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  • American Association for Cancer Research (AACR)  (42)
  • 1
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    Gene-Expression Profiling of Mucinous Ovarian Tumors and Comparison with Upper and Lower Gastrointestinal Tumors Identifies Markers Associated with Adverse Outcomes
    American Association for Cancer Research (AACR) ; 2022
    In:  Clinical Cancer Research Vol. 28, No. 24 ( 2022-12-15), p. 5383-5395
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 28, No. 24 ( 2022-12-15), p. 5383-5395
    Abstract: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. Experimental Design: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). Results: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04–7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04–1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01–1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). Conclusions: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-22-1206
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 2
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    The ABL Switch Control Inhibitor DCC-2036 Is Active against the Chronic Myeloid Leukemia Mutant BCR-ABLT315I and Exhibits a Narrow Resistance Profile
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 9 ( 2011-05-01), p. 3189-3195
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 9 ( 2011-05-01), p. 3189-3195
    Abstract: Acquired point mutations within the BCR-ABL kinase domain represent a common mechanism of resistance to ABL inhibitor therapy in patients with chronic myeloid leukemia (CML). The BCR-ABLT315I mutant is highly resistant to imatinib, nilotinib, and dasatinib, and is frequently detected in relapsed patients. This critical gap in resistance coverage drove development of DCC-2036, an ABL inhibitor that binds the switch control pocket involved in conformational regulation of the kinase domain. We evaluated the efficacy of DCC-2036 against BCR-ABLT315I and other mutants in cellular and biochemical assays and conducted cell-based mutagenesis screens. DCC-2036 inhibited autophosphorylation of ABL and ABLT315I enzymes, and this activity was consistent with selective efficacy against Ba/F3 cells expressing BCR-ABL (IC50: 19 nmol/L), BCR-ABLT315I (IC50: 63 nmol/L), and most kinase domain mutants. Ex vivo exposure of CML cells from patients harboring BCR-ABL or BCR-ABLT315I to DCC-2036 revealed marked inhibition of colony formation and reduced phosphorylation of the direct BCR-ABL target CrkL. Cell-based mutagenesis screens identified a resistance profile for DCC-2036 centered around select P-loop mutations (G250E, Q252H, Y253H, E255K/V), although a concentration of 750 nmol/L DCC-2036 suppressed the emergence of all resistant clones. A decreased concentration of DCC-2036 (160 nmol/L) in dual combination with either nilotinib or dasatinib achieved the same zero outgrowth result. Further screens for resistance due to BCR-ABL compound mutations (two mutations in the same clone) identified BCR-ABLE255V / T315I as the most resistant mutant. Taken together, these findings support continued evaluation of DCC-2036 as an important new agent for treatment-refractory CML. Cancer Res; 71(9); 3189–95. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-10-3224
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 3
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    Abstract 3266: Expression quantitative trait locus analysis of triple negative breast cancer
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 3266-3266
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 3266-3266
    Abstract: Recent studies have shown that associations between common genetic variation and gene expression in breast tumors provide insight into the functional mechanisms underlying breast cancer risk loci. However, the relationship between genetic variation, gene expression, and risk of triple negative (TN) breast cancer remains largely unexplored. We performed a genome-wide expression quantitative trait locus (eQTL) analysis of TN breast cancer using 668 formalin-fixed paraffin embedded TN tumors from the Triple Negative Breast Cancer Consortium (TNBCC) to identify novel genes relevant to TN breast cancer risk and to further explore the biology underlying known TN risk loci. Cis-eQTLs were defined as correlations between single nucleotide polymorphisms (SNP) and expression of genes within 1Mb, and trans-eQTLs were defined as the remainder of all SNP-gene correlations. In a genome-wide analysis, we identified 68,012 cis-eQTLs, representing correlations between 42,193 SNPs and 2,092 genes that were significant at a 10% false discovery rate (FDR). We also identified 70 trans-eQTLs across two unique genes at the same FDR threshold. Five cis-eQTLs involved SNPs previously associated with TN breast cancer risk (p & lt;5.0x10-5) in 3,700 TN cases and 4,700 controls from the TNBCC. Three of these, located on chromosomes 5p (cis-eQTL p=4.8x10-34; risk p=1.1x10-7), 7p (cis-eQTL p=6.1x10-10; risk p=1.3x10-7), and 17q (cis-eQTL p=1.8x10-15; risk p=2.9x10-7), have previously been reported in public databases of normal tissue. The remaining two TN breast cancer cis-eQTLs, located on chromosomes 8q (cis-eQTL p=6.3x10-6, risk p=8.3x10-6) and 14q (cis-eQTL