Paclitaxel and concomitant radiotherapy in high-risk endometrial cancer patients: preliminary findings

BACKGROUND: There is still much debate about the best adjuvant therapy after surgery for endometrial cancer (EC) and there are no current guidelines. Radiotherapy (RT) alone does not seem to improve overall survival. We investigated whether concomitant Paclitaxel (P) and RT gave better clinical results. METHODS: Twenty-three patients with high-risk EC (stage IIB, IIIA, IIIC or IC G3 without lymphadenectomy or with aneuploid tumor) underwent primary surgery and were then referred for adjuvant therapy. P was given at a dose of 60 mg/m2 once weekly for five weeks during RT, which consisted of a total radiation dose of 50.4 Gy. Three further weekly cycles of P at a dose of 80 mg/m2 were given at the end of RT. Overall survival and disease-free survival were calculated from the time of surgery. Patterns of failure were recorded by the sites of failure. RESULTS: A total of 157 cycles of P were administered both during radiotherapy and consolidation chemotherapy. Relapses occurred in five patients (21.7%). Median time to recurrence was 18.6 months (range 3–28). Survival rate for all the patients was 78.2%. Overall survival for the patients who completed chemo-radiation was of 81%. In this group median time to recurrence was 19.2 months (range 3–28). All recurrences were outside the radiation field. Mortality rate was 14.2%. CONCLUSION: This small series demonstrates pelvic radiotherapy in combination with weakly P followed by three consolidation chemotherapy cycles as an effective combined approach in high risk endometrial carcinoma patients

Publisher Correction: Stroke genetics informs drug discovery and risk prediction across ancestries.

In the version of this article initially published, the name of the PRECISE4Q Consortium was misspelled as “PRECISEQ” and has now been amended in the HTML and PDF versions of the article. Further, data in the first column of Supplementary Table 55 were mistakenly shifted and have been corrected in the file accompanying the HTML version of the article

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.

BACKGROUND: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. RESULTS: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. CONCLUSIONS: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.

BACKGROUND: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. RESULTS: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. CONCLUSIONS: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk

Abstract P5-12-06: Comprehensive assessment of the effect of genetic polymorphisms in drug metabolizing enzymes and transporters on tamoxifen activation to endoxifen

Abstract Background: Tamoxifen is the most commonly prescribed hormonal drug for estrogen receptor positive breast cancer treatment. Tamoxifen itself has weak anti-estrogenic activity, but is bioactivated to the more potent inhibitor endoxifen. Recent data suggest inferior efficacy of tamoxifen treatment in patients who have low systemic endoxifen concentration. Genetic variability in drug metabolizing enzymes and transporters, particularly CYP2D6, are known to effect serum endoxifen concentration. The association of CYP2D6 genotype and endoxifen concentration is well established; however, there is a paucity of data regarding the effects of genetic variants in other drug metabolizing enzymes and transporters on endoxifen concentrations. The objective of our study was to comprehensively screen known, functionally consequential polymorphisms and copy number variations in genes of interest to detect additional pharmacogenetic predictors of endoxifen concentration during tamoxifen treatment. Methods: This analysis includes patients prospectively enrolled on the Lineberger Comprehensive Cancer Center 0801 trial. Patients had received tamoxifen for a minimum of 4 months prior to enrollment and were not concurrently taking strong or moderate CYP2D6 inhibitors. Samples were collected at enrollment for measurement of steady state endoxifen level and collection of germline DNA. Genotyping was performed for CYP2D6 using the Amplichip® CYP450 test (Roche Diagnostics) and for other candidate genes (CYP2C9, CYP3A4, CYP3A5, ABCB1, SLCO1B1, SULT1A1, SULT1A2, and UGT2B7) using the iPLEX® ADME PGx Pro Panel (Agena Bioscience). Activity phenotype for each gene was inferred from genotype data based on known activity of variant alleles or copy numbers. Metabolite concentrations were measured via LC/MS-MS assay at Indiana University and square root transformed prior to analysis to improve normality. Linear regression models were used to evaluate the association of each gene individually with endoxifen concentration, assuming an additive pharmacogenetic effect, after adjustment for CYP2D6 phenotype (EM/UM, IM or PM). Results: 304 Patients with steady-state endoxifen concentration and successful genotyping were included in the analysis. After transformation and adjustment, endoxifen concentration was significantly associated with carrying low-activity CYP2C9 variant alleles (*2, *3, *5, *6, *8, *11, *12) (p=0.016). Predicted endoxifen concentration based on CYP2C9 and CYP2D6 genotype can be found in. Predicted endoxifen concentration (ng/mL) based on CYP2C9 and CYP2D6 Phenotype CYP2D6 EM/UMCYP2D6 IMCYP2D6 PMCYP2C9 WT/WT9.716.553.41CYP2C9 WT/Var8.375.482.63CYP2C9 Var/Var7.134.481.96Abbreviations: WT= wild-type, Var=Variant allele for CYP2C9 Phenotype activity of other enzymes and transporters was not associated with endoxifen concentration (all p&amp;gt;0.05). Conclusions: Polymorphisms in CYP2C9 and CYP2D6, but not other enzymes or transporters, contribute to variation in endoxifen exposure. If endoxifen exposure is validated to predict tamoxifen efficacy, personalized tamoxifen dosing algorithms should include CYP2C9, in addition to CYP2D6 and clinical factors, to improve efficacy and minimize side effects. Citation Format: Hertz DL, Danko W, Deal A, Walko CM, Flockhart DA, McLeod HL, Ibrahim JG, Irvin Jr WJ. Comprehensive assessment of the effect of genetic polymorphisms in drug metabolizing enzymes and transporters on tamoxifen activation to endoxifen. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-12-06.</jats:p

An Official ATS Clinical Practice Guideline: Interpretation of Exhaled Nitric Oxide Levels (F e

Background: Measurement of fractional nitric oxide (NO) concentration in exhaled breath (Fe(NO)) is a quantitative, noninvasive, simple, and safe method of measuring airway inflammation that provides a complementary tool to other ways of assessing airways disease, including asthma. While Fe(NO) measurement has been standardized, there is currently no reference guideline for practicing health care providers to guide them in the appropriate use and interpretation of Fe(NO) in clinical practice. Purpose: To develop evidence-based guidelines for the interpretation of Fe(NO) measurements that incorporate evidence that has accumulated over the past decade. Methods: We created a multidisciplinary committee with expertise in the clinical care, clinical science, or basic science of airway disease and/or NO. The committee identified important clinical questions, synthesized the evidence, and formulated recommendations. Recommendations were developed using pragmatic systematic reviews of the literature and the GRADE approach. Results: The evidence related to the use of Fe(NO) measurements is reviewed and clinical practice recommendations are provided. Conclusions: In the setting of chronic inflammatory airway disease including asthma, conventional tests such as FEV(1) reversibility or provocation tests are only indirectly associated with airway inflammation. Fe(NO) offers added advantages for patient care including, but not limited to (1) detecting of eosinophilic airway inflammation, (2) determining the likelihood of corticosteroid responsiveness, (3) monitoring of airway inflammation to determine the potential need for corticosteroid, and (4) unmasking of otherwise unsuspected nonadherence to corticosteroid therapy