Bayesian and frequentist analysis of an Austrian genome-wide association study of colorectal cancer and advanced adenomas

Most genome-wide association studies (GWAS) were analyzed using single marker tests in combination with stringent correction procedures for multiple testing. Thus, a substantial proportion of associated single nucleotide polymorphisms (SNPs) remained undetected and may account for missing heritability in complex traits. Model selection procedures present a powerful alternative to identify associated SNPs in high-dimensional settings. In this GWAS including 1060 colorectal cancer cases, 689 cases of advanced colorectal adenomas and 4367 controls we pursued a dual approach to investigate genome-wide associations with disease risk applying both, single marker analysis and model selection based on the modified Bayesian information criterion, mBIC2, implemented in the software package MOSGWA. For different case-control comparisons, we report models including between 1-14 candidate SNPs. A genome-wide significant association of rs17659990 (P=5.43x10(-9), DOCK3, chromosome 3p21.2) with colorectal cancer risk was observed. Furthermore, 56 SNPs known to influence susceptibility to colorectal cancer and advanced adenoma were tested in a hypothesis-driven approach and several of them were found to be relevant in our Austrian cohort. After correction for multiple testing (alpha=8.9x10(-4)), the most significant associations were observed for SNPs rs10505477 (P=6.08x10(-4)) and rs6983267 (P=7.35x10(-4)) of CASC8, rs3802842 (P=8.98x10(-5), COLCA1,2), and rs12953717 (P=4.64x10(-4), SMAD7). All previously unreported SNPs demand replication in additional samples. Reanalysis of existing GWAS datasets using model selection as tool to detect SNPs associated with a complex trait may present a promising resource to identify further genetic risk variants not only for colorectal cancer

The ASAMET trial: a randomized, phase II, double-blind, placebo-controlled, multicenter, 2 × 2 factorial biomarker study of tertiary prevention with low-dose aspirin and metformin in stage I-III colorectal cancer patients

Background: Epidemiological studies and cardiovascular prevention trials have shown that low-dose aspirin can reduce colorectal cancer (CRC) incidence and mortality, including inhibition of distant metastases. Metformin has also been associated with decreased colon adenoma recurrence in clinical trials and lower CRC incidence and mortality in epidemiological studies in diabetics. While both drugs have been tested as single agents, their combination has not been tested in cancer prevention trials. Methods/design: This is a randomized, placebo-controlled, double-blind, 2 × 2 biomarker trial of aspirin and metformin to test the activity of either agent alone and the potential synergism of their combination on a set of surrogate biomarkers of colorectal carcinogenesis. After surgery, 160 patients with stage I-III CRC are randomly assigned in a four-arm trial to either aspirin (100 mg day), metformin (850 mg bis in die), their combination, or placebo for one year. The primary endpoint biomarker is the change of IHC expression of nuclear factor kappa-B (NFκB) in the unaffected mucosa of proximal and distal colon obtained by multiple biopsies in two paired colonoscopies one year apart. Additional biomarkers will include: 1) the measurement of circulating IL-6, CRP and VEGF; 2) the IHC expression of tissue pS6K, p53, beta-catenin, PI3K; 3) the associations of genetic markers with treatment response as assessed by next generation sequencing of primary tumors; 4) the genomic profile of candidate genes, pathways, and overall genomic patterns in tissue biopsies by genome wide gene expression arrays; and 5) the evaluation of adenoma occurrence at 1 year. Discussion: A favorable biomarker modulation by aspirin and metformin may provide important clues for a subsequent phase III adjuvant trial aimed at preventing second primary cancer, delaying recurrence and improving prognosis in patients with CRC. Trial registration: EudraCT Number: 2015–004824-77; ClinicalTrial.gov Identifier: NCT03047837. Registered on February 1, 2017

NVP-AUY922: a small molecule HSP90 inhibitor with potent antitumor activity in preclinical breast cancer models