p=3.1x10-6, risk p=1.2x10-5), have not been reported as eQTLs in other tissues. In addition, 12 of 25 known TN breast cancer risk loci (PEX14, MDM4, 2q31.1, ESR1, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, 19p13.1, MLK1), contained at least one significant cis-eQTL. In summary, we have identified five cis-eQTLs that may identify novel risk loci for TN breast cancer. Citation Format: Kristen S. Purrington, Drakoulis Yannoukakos, Jane Carpenter, Heli Nevanlinna, Angela Cox, Gianluca Severi, Christine Ambrosone, Amanda Ewart Toland, Andrew K. Godwin, Hiltrud Brauch, Peter A. Fasching, Penelope Miron, Jenny Chang-Claude, Nicholas G. Martin, Grant W. Montgomery, Vessela Kristensen, Hoda Anton-Culver, Paul Goodfellow, Janet E. Olson, Hugues Sicotte, Naresh Prodduturi, Daniel W. Visscher, Jeanette E. Eckel-Passow, S. Keith Anderson, Seth Slettedahl, Curtis Olswold, Xianshu Wang, V. Shane Pankratz, Susan Slager, Wei Zheng, Arto Mannermaa, Ute Hamann, Diana M. Eccles, Celine M. Vachon, Fergus J. Couch. Expression quantitative trait locus analysis of triple negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3266. doi:10.1158/1538-7445.AM2014-3266
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-3266
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 4
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    Abstract 4305: Biodistribution and clearance of non-targeted DyLight dyes in tumor-free nude mice for in vivo imaging
    American Association for Cancer Research (AACR) ; 2014
    In:  Cancer Research Vol. 74, No. 19_Supplement ( 2014-10-01), p. 4305-4305
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 4305-4305
    Abstract: Far red to near infra red (NIR) fluorophores are commonly used in cell-based assays and for deep tissue in vivo imaging. The light emitting and physico-chemical characteristics of these fluorophores, e.g. excitation and emission spectra, relative hydrophilicity/hydrophobicity and molecule size, can significantly influence their performance in these applications. Currently there are no guidelines for selection of fluorophores optimal for targeted in vivo imaging. To address this issue we have designed a panel of DyLight dyes with maximum excitation wavelength in the range of 650 -785 nm, maximum emission wavelength in the range of 670 - 800 nm and different levels of sulfonation and/or PEGylation. We studied the kinetic of tissue distribution and clearance of these fluorophores as well as their effect on morphology of different tissues in mice after intravenous injection. Briefly, nude mice were anesthetized, injected with a dye (100 µL of dye at 0.5mg/ml in PBS) into retro-orbital plexus, and imaged using Carestream MSFX or Carestream XTREME Imager. Images were generated before dye injection, immediately after injection (0 hours) and 3, 6, 12 and 24 hours post injection. At the end of the experiment, animals were sacrificed; internal organs were collected and used for ex vivo analysis. The results of in vivo imaging experiments demonstrated that: hydrophobic fluorophores have a relatively slow kinetic of distribution and clearance, and often cleared via a hepatic pathway. Introduction of the negatively charged groups and or PEG chains increased dye solubility affected the kinetics of both fluorophore distribution and its clearance. In addition, negatively charged fluorophores had a tendency to be cleared predominantly via renal pathway. A histological analysis of the internal organs showed no detectable tissue damage. These results provide guidelines for the selection of optimal NIR dyes for in vivo imaging. Citation Format: Marie C. NLEND, Surbhi Desai, Suk J. Hong, Mary Beth Anderson, Georgyi V. Los, Greg T. Hermanson, Justin M. Diener, Warren M. Leevy, Peter A. Bell. Biodistribution and clearance of non-targeted DyLight dyes in tumor-free nude mice for in vivo imaging. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4305. doi:10.1158/1538-7445.AM2014-4305
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2014-4305
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
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  • 5
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    eQTL Set–Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Epidemiology, Biomarkers & Prevention Vol. 31, No. 9 ( 2022-09-02), p. 1735-1745
    Details
    In: Cancer Epidemiology, Biomarkers & Prevention, American Association for Cancer Research (AACR), Vol. 31, No. 9 ( 2022-09-02), p. 1735-1745
    Abstract: Over 20 susceptibility single-nucleotide polymorphisms (SNP) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett esophagus (BE), explaining a small portion of heritability. Methods: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene-expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTL), and set-based SKAT association using selected eQTLs that predict the gene expression. Results: Although the standard approach did not identify significant signals, the eQTL set–based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641, and HSP90AA1). Conclusions: This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set–based genetic association approach. Impact: This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set–based genetic association approach as an alternative method for TWAS analysis.
