tbuckley/cabot-search huggingface dataset:
Association of Rs1008805 polymorphism in the CYP19A1 gene with the prognosis of early breast cancer.
Authors: Wang Xiao Jia, Xiying Shao, Lei Luo, Yabing Zheng, zhan-Hong Chen
Journal: Journal of Clinical Oncology (2016)

e13026 Background: Aromatase, encoded by CYP19A1 gene, is a rate-limiting enzyme in the conversion of androgens into estrogens. Given the critical role of CYP19A1gene in estrogen synthesis, the potential impact of genetic polymorphisms in CYP19A1 gene on the survival of breast cancer deserves further study. Methods: Rs1008805 polymorphism in CYP19A1 gene were genotyped on 406 Chinese Han women with stage I-II and operable stage III breast cancer. Associations were explored betweenrs1008805 genotypes and disease-free survival (DFS). Results: Totally, there were 200 (49.3%) patients with AA genotype, 169 (41.6%) with AG variant, and 37 (9.1%) carrying GG variant. No significant differences were found in DFS or 5-year survival rate among the whole population with these three genotypes. However, in postmenopausal women, rs1008805 genotypes were significantly related to worse DFS and 5-years DFS rate (AA versus AG versus GG: 63.1 months versus 54.3 months versus 13.7 months; 48.6% versus 46.0% versus 14.3%; P = 0.015). In addition, women with GG variant had a poorer DFS, 5-years DFS rate when compared with those carrying AG or AA genotype (GG versus AG or AA: 13.7 months versus 56.3 months; 0% versus 52.1%; HR, 2.462; 95 % CI, 1.310-4.628; P = 0.004). Being adjusted by patients features in multivariate analyses, GG genotype remained an independent prognostic factor for DFS (HR, 2.706; 95 % CI, 1.393-5.257; P = 0.003). Besides, women with the homozygous minor allele had a marginally improved DFS, 5-years DFS rate when compared with those carrying the common allele (GG versus AG or AA: 87.0 months versus 48.7 months; 60.3% versus 42.7 %; HR, 0.544; 95% CI, 0.295-1.003; P= 0.051). However, there was no relationship between GG genotype and DFS or 5-year DFS when adjusted by patients features in multivariate analyses. Conclusions: The present study demonstrated that homozygous minor allele of rs1008805 SNP in CYP19A1 gene was significantly related to a worse DFS in postmenopausal women with early breast cancer. This founding is novel, if confirmed, CYP19A1 rs1008805 genotypes may turned to be a prognostic biomarker for early breast cancer.
Deliberations of a precision medicine tumor board.
Authors: Sarah A McGraw, Steven Joffe, Judy Ellen Garber, Pasi A. Janne, Neal Ian Lindeman, Nelly Oliver, Lynette M. Sholl, Eliezer Mendel Van Allen, Nikhil Wagle, Levi A. Garraway, Stacy W. Gray
Journal: Journal of Clinical Oncology (2016)

e13005 Background: While precision medicine shows increasing promise in oncology, substantial uncertainty surrounds the interpretation of genomic information and assigning clinical value. We examined the deliberations of a precision medicine tumor board formed as part of the CanSeq project, an institutional cancer precision medicine collaboration. This tumor board, the Cancer Genome Evaluation Committee (CGEC), consisted of 28 oncologists, geneticists, genetic counselors, cancer biologists, ethicists and bioinformaticians. CGEC reviewed somatic and germline whole exome sequencing (WES) results from patients with advanced lung and colorectal adenocarcinoma and determined which results to return to their oncologists. Methods: We employed ethnographic methods by observing meetings and conducting in-depth interviews with committee members over a 14-month period. Meetings and interviews were recorded, transcribed, and coded using both grounded theory and pre-determined codes. Results: Four major qualitative findings emerged from this study. First, despite a rigorous process to curate and annotate WES results, CGEC often confronted large volumes of data with uncertain evidence. Second, to address ambiguities surrounding clinical significance, CGEC sought principles to guide its decisions about return of results. Third, although these principles were predicated on measures of analytic validity and clinical utility, CGEC also weighed implications for the clinicians, patients and families. These included concerns about harmful outcomes due to errors of commission (returning results based on weak evidence) and errors of omission (withholding potentially meaningful results). Finally, social context shaped how CGEC weighed evidence, including the clinical experiences of individual committee members, professional orientation, and group dynamics. Conclusions: Those tasked with determining which genomic results should be returned to clinicians and patients should be aware that their decisions can be shaped by both the available scientific evidence and the larger social context surrounding the deliberation process. These subjective elements, while present in any scientific endeavor, may carry more weight in the face of ambiguous findings.
BRCA testing among Medicare beneficiaries with breast cancer from 2011 to 2013.
Authors: Brygida Berse, Julie Ann Lynch, Nicole Coomer, John Kautter
Journal: Journal of Clinical Oncology (2016)

