bluuebunny/crossref_metadata_2025_split huggingface dataset:
Localization of non-receptor tyrosine kinase (nRTK) variants in solid tumor patients using next-generation sequencing (NGS).
Authors: Sareen Srishti , Stein Matthew , Morris Lindsay Kaye , Karri Saradasri , Patel Kruti , Shibata David , Vanderwalde Ari M. , Schwartzberg Lee Steven , Martin Michael Gary 
Published: September 2018

1536 Background: Non-synonymous SNPs (nsSNPs) in nRTKs may serve as oncologic targets and predictive biomarkers, with significant lesions described in various nRTK regions including the tyrosine kinase domain (TKD). NGS allows the entire coding sequence to be evaluated, facilitating the identification of novel lesions. Methods: We searched all nsSNPs in 14 nRTKs in the tumors of patients (pts) at our institution that received NGS with Caris from 2013-2015 with a diagnosis of advanced breast, colon or lung cancer. Substitutions were classified as either within or extra-TKD; in the case of JAK1-3, pseudokinase domain lesions were also identified. In order to predict the pathogenicity of nsSNPs, in silico analysis with PolyPhen-2 (Harvard) was completed. Results: 356 pts (79 breast, 110 colon and 165 lung (156 NSCLC, 11 small cell)) were identified with a median age of 61 years (range 26-86); 58% female; 62% white, 35% black. 245 variants were found, with 200 nsSNPs and 45 known pathologic mutations (Pmut); Pmut were PIK3CA (21 breast, 13 colon, 5 NSCLC) and AKT1 (6 breast). 169/356 (47%) pts had ≥1 nRTK lesion (0-8). 52/200 (26%) nsSNPs were predicted-damaging (pnsSNPs) with in silico analysis among 49 pts (6 breast, 13 colon and 30 NSCLC). pnsSNPs were found in 14/14 nRTKs with median 3 (1-10). The most frequently mutated nRTKs in breast were SRC (2/2 variants were pnsSNPs) and ABL2 (1/5); in colon ABL1 (5/10), JAK3 (3/27) and CDK12 (2/8); and in NSCLC JAK3 (6/20), BTK (5/8), ABL1 (3/12), JAK2 (3/11), CDK12 (3/9) and JAK1 (3/3). Of 180 nsSNPs with in silico results, 68% were extra-TKD (29/122 variants were pnsSNPs), 23% within the TKD (13/42) and 9% in pseudokinase domains of JAK1-3 (10/16). Notably, 8/10 pseudokinase domain pnsSNPs were in NSCLC pts (3 JAK1, 2 JAK2 and 3 JAK3). Conclusions: > 13% solid tumors held an nRTK nsSNP that was predicted-damaging by in silico analysis, with 69% of these mutations occurring outside of the TKD-proper. Further work is needed to determine how these pnsSNPs affect function and if they are clinically actionable.
The relationship between statins and colorectal cancer stage in the Women's Health Initiative.
Authors: Rutledge Brian , Desai Pinkal M. , Abdel-Rasoul Mahmoud , Nassir Rami , Qi Lihong , Luo Juhua , Liu Simin , Arun Monica , Simon Michael S. 
Published: September 2018

1540 Background: Statins are the most widely prescribed cholesterol-lowering drugs in the United States. The anti-carcinogenic effect of statins may reduce the metastatic potential of cancer cells leading to ‘stage migration’ with users more likely diagnosed with early rather than late stage cancer. We evaluated the relationship between prior statin use and colorectal cancer (CRC) stage at diagnosis in the Women’s Health Initiative (WHI). Methods: The study population included 132,322 post-menopausal women aged 50-79 years, among which there were 2,628 pathologically confirmed cases of insitu (3.3%), local (43.6%), regional (40.4%) and distant (12.7) stage CRC, after an average of 13.9 (SD = 4.7) years of follow-up. To reduce the possibility of detection bias among women more likely to be prescribed statins, we excluded women who did not report a mammogram within 5 years of study entry and who had no health insurance or medical care provider (n = 28,237). Stage was coded using criteria implemented in the Surveillance, Epidemiology and End Results (SEER) Program into early (in situ and local) vs. late (regional and distant) stage disease. Information on statin use prior to diagnosis was collected by self and interviewer-administered questionnaires at baseline and at one, three, six and nine years post-baseline. Self- and interviewer-administered questionnaires were used to collect risk factor information. Hazards ratios (HR) and 95% confidence intervals (CIs) evaluating the relationship between statin use at baseline only, and in a time-dependent manner, and diagnosis of late-stage CRC were computed from multivariable-adjusted Cox proportional hazards analyses. Statistical tests were two-sided. Results: Statins were used by 10,868 women (8%) at baseline. There was no significant relationship between statin use at baseline and late stage CRC cancer (HR = 1.03, 95% CI (0.82-1.30) and no significant association by type of statin or duration of use. In the multivariable-adjusted time-dependent model, use of statins was associated with a reduction in diagnosis of late-stage colorectal cancer (HR 0.79, 95% CI 0.67-0.94, p = 0.007). Conclusions: Prior statin use may have an influence on colorectal cancer stage at diagnosis.
Use of a marketing plan for recruitment to a lung cancer screening study.
Authors: Goffin John R. , Pond Gregory Russell , Tremblay Alain , Johnston Michael R. , Goss Glenwood D. , Nicholas Garth Andrew , Martel Simon , Bhatia Rick , Liu Geoffrey , Roberts Heidi , Tammemagi Martin , Atkar-Khattra Sukhinder , Tsao Ming Sound , Lam Stephen C. , Rudkowski Janice ,   Pan-Canadian Early Detection of Lung Cancer Study Research Team
Published: September 2018