INTRODUCTION:Heat shock protein 90 (HSP90) is a key component of a multichaperone complex involved in the post-translational folding of a large number of client proteins, many of which play essential roles in tumorigenesis. HSP90 has emerged in recent years as a promising new target for anticancer therapies.METHODS:The concentrations of the HSP90 inhibitor NVP-AUY922 required to reduce cell numbers by 50% (GI50 values) were established in a panel of breast cancer cell lines and patient-derived human breast tumors. To investigate the properties of the compound in vivo, the pharmacokinetic profile, antitumor effect, and dose regimen were established in a BT-474 breast cancer xenograft model. The effect on HSP90-p23 complexes, client protein degradation, and heat shock response was investigated in cell culture and breast cancer xenografts by immunohistochemistry, Western blot analysis, and immunoprecipitation.RESULTS:We show that the novel small molecule HSP90 inhibitor NVP-AUY922 potently inhibits the proliferation of human breast cancer cell lines with GI50 values in the range of 3 to 126 nM. NVP-AUY922 induced proliferative inhibition concurrent with HSP70 upregulation and client protein depletion � hallmarks of HSP90 inhibition. Intravenous acute administration of NVP-AUY922 to athymic mice (30 mg/kg) bearing subcutaneous BT-474 breast tumors resulted in drug levels in excess of 1,000 times the cellular GI50 value for about 2 days. Significant growth inhibition and good tolerability were observed when the compound was administered once per week. Therapeutic effects were concordant with changes in pharmacodynamic markers, including HSP90-p23 dissociation, decreases in ERBB2 and P-AKT, and increased HSP70 protein levels.CONCLUSION:NVP-AUY922 is a potent small molecule HSP90 inhibitor showing significant activity against breast cancer cells in cellular and in vivo settings. On the basis of its mechanism of action, preclinical activity profile, tolerability, and pharmaceutical properties, the compound recently has entered clinical phase I breast cancer trials

Detection and localization of early- and late-stage cancers using platelet RNA

Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I–IV cancer patients and in half of 352 stage I–III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening

Trocar-site evisceration of the vermiform appendix following laparoscopic sigmoid colectomy: A case report

Introduction There is an ongoing debate whether prophylactic drainage or incidental appendectomy should be performed in patients undergoing colorectal surgery. On the other hand, it has been shown that the placement of drains through former trocar sites as well as the use of large (10 mm) trocars, incomplete fascial closure or closed laparoscopy technique all predispose for the occurrence of trocar site hernias. Presentation of case We report the case of a 59-year-old male patient who underwent laparoscopic sigmoid colectomy with primary anastomosis for recurrent sigmoid diverticulitis. Preoperative diagnostics revealed no abnormalities other than multiple diverticula in the sigmoid colon. The subsequent surgery was conducted without any complications. Due to inconspicuous intraoperative appearance of the vermiform appendix, no incidental appendectomy was performed. On the 4th postoperative day, the Easy Flow drain which had been placed prophylactically through the 12 mm trocar site in the right lower abdomen was removed. Four hours after drain removal, trocar-site evisceration of the vermiform appendix occurred, requiring emergency surgery. Discussion and conclusion The present case is yet another argument for restricting the use of prophylactic drains in colorectal surgery as well as closing port sites of 10 mm diameter. Furthermore, incidental appendectomy may be considered since it is able to prevent this type of complication and can be performed with minimal cost and morbidity.(VLID)485605

Early postoperative CRP predicts major complications following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC)

Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) is associated with significant postoperative complications. Early detection of at-risk patients may lead to improved outcomes. The role of C-reactive protein (CRP) in predicting postoperative complications has only been recently investigated

Wiener klinische Wochenschrift / Outcome of no oral antibiotic prophylaxis and bowel preparation in Crohns diseases surgery

