Metabolic predispositions and increased risk of colorectal adenocarcinoma by anatomical locations: a large population-based cohort study in Norway

Whether different definitions of metabolic syndrome (MetS) are differently associated with colorectal adenocarcinoma (CA) by anatomical location is unclear. A population-based cohort study, the Cohort of Norway (CONOR) Study, was conducted in Norway from 1995 to 2010. Anthropometric measurements, blood samples, and lifestyle data were collected at recruitment. CAs were identified through linkage to the Norwegian Cancer Register. A composite index of MetS as defined by the International Diabetes Federation (IDF) or/and the National Cholesterol Education Program's Adult Treatment Panel III (ATP III) and single components of MetS, including anthropometric factors, blood pressure, lipids, triglycerides, and glucose, were analyzed. Cox proportional hazards regression was performed to estimate hazard ratios and 95% confidence intervals. Significant associations between single MetS components and CA, except for reduced high-density lipoprotein cholesterol and nonfasting glucose levels, were observed. MetS defined by 2 criteria separately showed a similar association with CA in general, and MetS defined by both the IDF and ATP III showed consistent results. Stronger associations were observed in the proximal colon among men (IDF: hazard ratio (HR) = 1.51, 95% confidence interval (CI): 1.24, 1.84; ATP III: HR = 1.40, 95% CI: 1.15, 1.70) and in the rectum among women (IDF: HR = 1.42, 95% CI: 1.07, 1.89; ATP III: HR = 1.43, 95% CI: 1.08, 1.90).Swedish Society of MedicineKarolinska InstitutetSwedish Research CouncilAccepte

Anthropometry-based obesity phenotypes and risk of colorectal adenocarcinoma : a large prospective cohort study in Norway

BACKGROUND: It is unclear whether obesity phenotypes measured by different anthropometric indices are associated with a risk of colorectal adenocarcinoma by anatomical location. METHODS: We compiled harmonized population-based cohort studies (Cohort of Norway, CONOR) with 143,477 participants that were conducted between 1994 and 2010. General, abdominal, and gluteofemoral obesity were assessed by body mass index (BMI, kg/m(2)), waist circumference (cm), and hip circumference (cm). Other measures examined were waist to hip ratio, waist to height ratio, and body adiposity index. We performed Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of obesity relative to a risk of colorectal adenocarcinoma. RESULTS: In total, 2,044 incident cases of colorectal adenocarcinoma were identified. We observed a positive association between waist circumference (high versus low) and adenocarcinoma in the proximal colon (HR = 1.9, 95% CI = 1.5, 2.5) and distal colon (HR = 1.7, 95% CI = 1.3, 2.3) when adjusted for BMI. The association with waist circumference was especially strong in men. BMI was not associated with adenocarcinoma in the colon or rectum after adjusting for waist circumference. We found no association between hip circumference and colorectal adenocarcinoma. When adjusted for BMI plus waist circumference, body adiposity index was negatively associated with adenocarcinoma in the proximal or distal colon. CONCLUSION: Abdominal obesity, but not general or gluteofemoral obesity, was associated with an increased risk of adenocarcinoma in the proximal and the distal colon, especially in men. Muscularity may be negatively associated with risk of colon adenocarcinoma.Swedish Research CouncilAccepte

Dissociation of EphB2 Signaling Pathways Mediating Progenitor Cell Proliferation and Tumor Suppression

SummarySignaling proteins driving the proliferation of stem and progenitor cells are often encoded by proto-oncogenes. EphB receptors represent a rare exception; they promote cell proliferation in the intestinal epithelium and function as tumor suppressors by controlling cell migration and inhibiting invasive growth. We show that cell migration and proliferation are controlled independently by the receptor EphB2. EphB2 regulated cell positioning is kinase-independent and mediated via phosphatidylinositol 3-kinase, whereas EphB2 tyrosine kinase activity regulates cell proliferation through an Abl-cyclin D1 pathway. Cyclin D1 regulation becomes uncoupled from EphB signaling during the progression from adenoma to colon carcinoma in humans, allowing continued proliferation with invasive growth. The dissociation of EphB2 signaling pathways enables the selective inhibition of the mitogenic effect without affecting the tumor suppressor function and identifies a pharmacological strategy to suppress adenoma growth

Increased risk of colorectal cancer in patients diagnosed with breast cancer in women