    Type of Medium: Online Resource
    ISSN: 1055-9965 , 1538-7755
    URL: Article
    DOI: 10.1158/1055-9965.EPI-22-0096
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 6
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    Abstract 4342: Predictive precision medicine platform accurately predicts individual patient response to AML treatments to maximize outcomes
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 7_Supplement ( 2023-04-04), p. 4342-4342
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 4342-4342
    Abstract: Introduction: Offering the optimal frontline treatment to a patient with acute myeloid leukemia (AML) requires trading off expected benefit and risk. Typical standard of care intensive induction chemotherapy (e.g., cytarabine plus idarubicin (7+3)) results in high clinical response rates. However, many patients receive a less intensive regimen (e.g., venetoclax plus decitabine (VenDec)) because their individual toxicity risk is high based on lack of medical fitness. Predicting an individual patient’s clinical response prior to treatment has the potential to increase the benefit/risk ratio (therapeutic index) for some patients and optimize their treatment selection. Here, we demonstrate the ability of an automated high-throughput, multi-color flow cytometry predictive precision medicine platform (PPMP) to predict response to 7+3 or VenDec. Methods: To assess correlation between PPMP-predicted and actual clinical response to 7+3 or VenDec in clinical trial NCT04263181, pre-induction blood samples were collected from 31 patients of which 18 received 7+3 (all newly diagnosed (ND) AML) and 13 VenDec (7 ND AML, 5 secondary AML, 1 MDS). We measured drug effects on leukemic blasts by applying a cutoff at the total blast count that optimizes separation between predicted responders and non-responders (“conventional approach”) or by a machine learning (ML) approach considering multiple cell populations. For the former approach, training sets represented 13 patients for 7+3 and 8 for VenDec. Both 7+3 and VenDec models were validated with 5 patients. For the ML approach, the model was trained on all 13 VenDec patients and monitored using leave-one-out cross-validation. Results: For the conventional approach, predicted and true clinical responses were highly correlated for 7+3 (AUC = 0.91) and VenDec (AUC = 0.81), with 100% precision (positive predictive values (PPV)) for both, i.e., all predicted responders were true clinical responders. Some true clinical responders were not identified (negative predictive value (NPV) = 67% for 7+3 and 57% for VenDec), resulting in an accuracy of 94% (7+3) and 77% (VenDec). To maximize NPV and accuracy for predicting VenDec clinical outcomes, we applied a novel ML-based algorithm to integrate the behavior of malignant and non-malignant cell populations, yielding a model with 100% accuracy (100% PPV and NPV). Additional outcome data, including overall survival, are under evaluation. Summary: Total blast-based predictions yielded accuracies of 94% for 7+3 and 77% for VenDec. An ML algorithm for VenDec considering additional cell populations increased the accuracy to 100%. Further studies will expand patient numbers. We plan to use this platform to inform our frontline decision making with the goal to maximize the therapeutic benefit/risk ratio and ensure that the most appropriate frontline therapy is used for each individual patient. Citation Format: Meagan A. Jacoby, John S. Welch, Peter Westervelt, Matthew Christopher, Geoffrey L. Uy, Ravi Vij, Keith E. Stockerl-Goldstein, Brad S. Kahl, Iskra Pusic, John F. DiPersio, Mark A. Schroeder, Miriam Y. Kim, Todd A. Fehniger, Armin Ghobadi, Christine J. Gu, Wade Anderson, Kathryn Vanderlaag, Kamran Ali, Camille Pataki, Markus D. Lacher. Predictive precision medicine platform accurately predicts individual patient response to AML treatments to maximize outcomes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4342.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2023-4342
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 7
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    Abstract 229: Genome-wide association study by colorectal carcinoma subtype
