Cancer-testis gene expression is associated with the methylenetetrahydrofolate reductase 677 C\u3eT polymorphism in non-small cell lung carcinoma

BACKGROUND: Tumor-specific, coordinate expression of cancer-testis (CT) genes, mapping to the X chromosome, is observed in more than 60% of non-small cell lung cancer (NSCLC) patients. Although CT gene expression has been unequivocally related to DNA demethylation of promoter regions, the underlying mechanism leading to loss of promoter methylation remains elusive. Polymorphisms of enzymes within the 1-carbon pathway have been shown to affect S-adenosyl methionine (SAM) production, which is the sole methyl donor in the cell. Allelic variants of several enzymes within this pathway have been associated with altered SAM levels either directly, or indirectly as reflected by altered levels of SAH and Homocysteine levels, and altered levels of DNA methylation. We, therefore, asked whether the five most commonly occurring polymorphisms in four of the enzymes in the 1-carbon pathway associated with CT gene expression status in patients with NSCLC. METHODS: Fifty patients among a cohort of 763 with NSCLC were selected based on CT gene expression status and typed for five polymorphisms in four genes known to affect SAM generation by allele specific q-PCR and RFLP. RESULTS: We identified a significant association between CT gene expression and the MTHFR 677 CC genotype, as well as the C allele of the SNP, in this cohort of patients. Multivariate analysis revealed that the genotype and allele strongly associate with CT gene expression, independent of potential confounders. CONCLUSIONS: Although CT gene expression is associated with DNA demethylation, in NSCLC, our data suggests this is unlikely to be the result of decreased MTHFR function

Prognostic significance of early recurrence: a conditional survival analysis in patients with resected colorectal liver metastasis

AbstractBackgroundFor patients undergoing liver resection for colorectal metastases, specific clinico‐pathological variables have been shown to be prognostic at baseline. This study analyses how the prognostic capability of these variables changes in a conditional survival model.MethodsRetrospective review of a prospectively maintained database of patients who underwent an R0 resection of colorectal liver metastases from 1994 to 2004 at a single institution.ResultsIn total, 807 patients were identified, with an 87‐month median follow‐up for survivors. Five‐ and 10‐year disease‐specific survivals (DSS) were 68% and 55%, respectively. The probability of further survival increased as the survival time increased. For 3‐year survivors (n = 504), DSS were no longer significantly different between patients with a low (0–2) or high (3–5) clinical risk score (CRS, P = 0.19). On multivariate analysis, independent predictors of DSS for 3‐year survivors were recurrence within the first 3 years after a liver resection, a pre‐operative carcinoembryonic antigen (CEA) >200 ng/ml and disease‐free interval <12 months prior to the diagnosis of liver metastasis. However, for those patients who were recurrence free at 1 year, no clinico‐pathological variables retained prognostic significance.DiscussionAfter 3 years of DSS and 1 year of recurrence‐free survival, baseline clinico‐pathological variables have a limited ability to predict future survival. Early post‐operative recurrence appears to be the most useful single clinical feature in estimating conditional DSS

Role of the interval from completion of neoadjuvant therapy to surgery in postoperative morbidity in patients with locally advanced rectal cancer

Increasing the interval from completion of neoadjuvant therapy to surgery beyond 8 weeks is associated with increased response of rectal cancer to neoadjuvant therapy. However, reports are conflicting on whether extending the time to surgery is associated with increased perioperative morbidity. Patients who presented with a tumor within 15 cm of the anal verge in 2009-2015 were grouped according to the interval between completion of neoadjuvant therapy and surgery: &lt; 8 weeks, 8-12 weeks, and 12-16 weeks. Among 607 patients, the surgery was performed at &lt; 8 weeks in 317 patients, 8-12 weeks in 229 patients, and 12-16 weeks in 61 patients. Patients who underwent surgery at 8-12 weeks and patients who underwent surgery at &lt; 8 weeks had comparable rates of complications (37% and 44%, respectively). Univariable analysis identified male sex, earlier date of diagnosis, tumor location within 5 cm of the anal verge, open operative approach, abdominoperineal resection, and use of neoadjuvant chemoradiotherapy alone to be associated with higher rates of complications. In multivariable analysis, male sex, tumor location within 5 cm of the anal verge, open operative approach, and neoadjuvant chemoradiotherapy administered alone were independently associated with the presence of a complication. The interval between neoadjuvant therapy and surgery was not an independent predictor of postoperative complications. Delaying surgery beyond 8 weeks from completion of neoadjuvant therapy does not appear to increase surgical morbidity in rectal cancer patients