1548 Background: Recruitment to clinic trials is typically poor. Among barriers to recruitment may be the limited knowledge of trialists with respect to marketing techniques. Improvements in marketing could decrease recruitment time and shorten the time to access new interventions. We hypothesized that a marketing plan would improve recruitment to a lung cancer screening study. Methods: The Pan-Canadian Early Detection of Lung Cancer Trial recruited subjects from 8 centres to a screening study of low-dose CT scan and autofluorescence bronchoscopy. Recruitment processes were undertaken independently at each centre. One centre (M) used marketing expertise and a marketing plan, including surveying study candidates for motivators, resulting in specific newsprint advertisements. Screened trial candidates provided demographic and tobacco use data and indicated how they had heard about the study (bus, friend/family, MD, mail, newsprint, radio, TV, other). No site paid for radio or TV time. We used regression analyses to assess whether newsprint advertisements were more effective for recruitment at site M compared with all other sites. Results: From 2008 to 2010, 7059 candidates contacted all centres for eligibility screening, including 779 at centre M. Overall, 50.2% were female; median age was 59 yrs. Compared with other centres, candidates at centre M had less education (p < 0.001), a higher median 3-year lung cancer risk (2.3 vs 2.0%, p < 0.001), but were more likely to have learned of the study by newsprint (58.8 vs 53.3%, chi-squared p = 0.004), and were more likely to be recruited (44.0 vs 34.9%, p < 0.001). It was more likely that newsprint was the driver for screening contact among candidates with higher education level (OR 1.05/level), higher age (OR 1.03 / yr) and contact at site M (OR 1.31) (all < 0.001). Recruitment after eligibility screening was higher when newsprint was the driver for contact on univariable but not multivariable analysis. Conclusions: The effectiveness of newsprint advertising in motivating study contact may be improved by the formal use of marketing expertise. Newsprint advertising may improve the likelihood of recruitment after study screening, possibly through improved initial self-screening by the candidate. Clinical trial information: NCT00751660.
Risk factors of colorectal adenoma recurrence among individuals under 50 years of age compared to those 50 years of age or older.
Authors: Molmenti Christine Louise Sardo , Yang Jingyan , Thomson Cynthia A , Hibler Elizabeth A , Ho Gloria , Neugut Alfred I. , Lance M Peter , Alberts David S. , Jacobs Elizabeth T 
Published: September 2018

