Inflammation and Gut Barrier Function-Related Genes and Colorectal Cancer Risk in Western European Populations.

Gut barrier dysfunction and related inflammation are known to be associated with the development and progression of colorectal cancer (CRC). We investigated associations of 292 single-nucleotide polymorphisms (SNPs) from 27 genes related to endotoxins/lipopolysaccharide (LPS) sensing and tolerance, mucin synthesis, inflammation, and Crohn's disease with colon and rectal cancer risks. Incident CRC cases (N=1,374; colon=871, rectum=503) were matched 1:1 to controls nested within the European Prospective Investigation into Cancer and Nutrition cohort. Previously measured serum concentrations of gut barrier function and inflammation biomarkers (flagellin/LPS-specific immunoglobulins and C-reactive protein [CRP]) were available for a sub-set of participants (Ncases=1,001; Ncontrols=667). Forty-two unique SNPs from 19 different genes were associated with serum biomarkers at Punadjusted≤0.05 among controls. Among SNPs associated with a gut permeability score, 24 SNPs were in genes related to LPS sensing and mucin synthesis. Nine out of 12 SNPs associated with CRP were in genes related to inflammation or Crohn's disease. TLR4 was associated with colon cancer at the SNP level (nine SNPs, all Punadjusted≤0.04) and at the gene level (Punadjusted≤0.01). TLR4 rs10759934 was associated with rectal cancer but not colon cancer. Similarly, IL10 was associated with rectal cancer risk at a SNP and gene level (both Punadjusted ≤ 0.01), but not colon cancer. Genes and SNPs were selected a priori therefore we present unadjusted P-values. However, no association was statistically significant after multiple testing correction. This large and comprehensive study has identified gut barrier function and inflammation-related genes possibly contributing to CRC risk in European populations and is consistent with potential etiological links between host genetic background, gut barrier permeability, microbial endotoxemia and CRC development.

Porphyromonas gingivalis in Colorectal Cancer and its Association to Patient Prognosis.

Microbiota dysbiosis may affect both the development and progression of colorectal cancer (CRC). Large metagenomic studies have highlighted specific oral bacteria linked to CRC including Porphyromonas gingivalis. Few studies have however analysed the implications of this bacterium in CRC progression and survival. In this study, we investigated the intestinal presence of P. gingivalis by qPCR in both faecal and mucosal samples from two different patient cohorts, including patients with precancerous dysplasia or CRC, as well as controls. P. gingivalis was detected in 2.6-5.3% of CRC patients and significantly different levels of P. gingivalis were found in faeces of CRC patients compared to controls (P = 0.028). Furthermore, an association was found between the presence of P. gingivalis in faeces and tumour tissue (P < 0.001). Our findings further suggested a potential link between mucosal P. gingivalis and tumours of MSI subtype (P = 0.040). Last but not least, patients with faecal P. gingivalis were found to have a significantly decreased cancer-specific survival (P = 0.040). In conclusion, P. gingivalis could be linked to patients with CRC and to a worse patient prognosis. Further studies are needed to elucidate the role of P. gingivalis in CRC pathogenesis.

Ventral hernia repair with concurrent intra-abdominal surgery: Results from an eleven-year population-based cohort in Sweden.

BACKGROUND: One remaining question in ventral hernia repair is whether to perform concurrent abdominal surgery or plan two-stage procedures. The aim was to explore the risk for reoperation and mortality due to surgical complication during index admission. METHOD: Eleven-year data were retrieved from the National Patient Register and 68,058 primary surgical admissions were included, divided into minor and major hernia surgery and concurrent abdominal surgery. Results were evaluated by logistic regression analysis. RESULTS: The risk for reoperation during index admission was higher for patients with concurrent surgery. Major hernia surgery and major concurrent surgery had an OR 37.9 compared to major hernia surgery only. Mortality rate within 30 days increased, OR 9.32. The combined risk for serious adverse event was accumulative. CONCLUSION: These results stress the importance of critically evaluating needs for and planning of concurrent abdominal surgery during ventral hernia repair. Reoperation rate was a valid and useful outcome variable.