BackgroundEpidemiological studies have shown a potential association between sex hormones and colorectal cancer. The risk of colorectal cancer in breast cancer patients who may have been exposed to increased levels of endogenous sex hormones and/or exogenous sex hormones (e.g. anti-hormonal therapy) has not been thoroughly evaluated.MethodsUsing the National Swedish Cancer Register we established a population-based prospective cohort of breast cancer patients in women diagnosed in Sweden between 1961 and 2010. Subsequent colorectal cancers were identified from the same register. Standardized incidence ratios (SIRs) and 95% confidence intervals (95%CIs) were used to estimate the risk of colorectal cancer after a diagnosis of breast cancer. The association between breast cancer therapy and risk of colorectal cancer was evaluated in a subcohort of breast cancer patients treated in Stockholm between 1977 and 2007. Hazard ratios (HRs) and 95%CIs were estimated using Cox regression models.ResultsIn a cohort of 179,733 breast cancer patients in Sweden, 2571 incident cases of colorectal cancer (1008 adenocarcinomas in the proximal colon, 590 in the distal colon and 808 in the rectum) were identified during an average follow-up of 9.68 years. An increased risk of colorectal adenocarcinoma was observed in the breast cancer cohort compared with that in the general population (SIR=1.59, 95%CI: 1.53, 1.65). Adenocarcinoma in the proximal colon showed a non-significantly higher SIR (1.72, 95%CI: 1.61, 1.82) compared with the distal colon (1.46, 95%CI: 1.34, 1.58). In the subcohort of 20,171 breast cancers with available treatment data, 299 cases with colorectal cancers were identified. No treatment-dependent risk of colorectal cancer was observed among the breast cancer patients.ConclusionAn increased risk of colorectal adenocarcinoma - especially in the proximal colon - was observed in the breast cancer cohort. Breast cancer treatment did not alter this risk

Post-Operative Functional Outcomes in Early Age Onset Rectal Cancer

Background: Impairment of bowel, urogenital and fertility-related function in patients treated for rectal cancer is common. While the rate of rectal cancer in the young (<50 years) is rising, there is little data on functional outcomes in this group. Methods: The REACCT international collaborative database was reviewed and data on eligible patients analysed. Inclusion criteria comprised patients with a histologically confirmed rectal cancer, <50 years of age at time of diagnosis and with documented follow-up including functional outcomes. Results: A total of 1428 (n=1428) patients met the eligibility criteria and were included in the final analysis. Metastatic disease was present at diagnosis in 13%. Of these, 40% received neoadjuvant therapy and 50% adjuvant chemotherapy. The incidence of post-operative major morbidity was 10%. A defunctioning stoma was placed for 621 patients (43%); 534 of these proceeded to elective restoration of bowel continuity. The median follow-up time was 42 months. Of this cohort, a total of 415 (29%) reported persistent impairment of functional outcomes, the most frequent of which was bowel dysfunction (16%), followed by bladder dysfunction (7%), sexual dysfunction (4.5%) and infertility (1%). Conclusion: A substantial proportion of patients with early-onset rectal cancer who undergo surgery report persistent impairment of functional status. Patients should be involved in the discussion regarding their treatment options and potential impact on quality of life. Functional outcomes should be routinely recorded as part of follow up alongside oncological parameters

Rectal cancer : Staging, radiotherapy and surgery

In Sweden, about 1800 patients are annually diagnosed with adenocarcinoma of the rectum. Surgery remains the major primary treatment. Adjuvant radiotherapy and total mesorectal excision (TME) are two major achievements in rectal cancer treatment during the last two decades. The subsequent improvement in local control and survival with a reduced need for permanent colostomies is of great benefit for the patients. With the development of new treatment strategies for rectal cancer, including neoadjuvant treatment modalities, the necessity and importance of accurate preoperative staging has increased. The Stockholm Colorectal Cancer Study Group (SCCSG) was set up in 1980 with the aim of improving outcomes in patients with rectal cancer. Between 1980 and 1993, SCCSG completed two prospective randomised trials which evaluated the efficacy of preoperative radiotherapy (the Stockholm I and Stockholm II Trials). In 1994 the group initiated a collaborative education project, including surgical and pathological workshops, to introduce the concept of TME to colorectal surgeons and pathologists in Stockholm (the TME Project). Since 1995, all patients with colorectal cancer in Stockholm have been included and prospectively registered in a regional treatment programme initiated by the SCCSG (the Regional Treatment Programme Register). This thesis is based on patients from the Stockholm I and II Trial and the Regional Treatment Program and assesses the prognostic significance of staging, radiotherapy and surgery in patients with rectal adenocarcinoma with special focus on outcome in relation to preoperative short-term radiotherapy, TME based surgery, magnetic resonance imaging (MRI) and the individual operating surgeon. It is concluded that preoperative radiotherapy with 5x5 Gy reduces local recurrence rates with more than 50% and may improve survival. This beneficial effect is seen both with conventional surgical techniques and TME based surgery. Preoperative radiotherapy may increase postoperative morbidity and mortality in subgroups of patients and should be given with caution to patients with symptoms of severe arterioclerotic disease. The TME Project encouraged and enhanced a major shift in rectal cancer surgical practice in Stockholm with an increased centralisation and specialisation. As a result, local control and cancer specific survival was significantly improved. In addition, the rate of APRs declined. TME based surgery demands surgical skill, which can be achieved by participation in education programmes and increased personal training and experience. Patient outcome after surgery is related to the individual surgeon and is mainly related to the surgeon s case volume, with better results obtained in patients treated by high-volume surgeons. A tumour-involved circumferential resection margin (CRM) is of strong prognostic value and may be detected on preoperative MRI. If an involved CRM is identified, this is predictive of distant metastases and survival. The surgeon s postoperative statement regarding whether complete or incomplete tumour clearance was achieved at the operation is of strong prognostic significance with regard to recurrence and survival. An ambiguous report in this respect should be regarded as an indicator of incomplete clearance and of non-curative surgery. This highlights the importance of a clear definition of curative surgery. With current protocols combining standardised preoperative staging, modern radiotherapy techniques and TME based surgery, low rates of local recurrence should be achieved. The challenge for the future is to prevent and treat distant metastases and to further improve survival

Reproductive history and risk of colorectal adenocarcinoma.

