on vital signs and operative variables were retrieved from medical records and recorded retrospectively. Risk factors for postoperative complications and mortality within 30 days after operation were analyzed with multiple logistic regression. RESULTS: The 30-day complication and death rates were higher after emergency operations (80% and 60%) than after elective operations (32% and 25%). A multivariate analysis disclosed that hypoalbuminemia (< or = 32 g/l), comorbidity, high age, and hyponatremia (< 135 micromol/l) were significantly associated with postoperative death, whereas hypoalbuminemia, comorbidity, high age, and emergency operation were predictors of postoperative complications. CONCLUSIONS: Complications and mortality after gastroenterostomy due to gastric outlet obstruction are associated with modifiable and non-modifiable risk factors. Prior to surgery means should be taken to correct low albumin and sodium levels to prevent complications. In addition, the surgeon should consider alternative treatment modalities including laparoscopic gastroenterostomy, self-expanding metallic stents, or tube gastrostomy to relieve or palliate gastric outlet obstruction.

No effect on survival of home psychosocial intervention in a randomized study of Danish colorectal cancer patients.

OBJECTIVE: We investigated whether regular home visits to persons with newly diagnosed colorectal cancer influenced their overall survival and selected immune parameters. METHODS: A total of 249 Danish colorectal cancer patients undergoing abdominal surgery were randomly assigned to a control or an intervention group. The intervention group received 10 home visits from a project nurse or a medical doctor during the first 2 years after discharge. The home visits aimed at providing emotional support and information. A subgroup of 55 patients provided blood samples 3, 12 and 24 months after discharge for measurement of immune parameters. Survival was assessed 6.5-9.5 years after the first operation. RESULTS: A total of 148 patients died during follow-up. The intervention was not significantly associated with survival (p=0.68) after adjustment for Dukes' stage, radicality of the operation, age, sex, family social class and marital status. Likewise, no significant interactions were found between group and these covariates (all p > or = 0.08). In the substudy of the possible effect of the intervention on immune parameters, there were no differences between the two groups with respect to lymphocyte proliferation (all p > or = 0.078) or natural killer cell activity (all p > or = 0.33) and no consistent effect on the number of specific subsets of cells (phenotypes) during follow-up. CONCLUSION: The study failed to provide evidence that the psychosocial intervention provided as home visits significantly affected the prognosis or selected immune parameters of patients who had undergone surgery for colorectal cancer.

Transdermal nicotine patch enhances type I collagen synthesis in abstinent smokers.

Cigarette smokers deposit less collagen, expressed as hydroxyproline, in granulation tissue than nonsmokers. We studied the effect of abstinence from smoking and transdermal nicotine patches on deposition of hydroxyproline, proline, type I procollagen, and total proteins. Fifty-four healthy smokers were studied during 10 days of smoking and again from days 10 to 20 following smoking cessation. After the first 10 days of abstinence they were randomized to double-blind treatment with transdermal nicotine patches of 25 mg/day or placebo for a period of 10 days. During this period and during smoking, an expanded polytetrafluoroethylene tube was implanted into the subcutis. Following removal of the implant, total amino acids and peptides were extracted. Hydroxyproline and proline were analyzed by high-pressure liquid chromatography, type I procollagen was analyzed by enzyme-linked immunoassay, and total proteins were determined colorimetrically. In the 39 subjects who complied with the study protocol, abstinence from smoking did not affect the deposition of hydroxyproline, proline, type I procollagen, or total protein in the implants. During abstinence, the type I procollagen level increased by 18% in the transdermal nicotine patches group and decreased by 10% in the placebo group (p<0.05). We conclude that 20 days of abstinence from smoking does not affect collagen deposition in granulation tissue. However, in abstinent smokers, transdermal nicotine patches appears to increase type I collagen synthesis.