Tumour Colonisation of Parvimonas micra Is Associated with Decreased Survival in Colorectal Cancer Patients.

Increasing evidence suggests that the gut microbiota may impact colorectal cancer (CRC) development and progression. In this study, the tumour colonisation of two CRC-associated bacteria, Parvimonas micra and Fusobacterium nucleatum, was studied in relation to patient survival in a cohort of 257 CRC patients. Colonisation of P. micra and F. nucleatum was analysed in fresh frozen tumour tissue (n = 112) and in faeces (n = 250) by qPCR. When analysing tumour tissues, both P. micra and F. nucleatum were found to be associated with decreased five-year cancer-specific survival, an association that remained significant in multivariable analysis for P. micra. Furthermore, we found significant associations of high levels of P. micra and F. nucleatum with tumour molecular characteristics, i.e., tumours mutated in BRAFV600E, and tumours of the MSI subtype. The analysis of faecal samples showed weaker associations with prognosis and tumour molecular characteristics. In conclusion, our findings support a novel association of tumour colonisation of P. micra with decreased patient survival. A better understanding of the role of the gut microbiota in CRC might contribute to the advancement of prognostic tools and new targets for therapy.

Major complications and mortality after ventral hernia repair: an eleven-year Swedish nationwide cohort study.

BACKGROUND AND AIMS: Ventral hernia repair is one of the most common surgical procedures performed worldwide. Despite the large volume, consensus is lacking regarding indications for repair or choice of surgical method used for reconstruction. The aim of this study was to explore the risk for major complications and mortality in ventral hernia repair using data from a nationwide patient register. METHOD: Patient data of individuals over 18 years of age who had a ventral hernia procedure between 2004 and 2014 were retrieved from the Patient Register kept by the Swedish National Board of Health and Welfare. After exclusion of patients with concomitant bowel surgery, 45 676 primary surgical admissions were included. Procedures were dichotomised into laparoscopic and open surgery, and stratified for primary and incisional hernias. RESULTS: A total of 45 676 admissions were analysed. The material comprised 36% (16 670) incisional hernias and 64% (29 006) primary hernias. Women had a higher risk for reoperation during index admission after primary hernia repair (OR 1.84 (1.29-2.62)). Forty-three patients died of complications within 30 days of index surgery. Patients aged 80 years and older had a 2.5 times higher risk for a complication leading to reoperation, and a 12-fold higher mortality risk than patients aged 70-79 years. CONCLUSION: Age is the dominant mortality risk factor in ventral hernia repair. Laparoscopic surgery was associated with a lower risk for reoperation during index admission. Reoperation seems to be a valid outcome variable, while registration of complications is generally poor in this type of cohort.

Parvimonas micra is associated with tumour immune profiles in molecular subtypes of colorectal cancer.

The importance of the tumour microbiome in different aspects of colorectal cancer (CRC) has been increasingly recognised, but many questions remain. The aim of this study was to explore the effect of specific CRC associated microbes on the tumour immune response, which has a considerable prognostic value in CRC. We applied specific qPCR to detect Parvimonas micra and Fusobacterium nucleatum in tumour tissues from an immunologically well-characterised cohort of 69 CRC patients. This cohort included detailed analyses of immune profiles based on flow cytometry and transcriptomics in tumour tissue and blood, along with comprehensive analyses of molecular subtypes. P. micra and F. nucleatum were detected in 24% and 64% of tumour tissues, respectively. We found a significant association of P. micra with high-grade tumours and tumours of CMS1 subtype. F. nucleatum was significantly associated with right-sided tumours, microsatellite instability, and CMS1 tumours. The immunological analyses revealed significant associations of P. micra with activated CD69+ T lymphocytes and increased antigen-presenting HLA-DR+ B lymphocytes. P. micra was also positively associated with M1 and M2 macrophage traits. The impact of P. micra tumour colonisation on the immune response was further assessed using transcriptomics in validation of our findings. No associations were found between F. nucleatum and immune profiles in this study. Our findings support novel associations between P. micra and the immune response in CRC. A better understanding of these interactions might help to identify important predictive and prognostic tools as well as new targets for therapy.