1588 Background: Used appropriately, BRCA testing can improve health outcomes for breast cancer patients. However, genetic tests have been poorly documented in claims data, electronic health records, and cancer registries, which has impeded health services research on BRCA testing. Until 2013, BRCA tests were offered exclusively by Myriad Genetics. We analyzed characteristics associated with the use of BRCA testing among Medicare beneficiaries in 2011. We also tracked the transition in BRCA testing in 2013, when it was opened to competition and when new, gene-specific billing codes allowed for identification of specific tests in claims. Methods: Using 2011 and 2013 Medicare claims data, we conducted a retrospective cohort study of Medicare fee-for-service beneficiaries diagnosed with breast cancer. The outcome variable was whether the beneficiary had a BRCA claim. Independent variables expected to predict testing were patient age, gender, race, Medicaid status, clinical characteristics, and the hospital referral region (HRR) in which they lived. Results: From 2011 to 2013, the number of beneficiaries with breast cancer who underwent a BRCA test increased from 10,145 to 31,333. Regional factors had the greatest impact on likelihood to be tested, with odds ratios ranging from 0.18 (95% CI 0.04-0.73) for Terre Haute, Indiana HRR to 14.75 (95% CI 4.82-45.19) for Anchorage, Alaska HRR. Each 100 mile increment in distance from an NCI cancer center decreased the likelihood of testing by 11.12%. Other predictors of testing were male gender (OR = 6.33; 95% CI 5.70-7.03) and undergoing another molecular test (OR = 2.76; 95% CI 2.64-2.87). Age, race, Medicaid eligibility, and risk score influenced likelihood of BRCA testing. Conclusions: Data suggest a combination of appropriate use, overutilization, and underutilization of BRCA testing. Consistent with clinical practice guidelines, male breast cancer patients and patients under age 50 are more likely to be tested. However, for many patients, the indication for testing and impact of testing on treatment decisions were not apparent. Practice patterns had the strongest influence on testing. Despite widespread use, minorities and Medicaid recipients are less likely to undergo BRCA testing.
Time-to-Furosemide Treatment and Mortality in Patients Hospitalized With Acute Heart Failure
Authors: Yuya Matsue, Kevin Damman, Adriaan A. Voors, Nobuyuki Kagiyama, Tetsuo Yamaguchi, Shunsuke Kuroda, Takahiro Okumura, Keisuke Kida, Atsushi Mizuno, Shogo Oishi, Yasutaka Inuzuka, Eiichi Akiyama, Ryuichi Matsukawa, Kota Kato, Satoshi Suzuki, Takashi Naruke, Kenji Yoshioka, Tatsuya Miyoshi, Yuichi Baba, Masayoshi Yamamoto, Koji Murai, Kazuo Mizutani, Kazuki Yoshida, Takeshi Kitai
Journal: Journal of the American College of Cardiology (2017)
Identifying actionable mutations in uterine leiomyosarcoma.
Authors: Tara Soumerai, David Michael Hyman, Rajmohan Murali, Ahmet Zehir, Roisin Eilish O'Cearbhaill, Maria E. Arcila, Carol Aghajanian, Robert A. Soslow, David B. Solit, Martee Leigh Hensley
Journal: Journal of Clinical Oncology (2015)