1554 Background: Colorectal cancer incidence and mortality are increasing among individuals < 50 years of age. Data are limited regarding the epidemiology of colorectal adenomas in this younger age group. This study investigated and compared risk factors associated with recurrence of adenomas in individuals under and over 50 years of age. Methods: Pooled analyses from the Wheat Bran Fiber and Ursodeoxycholic Acid phase III, randomized, controlled clinical trials included 1,623 participants, aged 40-80 years. Each completed baseline questionnaires related to family history and lifestyle habits, had one or more colorectal adenomas removed at baseline, and had a follow-up colonoscopy during the trial (mean follow up 36 months). Univariate and multivariate logistic regression modeling estimated the association between age and colorectal adenoma recurrence, and evaluate multiple risk factors, while controlling for confounding factors. Results: A statistically significant increased trend was found for colorectal adenoma recurrence with increasing age ( Ptrend= < 0.001). Multivariate logistic regression revealed that risk factors significantly associated with adenoma recurrence in the ≥50 age group (n = 1,523) included history of previous polyps, characteristics of adenomas removed at baseline (multiple adenomas and villous feature), current smoking, and an increased waist circumference. Although risk profile in the < 50 age group (n = 95) shared similarities with that in the ≥50 age group (e.g., current smoking), there were a few notable differences: history of previous polyps was a more prominent predictor for recurrence for the < 50 (OR< 50 = 4.76 and OR≥50 = 1.33, Pinteraction = 0.042), whereas baseline characteristics of adenomas were more important for the ≥50 (multiple adenomas: OR< 50 = 0.40 and OR≥50 = 2.28, Pinteraction = 0.043). Conclusions: Predisposition to colorectal adenoma is a more important risk factor for recurrence in the < 50 as compared to the ≥50. Future studies need to identify susceptibility factors contributing to the increasing incidence of colorectal cancer in this younger age group.
High accumulation of metformin in colonic tissue of subjects with diabetes or metabolic syndrome.
Authors: De Censi Andrea , Burhenne Juergen , Haefeli Walter E. , Weiß Johanna , Roth Wilfried , Parodi Andrea , Gnant Michael , Bachleitner-Hofmann Thomas , Scherer Dominique , Ulrich Neli , Štabuc Borut , Petrera Marilena , Puntoni Matteo , Coccia Gianni , Paleari Laura 
Published: September 2018

1557 Background: Epidemiological studies consistently observed an association between metformin use in diabetic patients and decreased colon cancer incidence and mortality at clinical doses (1500-2250 mg day), corresponding to plasma levels of 0.003-0.045 mM. Preclinical models report much higher doses of metformin, ranging between 1 and 40 mM for in vitro and 0.006-0.145 mM for in vivo studies. A recent trial using a low dose of metformin (250 mg/day, Higurashi T et al. Lancet 2016;17:475) showed a 40% reduction of colorectal adenoma recurrence. We performed a pilot study to measure metformin in plasma and colonic tissue of subjects with diabetes or metabolic syndrome and to explore their correlation with different tissue biomarkers, including Ki-67, pS6k, a mTOR effector protein, and EGFR expression. Methods: We used LC-MS/MS to quantify metformin in plasma and colonic tissues from 13 volunteers with diabetes or metabolic syndrome undergoing screening colonoscopy. All patients had received metformin at 1000-1850 mg/day for a median of 6.5 yrs (range 2-15), except for one who served as untreated control. Tissue quantifications were performed on specimens derived from right and left colon biopsies with or without washing to exclude a potential contamination due to lumen accumulation by the drug. Biomarker assessment was performed by standard IHC assay. Results: The mean plasma metformin was 0.025 mM/L (range 5x10-5-0.017), whereas the colonic tissue was ~100 fold higher in right [0.39 mM/Kg (range 0.034-1.75)] and left colon [0.46 mM/Kg (range 5x10-3-1.86)]. There was no significant difference between washed and unwashed biopsies. No significant correlations were detected between metformin levels in plasma/tissue and tissue biomarkers. Conclusions: Metformin can attain ~100 fold higher colonic tissue levels than in plasma. These levels are in the range of a direct antitumor effect observed in in vivo preclinical models. A two-by-two clinical trial of metformin and aspirin in colon cancer patients is underway by our group to further elucidate independent and synergistic antitumor effects.
Breast cancer in male veterans: The Veterans Affairs (VA) informatics and computing infrastructure (VINCI) big data analysis.
Authors: Aggarwal Anita , Maron David , Krasnow Steven H. 
Published: September 2018

1559 Background: Male breast cancer (MBC) management from diagnosis to treatment is generalized from female breast cancer (FBC) because of its rarity and paucity in literature. VINCI is a unique database for cross sectional and longitudinal analysis. The objective of this retrospective analysis was to compare characteristics and outcome of MBC with FBC in veterans. Methods: Detailed demographics, diagnosis, treatment and outcome of all patients diagnosed with breast cancer between 1998 and 2016 at 152 VA medical centers were obtained and analyzed with Chi-square and t-test univariate statistics. Results: In total 9765 patients' records were reviewed, 1613 MBC were compared with 8152 FBC. The mean age at diagnosis is 68.5 and 57.3 years for MBC and FBC, respectively (Table1). After a median follow up of 3.5 years, 48% MBC and 22% FBC died. Breast cancer mortality is 18% and 9% in MBC and FBC, respectively. A cox regression survival analysis indicates that males were 33% (Hazard Ratio 1.33, P=<0.0001) more likely to die from breast cancer than females. Conclusions: This is the largest comparison series of MBC with FBC to date in the Veteran population to author’s knowledge. Males have higher breast cancer specific mortality than females most likely because of older age and higher stage at the time of diagnosis. Differences in the biology and pathology may be contributing factors which needs further prospective studies. [Table: see text]
Socio-demographic variations in lung cancer screening before and after USPSTF recommendation: Results from national health interview surveys (NHIS).
Authors: Wang Qian , Jiang Changchuan , Deng Lei , Zhang Yaning , Sara Gabriel Albert 
Published: September 2018