Association of Pre-diagnostic Antibody Responses to Escherichia coli and Bacteroides fragilis Toxin Proteins with Colorectal Cancer in a European Cohort.

Experimental evidence has implicated genotoxic Escherichia coli (E. coli) and enterotoxigenic Bacteroides fragilis (ETBF) in the development of colorectal cancer (CRC). However, evidence from epidemiological studies is sparse. We therefore assessed the association of serological markers of E. coli and ETBF exposure with odds of developing CRC in the European Prospective Investigation into Nutrition and Cancer (EPIC) study.Serum samples of incident CRC cases and matched controls (n = 442 pairs) were analyzed for immunoglobulin (Ig) A and G antibody responses to seven E. coli proteins and two isoforms of the ETBF toxin via multiplex serology. Multivariable-adjusted conditional logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the association of sero-positivity to E. coli and ETBF with CRC.The IgA-positivity of any of the tested E. coli antigens was associated with higher odds of developing CRC (OR: 1.42; 95% CI: 1.05-1.91). Dual-positivity for both IgA and IgG to E. coli and ETBF was associated with >1.7-fold higher odds of developing CRC, with a significant association only for IgG (OR: 1.75; 95% CI: 1.04, 2.94). This association was more pronounced when restricted to the proximal colon cancers (OR: 2.62; 95% CI: 1.09, 6.29) compared to those of the distal colon (OR: 1.24; 95% CI: 0.51, 3.00) (pheterogeneity = 0.095). Sero-positivity to E. coli and ETBF was associated with CRC development, suggesting that co-infection of these bacterial species may contribute to colorectal carcinogenesis. These findings warrant further exploration in larger prospective studies and within different population groups.

Parvimonas micra as a putative non-invasive faecal biomarker for colorectal cancer.

The use of faecal microbial markers as non-invasive biomarkers for colorectal cancer (CRC) has been suggested, but not fully elucidated. Here, we have evaluated the importance of Parvimonas micra as a potential non-invasive faecal biomarker in CRC and its relation to other microbial biomarkers. The levels of P. micra, F. nucleatum and clbA + bacteria were quantified using qPCR in faecal samples from a population-based cohort of patients undergoing colonoscopy due to symptoms from the large bowel. The study included 38 CRC patients, 128 patients with dysplasia and 63 controls. The results were validated in a second consecutive CRC cohort including faecal samples from 238 CRC patients and 94 controls. We found significantly higher levels of P. micra in faecal samples from CRC patients compared to controls. A test for P. micra could detect CRC with a specificity of 87.3% and a sensitivity of 60.5%. In addition, we found that combining P. micra with other microbial markers, could further enhance test sensitivity. Our findings support the potential use of P. micra as a non-invasive biomarker for CRC. Together with other microbial faecal markers, P. micra may identify patients with "high risk" microbial patterns, indicating increased risk and incidence of cancer.

Risk Factors for Surgical Complications in Ventral Hernia Repair.