    American Association for Cancer Research (AACR) ; 2018
    In:  Cancer Research Vol. 78, No. 13_Supplement ( 2018-07-01), p. 229-229
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 229-229
    Abstract: Over 50 genetic variants have been associated with colorectal cancer (CRC) risk through genome-wide association studies (GWAS), yet these variants represent only a fraction of the total estimated heritability. CRC is a heterogenous disease with diverse tumor etiology. Assessing genetic risk in molecular subtypes may help to identify novel loci and characterize genetic risk among tumor subtypes. We used microsatellite instability (MSI), an established CRC classifier with etiological and therapeutic relevance, to define CRC subtypes for GWAS analyses. We conducted a case-case analysis to estimate odds ratios (OR) and 95% confidence intervals (CI) for association of genome-wide variants with microsatellite stable (MSS) versus unstable (MSI) carcinomas. We ran an inverse-variance weighted fixed-effects meta-analysis across GWAS in a discovery set of 4,163 population-based CRC cases with harmonized microsatellite instability (MSI) marker and imputed genotype data. For each analysis, we used log-additive logistic regression, adjusting for age, sex, and principal components to account for population substructure. We then followed up with replication of 102 SNPs that reached p-values less than 5x10-6 in 1,698 cases. A total of 845 (20.3%) cancer cases were microsatellite unstable in the discovery population and 174 (10.2%) were unstable in the replication population. No variants reached the genome-wide significance level of 5x10-8 in the discovery set. However, we identified two variants that reached a Bonferroni corrected p-value of 4.0x10-4 in the replication set. This included one variant in MLH1 (Replication: OR=1.74, 95% CI=1.53-1.98, p=1.63x10-5; Discovery+Replication: OR=1.45, 95% CI=1.37-1.54, p=9.76x10-11) and one variant in LOC105377645 (Replication: OR=1.70, 95% CI=1.49-1.94, p=5.13x10-5; Discovery+Replication: OR=1.45, 95% CI=1.37-1.54, p=9.76 x 10-11). The MLH1 gene is a DNA mismatch repair gene implicated in Lynch Syndrome, the hallmark of which is microsatellite instability. This is the first genome-wide scan to identify a common variant in MLH1 that is associated with CRC. This variant (minor allele frequency, MAF = 23% in this all European ancestry population) is located in the 5'-untranslated region of MLH1 and is thought to act as a long-range regulator of DCLK3, a potential tumor driver gene. The second variant, located in LOC105377645 with an MAF of 22%, is in an uncharacterized region of the genome and has not previously been implicated in cancer development. These findings suggest that accounting for molecular heterogeneity is important for discovery and characterization of genetic variants associated with CRC risk. We plan to run polytomous regression analyses, increase our sample size, and further investigate CRC subtypes by CIMP, BRAF mutation, KRAS mutation status. Citation Format: Tabitha A. Harrison, Yiwen Lu, Chenjie Zeng, Flora Qu, Kristin Anderson, Hermann Brenner, Daniel D. Buchanan, Peter T. Campbell, Andrew T. Chan, Jenny Chang-Claude, Graham G. Giles, Bethany Van Guelpen, Michael Hoffmeister, Mark A. Jenkins, Noralane M. Lindor, Roger L. Milne, Polly A. Newcomb, Reiko Nishihara, Michael O. Woods, Shuji Ogino, John D. Potter, Martha L. Slattery, Wei Sun, Stephen N. Thibodeau, Li Hsu, Ulrike Peters. Genome-wide association study by colorectal carcinoma subtype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philade lphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 229.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2018-229
    RVK:
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    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 8
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    Body Size and Incident Colorectal Cancer: A Prospective Study of Older Women
    American Association for Cancer Research (AACR) ; 2010
    In:  Cancer Prevention Research Vol. 3, No. 12 ( 2010-12-01), p. 1608-1620
    Details
    In: Cancer Prevention Research, American Association for Cancer Research (AACR), Vol. 3, No. 12 ( 2010-12-01), p. 1608-1620