Cancer-testis gene expression is associated with the methylenetetrahydrofolate reductase 677 C>T polymorphism in non-small cell lung carcinoma

Background: Tumor-specific, coordinate expression of cancer-testis (CT) genes, mapping to the X chromosome, is observed in more than 60% of non-small cell lung cancer (NSCLC) patients. Although CT gene expression has been unequivocally related to DNA demethylation of promoter regions, the underlying mechanism leading to loss of promoter methylation remains elusive. Polymorphisms of enzymes within the 1-carbon pathway have been shown to affect S-adenosyl methionine (SAM) production, which is the sole methyl donor in the cell. Allelic variants of several enzymes within this pathway have been associated with altered SAM levels either directly, or indirectly as reflected by altered levels of SAH and Homocysteine levels, and altered levels of DNA methylation. We, therefore, asked whether the five most commonly occurring polymorphisms in four of the enzymes in the 1-carbon pathway associated with CT gene expression status in patients with NSCLC.Publisher's Versio

Extensions to decision curve analysis, a novel method for evaluating diagnostic tests, prediction models and molecular markers

<p>Abstract</p> <p>Background</p> <p>Decision curve analysis is a novel method for evaluating diagnostic tests, prediction models and molecular markers. It combines the mathematical simplicity of accuracy measures, such as sensitivity and specificity, with the clinical applicability of decision analytic approaches. Most critically, decision curve analysis can be applied directly to a data set, and does not require the sort of external data on costs, benefits and preferences typically required by traditional decision analytic techniques.</p> <p>Methods</p> <p>In this paper we present several extensions to decision curve analysis including correction for overfit, confidence intervals, application to censored data (including competing risk) and calculation of decision curves directly from predicted probabilities. All of these extensions are based on straightforward methods that have previously been described in the literature for application to analogous statistical techniques.</p> <p>Results</p> <p>Simulation studies showed that repeated 10-fold crossvalidation provided the best method for correcting a decision curve for overfit. The method for applying decision curves to censored data had little bias and coverage was excellent; for competing risk, decision curves were appropriately affected by the incidence of the competing risk and the association between the competing risk and the predictor of interest. Calculation of decision curves directly from predicted probabilities led to a smoothing of the decision curve.</p> <p>Conclusion</p> <p>Decision curve analysis can be easily extended to many of the applications common to performance measures for prediction models. Software to implement decision curve analysis is provided.</p

Quantitating whole lesion tumor biology in rectal cancer MRI: taking a lesson from FDG-PET tumor metrics

PURPOSE To determine the value of novel whole tumor metrics in DWI-MRI and DCE-MRI of rectal cancer treatment assessment. MATERIALS AND METHODS This retrospective study included 24 uniformly treated patients with rectal adenocarcinoma who underwent MRI including diffusion-weighted (DW) and dynamic contrast-enhanced (DCE) sequences, before and after chemoradiotherapy. Two experienced readers independently measured tumor volume and apparent diffusion coefficient (ADC) on DWI-MRI and tumor volume and transfer constant K on DCE-MRI. In addition, we explored and defined Total Lesion Diffusion (TLD) as Total DWI tumor volume multiplied by mean volumetric ADC and Total Lesion Perfusion (TLP) as the total DCE tumor volume multiplied by the mean volumetric K . These metrics were correlated with histopathologic percent tumor regression in the resected specimen (%TR). Inter-reader agreement was assessed using the concordance correlation coefficient (CCC). RESULTS For both readers, post-treatment TLP revealed comparable correlations with %TR compared with K (reader 1; Spearman's rho = - 0.36 vs. - 0.32, reader 2; Spearman's rho = - 0.32 vs. - 0.28). In addition, TLP afforded the highest inter-reader agreement at post-treatment among TLP, DCE vol, and K (CCC: 0.64 vs. 0.36 vs. 0.35). Post-treatment TLD showed similar correlation with %TR as DWI volume in reader 1 and superior correlation with %TR for reader 2 (reader 1; Spearman's rho - 0.56 vs. - 0.57, reader 2; Spearman's rho - 0.59 vs. - 0.45). CONCLUSION The novel tumor metrics TLD and TLP revealed similar results to established metrics for correlation with tumor response with equivalent or superior inter-reader agreements and we recommend that these be studied in larger trials