BACKGROUND: The aim of this study was to identify risk factors for an adverse event, i.e. early surgical complication, need for ICU care and readmission, following ventral hernia repair. Our hypothesis was that there is an association between an increased complication rate following ventral hernia repair and specific factors, including hernia size, BMI > 35, concomitant bowel surgery, ASA-class, age, gender and method of hernia repair. METHODS: Data from a hernia database with prospectively entered data on 408 patients operated for ventral hernia between 2007 and 2014 at two Swedish university hospitals were analysed. A 3-month follow-up of complications, need for intensive care and readmission, was performed by reviewing the medical records. RESULTS: Eighty-one of 408 patients (20%) had a registered complication. Fifty-eight (14%) of these were classed as Clavien I-IIIa, and in 19 cases a Clavien IIIb-IV complication was reported. Large hernia size was associated with increased risk for early complication. A Kendall Tau test analysis revealed a proportional relationship between hernia size and modified Clavien outcome class (p < 0.001). Morbid obesity, ASA-class, method, hernia recurrence, age and concomitant bowel surgery were not statistically significant predictors of adverse events. CONCLUSIONS: Assessment of hernia aperture size is of great importance in the preoperative evaluation of ventral hernia patients to consider risk for post-operative complications. These results suggest a careful attitude when applying watchful waiting concepts and when postponing hernia surgery to achieve weight loss. A delaying attitude may result in increased risk of complications caused by increasing hernia size.

Quality of life in patients with a permanent stoma after rectal cancer surgery.

AIM: Health-related quality of life (HRQoL) assessment is important in understanding the patient's perspective and for decision-making in health care. HRQoL is often impaired in patients with stoma. The aim was to evaluate HRQoL in rectal cancer patients with permanent stoma compared to patients without stoma. METHODS: 711 patients operated for rectal cancer with abdomino-perineal resection or Hartman's procedure and a control group (n = 275) operated with anterior resection were eligible. Four QoL questionnaires were sent by mail. Comparisons of mean values between groups were made by Student´s independent t test. Comparison was made to a Swedish background population. RESULTS: 336 patients with a stoma and 117 without stoma replied (453/986; 46 %). A bulging or a hernia around the stoma was present in 31.5 %. Operation due to parastomal hernia had been performed in 11.7 % in the stoma group. Mental health (p = 0.007), body image (p < 0.001), and physical (p = 0.016) and emotional function (p = 0.003) were inferior in patients with stoma. Fatigue (p = 0.019) and loss of appetite (p = 0.027) were also more prominent in the stoma group. Sexual function was impaired in the non-stoma group (p = 0.034). However in the stoma group, patients with a bulge/hernia had more sexual problems (p = 0.004). Pain was associated with bulge/hernia (p < 0.001) and fear for leakage decreased QoL (p < 0.001). HRQoL was impaired compared to the Swedish background population. CONCLUSION: Overall HRQoL in patients operated for rectal cancer with permanent stoma was inferior compared to patients without stoma. In the stoma group, a bulge or a hernia around the stoma further impaired HRQoL.

The prognostic role of systemic inflammation in patients undergoing resection of colorectal liver metastases: C-reactive protein (CRP) is a strong negative prognostic biomarker.

BACKGROUND AND OBJECTIVES: Systemic inflammation has been associated with poor survival in several tumor types, but has been less extensively studied in resectable metastatic disease. The aim of the present study was to evaluate the prognostic role of CRP in colorectal cancer patients with liver metastases (CRLM) compared to conventional tumor- and patient-related clinicopathological features as well as other indicators of the systemic inflammatory response (SIR). METHODS: A multinational retrospective study of 492 CRLM patients undergoing potentially curative resection of liver metastases between 1999 and 2009. Clinicopathological findings and the SIR markers CRP, hypoalbuminemia, and their combined Glasgow Prognostic Score (GPS) were analyzed. RESULTS: Multivariate analysis showed that preoperative CRP >10 mg/L was a strong predictor of compromised survival (HR = 1.72, 95%CI 1.84-2.50, P < 0.01). Patients with CRP ≤10 mg/L had a median survival of 4.27 years compared to only 47 days in patients with CRP ≥30 mg/L (P < 0.01). Similarly, increased GPS was independently predictive of poor survival (HR 1.67, 95%CI 1.22-2.27, P < 0.01), but hypoalbuminemia alone did not have significant prognostic value. CONCLUSIONS: CRP alone is a strong prognostic factor, following curative resection of colorectal liver metastases and should be taken into consideration when selecting treatment strategies in CRLM patients. J. Surg. Oncol. 2016;114:895-899. © 2016 2016 Wiley Periodicals, Inc.