    Abstract: Obesity is a controversial risk factor for colorectal cancer (CRC) in older women. We evaluated associations between multiple body size parameters and incident CRC in the prospective, population-based Iowa Women's Health Study (IWHS). IWHS participants, ages 55 to 69 years, provided data regarding height; weight; weight at ages 50, 40, 30, 18 years; hip circumference; and waist circumference at baseline (1986). Derived variables included body mass index (BMI), waist-to-hip ratio (WHR), and “overweight years” (OWY; conceptually similar to cigarette pack-years). Incident CRC cases (n = 1,464) were ascertained from the State Health Registry of Iowa, through 2005. Multivariable Cox regression models were fit to estimate body size–associated CRC risks. Among 36,941 women (619,961 person-years), baseline height, weight, BMI, hip circumference, waist circumference, and WHR were all positively associated with incident CRC (Ptrend ≤ 0.003 for each). Baseline BMI yielded the highest CRC risk estimates (obese III versus normal, RR = 1.56; 95% CI = 1.10–2.22; Ptrend & lt; 0.001) and was more closely associated with distal than proximal tumors (Ptrend & lt; 0.001 versus 0.06). Conversely, height was more closely associated with proximal than distal tumors (Ptrend & lt; 0.001 versus 0.04). Other body size parameters were less predictive of incident CRC. These data strongly support a positive association between increased body size and CRC risk among older women. Further investigation of when increased body size has the greatest effect on CRC risk (i.e., early adulthood versus later adulthood) might also be informative, particularly with respect to defining subsite-specific pathways of colorectal carcinogenesis. Cancer Prev Res; 3(12); 1608–20. ©2010 AACR.
    Type of Medium: Online Resource
    ISSN: 1940-6207 , 1940-6215
    URL: Article
    DOI: 10.1158/1940-6207.CAPR-10-0116
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 9
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    Alcohol Intake and Colorectal Cancer Risk by Molecularly Defined Subtypes in a Prospective Study of Older Women
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Prevention Research Vol. 4, No. 12 ( 2011-12-01), p. 2035-2043
    Details
    In: Cancer Prevention Research, American Association for Cancer Research (AACR), Vol. 4, No. 12 ( 2011-12-01), p. 2035-2043
    Abstract: Increased alcohol consumption is a putative colorectal cancer (CRC) risk factor. However, existing data are less conclusive for women than men. Also, to date, relatively few studies have reported alcohol-related CRC risks based on molecularly defined tumor subtypes. We evaluated associations between alcohol intake and incident CRC, overall and by microsatellite instability [MSI high (MSI-H) or MSI low/microsatellite stable (MSI-L/MSS)], CpG island methylator phenotype (CIMP positive or CIMP negative), and BRAF mutation (mutated or wild-type) status in the prospective, population-based Iowa Women's Health Study (IWHS; n = 41,836). Subjects were 55 to 69 years at baseline (1986), and exposure data were obtained by self-report. Incident CRCs were prospectively identified and archived, paraffin-embedded tissue specimens were collected from 732 representative cases, diagnosed through December 31, 2002. Multivariate Cox regression models were fit to estimate relative risks (RR) and 95% confidence intervals (CI). Among alcohol consumers, the median intake (range ) was 3.4 (0.9–292.8) g/d. Compared with nonconsumers, alcohol intake levels of 3.4 g/d or less (RR = 1.00; 95% CI, 0.86–1.15) and more than 3.4 g/d (RR = 1.06; 95% CI, 0.91–1.24) were not significantly associated with overall CRC risk. Analyses based on alcohol intake levels of 30 g/d or less and more than 30 g/d or quartile distributions yielded similar risk estimates. Null associations were also observed between each alcohol intake level and the MSI-, CIMP- or, BRAF-defined CRC subtypes (P & gt; 0.05 for each comparison). These data do not support an adverse effect from alcohol intake on CRC risk, overall or by specific molecularly defined subtypes, among older women. Cancer Prev Res; 4(12); 2035–43. ©2011 AACR.