1563 Background: In 2013, USPSTF recommended low-dose CT screening (LCS) for lung cancer in high-risk adults. The change in real-world practice is largely unknown, as well as the association with socio-demographic factors. Methods: Data were extracted from the population-based 2010 and 2015 NHIS. LCS was defined as a chest CT to check for lung cancer within the past year. We included adults aged 55 to 80 years who 1) have 30+ pack-year smoking history; 2) are currently smokers or have quitted within the past 15 years. We excluded adults who 1) have lung cancer; 2) had not seen a physician in the past year. We used weighted analyses to estimate national lung cancer screening rates. Results: A total of 874 and 1041 high-risk smokers responded to the LCS questions for lung cancer in 2010 and 2015, respectively. The screening rate more than doubled from 4.1% to 9.1% (P < 0.01) in all respondents. The increase was greater in women (2.9% to 9.5%, p < 0.01) than men (5.2% to 8.8%, p = 0.03) and in age 65-80 (4.7% to 12.3%, p < 0.01) than age 55-64 (3.8% to 6.3%, p = 0.16). White saw the largest increase and highest rate in 2015 (4.0% to 9.3%, p = < 0.01). Those with some college or above education had the highest rate in 2010, but the lowest in 2015. Household income above 75,000 dollars was associated with the lowest rate in both 2010 and 2015. Conclusions: Since the recommendation of USPSTF, LCS rate for lung cancer has doubled but remains less than 10%. Higher education and household income are associated with lower screening rate, in contrast to studies of other cancers. [Table: see text]
Germline mutations in cancer predisposition genes among patients with thyroid cancer.
Authors: Kamihara Junne , LaDuca Holly , Dalton Emily , Speare Virginia , Garber Judy Ellen , Black Mary Helen 
Published: September 2018

1581 Background: Thyroid cancers are known component tumors of both well-described and emerging hereditary cancer syndromes. To assess the contribution of germline variants in thyroid cancer predisposition, we examined the prevalence of germline mutations among individuals with a history of thyroid cancer, compared to those with thyroid and breast cancer or breast cancer alone. Methods: Clinical histories and molecular results were reviewed for individuals with a history of thyroid and/or breast cancer, ascertained from a cohort of > 140,000 patients who underwent hereditary cancer multigene panel testing at a single commercial laboratory. Clinical history information was obtained from test requisition forms completed by ordering clinicians and from pedigrees/clinic notes, if provided. Results: Among 2,678 thyroid cancer patients, the majority were Caucasian (66.9%), female (92.3%), and/or had an additional cancer primary (71.9%), with nearly half reporting an additional breast cancer primary (49.1%). Among those with available pathology information, 4.1% had medullary thyroid cancer. The median (IQR) age at diagnosis was 38 (26,48) years, and while 94.1% had a family history of cancer, 78.8% had at least one affected 1st degree relative. Overall, 11.1% were identified as mutation carriers, defined as ≥1 pathogenic or likely pathogenic variant. Among those with thyroid cancer alone, 9.7% had a mutation, similar to those with breast cancer alone (9.7%) and those with breast and thyroid cancer only (10.5%). Genes most frequently mutated in the thyroid only group included CHEK2 (3.1%), MUTYH (monoallelic) (2.4%), APC (2.0%), ATM (1.6%), and PALB2 (1.2%). CHEK2 was the most frequently mutated gene observed in all groups, with a higher frequency seen among those with thyroid and breast cancer (5.5%) compared to breast cancer (2.5%) or thyroid cancer (3.1%) alone (p < 0.001). Conclusions: A high rate of germline mutations is observed among individuals with thyroid cancer presenting for clinical genetic testing, even in the absence of other primary cancer diagnoses. Thyroid cancer may be an under-recognized component tumor of hereditary cancer predisposition syndromes suggesting the need for further investigation.
Are we still adjusting to multigene panel testing? An NCI-designated cancer center's 2-year experience.
Authors: Ramamurthy Chethan , Hitrik Mark A. , DeMora Lyudmila , Forman Andrea , Rainey Kim , Savage Michelle , Montgomery Susan , Masny Agnes , Schwartz Sharon , Hall Michael J. , Daly Mary Beryl , Obeid Elias 
Published: September 2018