BackgroundSex hormones may be associated with colorectal adenocarcinoma, although the association of pregnancy history and risk of colorectal cancer is not consistent.MethodsWe conducted a population-based nested case-control study of persons born between 1932 and 2008 who are in the Swedish Multi-Generation Register. In total, 12,915 women and 15,519 men with colorectal adenocarcinoma were identified during follow-up in the Swedish Cancer Register; 10 age- and sex-matched controls were selected for each case. Number of children and age at first and last birth were analyzed in relation to the risk of colorectal adenocarcinoma, using conditional logistic regression, to estimate odds ratios (ORs) and 95% confidence intervals (CIs).ResultsCompared with women without children, women with 1 or 2 children had an OR of 1.02 (95% CI = 0.93-1.13) of developing adenocarcinoma in the proximal colon; those with 3 or 4 children, 1.18 (1.06-1.32); and those with ≥5 children, 1.30 (1.05-1.61) (test for trend P < 0.01). The corresponding associations in men were 0.92 (0.84-1.00), 1.02 (0.92-1.13), and 0.97 (0.78-1.20), respectively (test for trend P = 0.13).ConclusionsHigher parity in women was associated with the risk of adenocarcinoma of the proximal colon, although not the distal colon or rectum. A similar risk with family size was not seen for fathers. Still, the influence of lifestyle factors cannot be ruled out

Reproductive History and Risk of Colorectal Adenocarcinoma

BackgroundSex hormones may be associated with colorectal adenocarcinoma, although the association of pregnancy history and risk of colorectal cancer is not consistent.MethodsWe conducted a population-based nested case-control study of persons born between 1932 and 2008 who are in the Swedish Multi-Generation Register. In total, 12,915 women and 15,519 men with colorectal adenocarcinoma were identified during follow-up in the Swedish Cancer Register; 10 age- and sex-matched controls were selected for each case. Number of children and age at first and last birth were analyzed in relation to the risk of colorectal adenocarcinoma, using conditional logistic regression, to estimate odds ratios (ORs) and 95% confidence intervals (CIs).ResultsCompared with women without children, women with 1 or 2 children had an OR of 1.02 (95% CI = 0.93-1.13) of developing adenocarcinoma in the proximal colon; those with 3 or 4 children, 1.18 (1.06-1.32); and those with ≥5 children, 1.30 (1.05-1.61) (test for trend P < 0.01). The corresponding associations in men were 0.92 (0.84-1.00), 1.02 (0.92-1.13), and 0.97 (0.78-1.20), respectively (test for trend P = 0.13).ConclusionsHigher parity in women was associated with the risk of adenocarcinoma of the proximal colon, although not the distal colon or rectum. A similar risk with family size was not seen for fathers. Still, the influence of lifestyle factors cannot be ruled out

Incidence of wound dehiscence after colorectal cancer surgery : results from a national population-based register for colorectal cancer

Background: Patient-related risk factors for wound dehiscence after colorectal surgery remain obscure. Methods: All open abdominal procedures for colorectal cancer registered in the Swedish Colorectal Cancer Registry (SCRCR, 5) 2007-2013 were identified. Potential risk factors for wound dehiscence were identified by cross-matching between the SCRCR and the National Patient Register (NPR). The endpoint in this study was reoperation for wound dehiscence registered in either the SCRCR or NPR and patients not reoperated were considered controls. Results: A total of 30,050 patients were included in the study. In a multivariable regression analysis, age > 70 years, male gender, BMI > 30, history of chronic obstructive pulmonary disease, history of generalised inflammatory disease, and duration of surgery less than 180 min were independently and significantly associated with increased risk for wound dehiscence. A history of diabetes, chronic renal disease, liver cirrhosis, and distant metastases was not associated with wound dehiscence. The hazard ratio for postoperative death was 1.24 for patients who underwent reoperation for wound dehiscence compared with that for controls. Discussion: Patients reoperated for wound dehiscence face a significantly higher postoperative mortality than those without. Risk factors include male gender, age > 70 years, obesity, history of chronic obstructive pulmonary disease, and history of generalised inflammatory disease. Patients at high risk for developing wound dehiscence may, if identified preoperatively, benefit from active prevention measures implemented in routine surgical practice