    Type of Medium: Online Resource
    ISSN: 1940-6207 , 1940-6215
    URL: Article
    DOI: 10.1158/1940-6207.CAPR-11-0276
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 10
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    Abstract P1-03-02: CYP2D6 intermediate metabolizers includes patient groups with distinct metabolic activity
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 9_Supplement ( 2015-05-01), p. P1-03-02-P1-03-02
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 9_Supplement ( 2015-05-01), p. P1-03-02-P1-03-02
    Abstract: Background: Tamoxifen is a selective estrogen receptor modulator that is the most commonly used and cost effective hormonal agent for pre-menopausal hormone-receptor positive breast cancer patients. CYP2D6 activity phenotype, which is classified by genotype, predicts the extent of metabolic activation of tamoxifen to endoxifen. We previously reported that increasing the daily dose to 40 mg/day in intermediate metabolizers (IMs), but not poor metabolizers (PMs), achieves target endoxifen concentrations, defined as that of extensive metabolizers (EMs) on 20 mg/day. There was substantial endoxifen variability in the IM phenotype group, which is composed of several discrete diplophenotypes (EM/IM, EM/PM, IM/IM, IM/PM). We enrolled a second, larger cohort of patients in order to determine whether these diplophenotypes should be combined into a single IM phenotype or segregated. Methods: 380 patients on tamoxifen ≥ 4 months and not on potent CYP2D6 inhibiting medications enrolled in Lineberger Comprehensive Cancer Center (LCCC) trial 0801. Genotyping was performed using the Amplichip® CYP450 test (Roche Diagnostics) for CYP2D6, followed by systematic assignment of phenotype based on diplophenotype. Tamoxifen was increased from 20 to 40 mg/day in PMs and IMs. Endoxifen concentrations in IM diplophenotypes were compared with EM/EMs and PM/PMs at baseline and at 4 months (after dose increase in patients with IM and PM phenotypes). Results: After exclusion of UM patients and patients missing endoxifen data at baseline and/or 4 months, 295 patients were included in this analysis. At baseline the EM/IM patients had similar endoxifen level to the EM/EM patients while the IM/IM and IM/PM patients had similar levels to the PM/PMs. After 4 months on 40 mg/day the endoxifen concentrations in EM/IM patients were significantly greater than EM/EMs; EM/PM and IM/IM patients were similar to EM/EMs; but IM/PM patients remained significantly lower than EM/EMs and similar to PM/PMs (See Table 1 for results). Conclusions: The large group of patients currently defined as CYP2D6 intermediate metabolizers is comprised of four distinct CYP2D6 diplophentoypes. The most metabolically active diplophenotype (EM/IM) are very similar to EM/EMs while the least active diplophenotype (IM/PM) are similar to PM/PMs. A more accurate CYP2D6 activity classification system may be necessary if genetic association testing and genotype-guided therapy are pursued. Endoxifen Level at Baseline and 4 Months by CYP2D6 Diplophenotype  Baseline Endoxifen  4-Month Endoxifen  DiplophenotypenMedian (SD)P-val vs. EM/EMP-val vs. PM/PMMedian (SD)P-val vs. EM/EMP-val vs. PM/PMEM/EM11038.67 (6.01)NAp=0.00018.23 (5.09)NAp=0.007EM/IM2568.02 (4.75)p=0.09p=0.00213.11 (9.38)p & lt;0.0001p & lt;0.0001EM/PM2745.72 (4.45)p=0.0001p=0.028.91 (5.28)p=0.42p=0.003IM/IM2174.29 (4.10)p=0.001p=0.266.52 (5.53)p=0.27p=0.24IM/PM2323.90 (3.17)p & lt;0.0001p=0.485.82 (3.47)p=0.0009p=0.77PM/PM3133.33 (2.89)p=0.0001NA6.08 (2.57)p=0.007NA1Diplophenotype classified as extensive metabolizer phenotype, continued on 20 mg/day. 2Diplophenotypes classified as intermediate metabolizer phenotype, changed to 40 mg/day. 3Diplophenotype classified as poor metabolizer phenotype, changed to 40 mg/day. Citation Format: Daniel L Hertz, Anna C Snavely, Howard L McLeod, Christine M Walko, Joseph G Ibrahim, Steven Anderson, Karen E Weck, Peter Rubin, Oludamilola Olajide, Susan Moore, Rachel Raab, Daniel R Carrizosa, Steven Corso, Gary Schwartz, Jeffrey M Peppercorn, James P Evans, Zeruesenay Desta, David A Flockhart, Lisa A Carey, William J Irvin Jr. CYP2D6 intermediate metabolizers includes patient groups with distinct metabolic activity [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-03-02.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS14-P1-03-02
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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