1585 Background: Genetic testing for hereditary cancer predisposition has rapidly changed over the past few years with the introduction of multigene panel testing. Multigene testing has evolved from disease-agnostic comprehensive (C) panels alone to include disease-specific but expanded (DSE) panels as well as guideline-based (GB) panels. We analyzed trends in utilization of genetic testing over a two-year period in one NCI-designated Cancer Center, hypothesizing that over time genetic testing usage would trend toward more disease-specific panels. Methods: We conducted a retrospective analysis of our program’s database for all germline genetic tests ordered from 9/1/2013 to 8/31/2015 (n = 619; 246 in year 1, and 373 in year 2). Tests were categorized into three groups based on specificity: GB (range: 2-12 genes tested), DSE (12-35 genes tested), and C (28-80 genes tested). The Chi-square test was used to analyze test types ordered in year 1 (9/1/2013-8/31/2014) and year 2 (9/1/2014 – 8/31/2015) and the proportions of resulting mutation types. Results: A total of 604 germline genetic tests met the inclusion criteria: 39 GB (20 year 1, 19 year 2), 171 DSE (43 year 1, 128 year 2), and 394 C (180 year 1, 214 year 2). Compared to year 1, a larger proportion of DSE tests (35% v. 18%, p < 0.001), and a smaller proportion of C tests (59% v. 74%, p < 0.001) and GB tests (5% vs. 8%, p = 0.146) were ordered. DSE panels revealed a pathogenic variant (PV) at a rate of 16% and a variant of unknown significance (VUS) at a rate of 24%. C tests revealed a PV and VUS at rates of 14% and 29%, respectively. GB tests revealed a PV and VUS at rates of 21% and 18%, respectively. No statistically significant differences in detection rates of mutation types (PV or VUS) were found between GB, DSE, or C tests. Conclusions: The rates of PV detection were not significantly different between test types, but the profile of tests ordered changed over time to favor DSE panels. Exploration of factors contributing to changing trends in genetic testing are warranted as counselors and clinicians adapt to the quickly expanding number of genes associated with hereditary cancer risks, many of them moderate-risk, and the evolving landscape of multigene panel testing.
Decision support for family history intake to determine eligibility for BRCA testing among multiethnic women.
Authors: McGuinness Julia E. , Trivedi Meghna S. , Vanegas Alejandro , Colbeth Hilary , Sandoval Rossy , Kukafka Rita , Crew Katherine D. 
Published: September 2018

1586 Background: The U.S. Preventive Services Task Force (USPSTF) recommends that women who meet family history criteria for hereditary breast and ovarian cancer (HBOC) be referred for genetic counseling. However, HBOC genetic testing is under-utilized, particularly among racial/ethnic minorities. We evaluated different methods of family history intake, including a validated family history screener, documentation in the electronic health record (EHR), and a web-based decision aid (DA). Methods: Among women undergoing screening mammography, we administered a validated family history screener to determine eligibility for BRCA genetic testing based upon USPSTF guidelines. We developed a patient-centered DA ( RealRisks) which includes modules on breast cancer risk, collection of detailed family history, and information on HBOC genetic testing. Women who met high-risk criteria for breast cancer were enrolled in an intervention trial to determine whether exposure to RealRisks increases referrals for high-risk consultations. BRCA genetic counseling/testing uptake was assessed by self-report and EHR review. Results: From November 2014 to June 2016, 3077 women completed the family history screener. Median age was 59 years (range, 29-99), including 76% Hispanic, 4% Ashkenazi Jewish, and 60% with a high school education or less. 12% met family history criteria for BRCA genetic testing based upon the family history screener, of which only 5.9% had previously undergone genetic counseling or testing. Sixty high-risk women were enrolled to access RealRisks. When family histories based upon the screener, DA, and EHR were compared, 12 (20%) had discrepancies in number of affected relatives, type of cancer, and age at diagnosis which changed eligibility for BRCA testing. Follow-up is ongoing to determine whether the DA facilitates appropriate referrals for genetic counseling. Conclusions: In a population of predominantly Hispanic and less educated women, a large proportion met USPSTF family history criteria for BRCA testing, but uptake of genetic counseling was low. Developing decision support for accurate family history intake is critical to identifying appropriate candidates for genetic referrals.