Background Recent studies support the use of mechanical bowel preparation and/or oral antibiotic prophylaxis in patients operated on for Crohns disease (CD); however, data are scarce, especially for laparoscopic surgery. Therefore, this study was carried out to investigate the effect of laparoscopic surgery on complication rates in patients not undergoing standardized bowel preparation but single shot antibiotics. Methods In this study 255 consecutive patients who underwent a laparoscopic intestinal resection for CD at a tertiary referral center between 1997 and 2014 were retrospectively analyzed. Superficial surgical site infections (SSI), organ/space infections and ileus were recorded and grouped according to the type of resection (colorectal vs. small intestine ileocecal). Results The baseline characteristics of the groups were comparable. Colorectal resections showed a significantly increased risk of organ/space infection (4.6% in small intestine ileocecal vs. 14.3% in colorectal resections p = 0.039). The superficial SSI rate was low in both groups (1.8% in small intestine ileocecal resection vs. 0% in colorectal resections, p = 1.000). Univariate binary logistic regression analysis revealed a statistically significant influence of duration of surgery (p = 0.001) and type of resection (p = 0.031) on organ/space infection. In multivariate analysis, only duration of surgery (OR 1.111, 95% CI 1.0261.203 for every 10 min, p = 0.009) remained significant for postoperative organ/space infections. Conclusions Single-shot antibiotic therapy without bowel preparation is safe in patients undergoing minimally invasive surgery and was associated with a low number of complications; however, organ/space infections were more common if colorectal resections were performed. Therefore, combined bowel preparation might be beneficial when the (sigmoid) colon or rectum are involved.(VLID)509600

Genomic classifier coloprint predicts recurrence in stage ii colorectal cancer patients more accurately than clinical factors

Background. Approximately 20% of patients with stage II colorectal cancer will experience a relapse. Current clinicalpathologic stratification factors do not allowclear identification of these high-risk patients. ColoPrint (Agendia, Amsterdam, The Netherlands, http://www.agendia.com) is a gene expression classifier that distinguishes patients with low or high risk of disease relapse. Methods. ColoPrint was developed using whole-genome expression data and validated in several independent validation cohorts. Stage II patients from these studieswere pooled (n5416), and ColoPrint was compared with clinical risk factors described in the National Comprehensive Cancer Network (NCCN) 2013 Guidelines for Colon Cancer. Median follow-up was 81 months. Most patients (70%) did not receive adjuvant chemotherapy. Risk of relapse (ROR) was defined as survival until first event of recurrence or death fromcancer. Results. In the pooled stage II data set, ColoPrint identified 63% of patients as low risk with a 5-year ROR of 10%, whereas high-risk patients (37%) had a 5-yearRORof 21%, with a hazard ratio (HR) of 2.16 (p =.004). This remained significant in a multivariate model that included number of lymph nodes retrieved and microsatellite instability. In the T3 microsatellitestable subgroup (n5301), ColoPrint classified 59% of patients as low risk with a 5-year ROR of 9.9%. High-risk patients (31%) had a 22.4% ROR (HR: 2.41; p =.005). In contrast, the NCCN clinical high-risk factors were unable to distinguish high-and low-risk patients (15% vs. 13% ROR; p =.55). Conclusion. ColoPrint significantly improved prognostic accuracy independent of microsatellite status or clinical variables, facilitating the identification of patients at higher risk who might be considered for additional treatment

ARTICLE IN PRESS Inosine 5V-monophosphate dehydrogenase inhibition by mycophenolic acid impairs maturation and function of dendritic cells

Abstract Background: The mechanism of action of mycophenolic acid (MPA) has been described as a blockade of inosine 5V -monophosphate dehydrogenase (IMPDH) and is thought to selectively influence T-and B-lymphocytes due to their strong dependency on guanine nucleotides synthesized via the de novo purine synthesis pathway. Recent evidence suggests MPA to affect antigenpresenting cells. Methods: Using CD14 + derived human dendritic cells (DC) we have investigated the effects of MPA on differentiation, maturation and function and studied intracellular nucleotide content and IMPDH activity. Results: GTP content and IMPDH activities of DC were strongly and dose-dependently decreased when MPA was present during the entire culture period or was added after the fifth (immature DC) or the seventh (mature DC) day of culture. Concurrent to low GTP levels, a dose-dependent reduction in the expression of CD80, CD86, CD40, CD54 and CD83 was seen which was accompanied by a decreased capacity of DC to stimulate T-cells. Our data for the first time shows a direct effect of MPA on the maturation and function of human CD14 + derived DC, indicates a role of IMPDH and a dependency on the de novo purine synthesis pathway.