5586 Background: Uterine leiomyosarcoma (uLMS) is a rare gynecologic malignancy affecting 2000 women annually in the United States. Little is known about the genomic basis of uLMS and there are no targeted therapies currently approved for this disease. We aimed to describe the genetic alterations present in a cohort of patients with uLMS in order to identify those that are potentially targetable by available or investigational agents. Methods: Thirty-one tumor samples were prospectively collected from 2/2014 to 1/2015; all had central pathology review at Memorial Sloan-Kettering. Patients were consented to an IRB-approved biospecimen protocol and samples were analyzed in a CLIA-compliant laboratory with the Memorial Sloan-Kettering Integrated Mutation Profiling for Actionable Cancer Targets (MSK-IMPACT). This NGS, bait-capture platform assesses for mutations, copy number variations, and fusions within 341 genes that are common drivers of oncogenic transformation. Variant calls were made against matched germline DNA. Results: All samples were successfully assessed by MSK-IMPACT. The most commonly identified genetic aberrations were deletions/truncating mutations of TP53 in 19 (61%) cases, RB1 in 15 (48%) cases, and ATRX in 10 (32%) cases. MED12 mutations were seen in 3 (10%) cases, 2 of which were hotspot mutations G44A/C. Genetic events activating the PI3K signaling pathway were identified in 9 (29%) cases, including PTEN deletions or truncating mutations, PIK3CA activating mutations, or deletions/mutations of PIK3R1 or PIK3CG. One case was hypermutated (epithelioid LMS) with 65 somatic mutations; this tumor was tested for mismatch repair gene deficiency and showed equivocal immunohistochemistry for MSH6. One case had a BRAF V600E mutation and this patient was enrolled on a clinical trial of a BRAF inhibitor. In total, three (10%) patients have been enrolled in clinical trials of targeted therapy matched to their mutational status. Conclusions: Among 31 patients with uLMS, 10 (32%) were found to have potentially actionable somatic tumor mutations. Genomic characterization of uLMS may offer insights into tumorigenesis and identify potential therapeutic targets in this rare and heterogeneous disease.
First-in-class oral ERK1/2 inhibitor Ulixertinib (BVD-523) in patients with advanced solid tumors: Final results of a phase I dose escalation and expansion study.
Authors: Bob T. Li, Filip Janku, Manish R. Patel, Ryan J. Sullivan, Keith Flaherty, Elizabeth Iannotti Buchbinder, Mario E. Lacouture, Anna M. Varghese, Deborah Jean Lee Wong, Mario Sznol, Jeffrey Alan Sosman, Vicki Leigh Keedy, Andrea Wang-Gillam, Antoni Ribas, Anthony W. Tolcher, Sapna Pradyuman Patel, Mary Laura Varterasian, Dean Welsch, David Michael Hyman, Jeffrey R. Infante
Journal: Journal of Clinical Oncology (2017)

2508 Background: Aberrant MAPK pathway activation is known to be an oncogenic driver in many solid tumors, making ERK inhibition an attractive therapeutic strategy. Ulixertinib is an oral ERK1/2 inhibitor that demonstrated potent activity in vitro and tumor regression in BRAF and RAS mutant xenograft models. Methods: This multi-center phase I trial enrolled patients (pts) with advanced solid tumors. Dose escalation utilized an accelerated 3+3 design; expansion cohorts included BRAF or NRAS mutant melanoma and other BRAF or MEK mutant cancers. Study objectives were to characterize dose limiting toxicities (DLTs), maximum tolerated dose (MTD), toxicity profile, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity by RECIST 1.1. Results: A total of 135 pts were enrolled. Dose escalation enrolled 27 pts (10-900 mg BID) and established the MTD and recommended phase 2 dose (RP2D) of 600 mg BID. DLTs included rash, diarrhea, elevated AST, and elevated creatinine. Drug exposure was dose proportional up to the RP2D, which provided near-complete inhibition of ERK activity in whole blood. In the 108 pt expansion cohort, there were no drug related deaths; however, 32% of pts required a dose reduction. The most common adverse events were rash (49%), diarrhea (47%), fatigue (41%), and nausea (37%). In addition to 3 pts with partial responses during escalation (11%), an additional 9 of 83 (11%) evaluable pts at expansion had a partial response: 1 melanoma pt refractory to prior BRAFi/MEKi treatment, 3 NRAS mutant melanoma pts, 2 pts with BRAF V600E mutant lung cancers including response in brain metastases, 1 with BRAF V600E mutant glioblastoma multiforme, 1 with BRAF G469A head &amp; neck cancer, and 1 with BRAFL485W gallbladder cancer. The duration of response ranged from 2 to 24+ months. Conclusions: Ulixertinib at 600 mg twice a day has an acceptable safety profile and has produced durable responses in pts with NRAS mutant melanoma, BRAF V600 and non-V600 mutant solid tumors including melanoma, glioblastoma multiforme, lung cancers with brain metastases, gallbladder and head &amp; neck cancers. These data support further clinical development of ulixertinib. Clinical trial information: NCT01781429.
SDBC: A novel method for detection of nucleotide changes in cDNA libraries.
Authors: Ovidiu Platica
Journal: Clinical Cancer Research (2007)

A30  SDBC (Simultaneous Detection of Base Changes) is a method for detecting the entire spectrum of mutations and SNPs in a cDNA library without any prior knowledge about the genes carrying those alterations. The method is based on the digestion with Surveyor nuclease of the hybrids formed between the cDNA from the target cells and a reference homologous cDNA library. This enzyme hydrolyses both DNA strands at the site of nucleotide mismatches produced by mutations, polymorphic changes or deletions in one of the DNA strands. The clones opened by nuclease are then re-circularized by ligation of a “stuffer” primer. Then the DNA is transfected into E coli cells, plated and the new library screened with the stuffer probe. The clones containing the stuffer are identified and their plasmid DNA prepared and sequenced with primers included in the stuffer sequence.  The computer analysis of these sequences allows identification of the genes split by the nuclease as well as the accurate site of nucleotide mismatch indicative of the mutation location in the gene sequence.  Using SDBC method we looked for nucleotide changes in the cDNA from DU145 prostatic cancer cell line and a normal prostatic cDNA library as reference. Several clones were analyzed so far and the majority of them were confirmed as known mutations and SNPs.  This method requires about two weeks of bench work up to the sequencing step and can be carried out by any investigator with basic molecular biology experience using standard laboratory equipment.  The SDBC method could have wide applications for biomedical research and patients management.  These include the detection of mutations in the cells exposed to physical, chemical, hormonal and viral agents, the determination of sequential molecular alterations leading to cancer, senescence, degenerative diseases and others.  For cancer patients, SDBC could be used to detect the whole spectrum of mutations in a specific tumor and probably, to predict more accurately the patients9 prognosis and to identify the potential targets for therapy in each individual patient.
Suicide attempts in patients with borderline personality disorder
Authors: M R Fyer, A J Frances, T Sullivan, S W Hurt, J Clarkin
Journal: American Journal of Psychiatry (1988)

Among 180 patients with DSM-III borderline personality disorder, patients with concurrent affective and substance use disorders had a higher rate of serious suicide attempts than other patients. Clinicians should be alert to axis I disorders in assessing suicide potential in borderline patients.
CHANGES IN TORQUE-ANGLE PROFILES OF THE HAMSTRINGS AND HAMSTRINGS-TO-QUADRICEPS RATIO FOLLOWING TWO HAMSTRINGS STRENGTHENING EXERCISE INTERVENTIONS IN FEMALE HOCKEY PLAYERS
Authors: Anne Delextrat, James Bateman, Vanrenterghem Jos, Cohen Daniel
Journal: British Journal of Sports Medicine (2017)

Background Field hockey is characterised by high rates of hamstings strain injuries (HSI). While the Nordic Hamtrings (NH) is the most commonly used exercise in the prevention and rehabilitation of HSI, no study has investigated its isolated benefits compared to other well-established exercises in hockey players. Objective To compare the effects of two hamstring strengthening interventions (nordic hamstrings (NH) vs. eccentric leg curl (ELC)) on the hamstrings torque-angle profiles and functional hamstrings-to-quadriceps ratio (H ecc :Q con ) in female hockey players. Design A randomised-control trials with repeated measures was used. Settings The intervention for this study was used during practice sessions of university-level hockey players. Participants Female university-level players were randomly allocated to a NH (n=9, age: 19.7±1.4 years; height: 168.4±4.4 cm; body mass: 66.2±7.2 kg), ELC (n=8, age: 19.5±1.0 years; height: 168.1±3.4 cm; body mass: 66.7±4.5 kg), and C (n=8, age: 19.6±1.4 years; height: 169.9±7.5 cm; body mass: 70.7±13.0 kg) groups. Main Outcome Measurements Isokinetic concentric strength tests of the quadriceps (Q con ), eccentric strength of the hamstrings (H ecc ) at 120°.s −1 , and H ecc :Q con. Interventions Six-week intervention with ELC, NH or no (C) exercises performed three times weekly, before redoing the baseline strength assessments. Analyses of variance with repeated measures were used to assess the effects of angle, group and time on outcome measures. Results Significant increases were observed in H ecc and H ecc :Q con after the NH (+29.9% and +27.8%) and ELC (+30.5% and +38.3%) in the non-dominant leg only. Furthermore, significant shifts in the hamstrings eccentric APT towards a longer muscle length were shown in both legs (14.3 to 28.6%). Conclusions These findings suggest that NH and ELC both resulted in significant improvements in peak and muscle length specific neuromuscular risk factors in the weaker limb, thereby reducing interlimb peak strength asymmetries.
评论：肝功能检测：确定何为正常
Authors: PaulRoderick, 邓瑞雪, 陆星华
Journal: BMJ (2004)

在病毒性肝炎(乙型和丙型)高发的国家，慢性肝炎和肝细胞癌是一个突出的公共卫生问题。即使在西方国家，慢性肝病问题也日益明显，不仅是由于病毒性肝炎，而且由于生活方式的影响，如酗酒和肥胖。
A pilot phase II trial of cabergoline in the treatment of metastatic breast cancer.
Authors: Ricardo Lima Barros Costa, Cesar Augusto Santa-Maria, Denise M. Scholtens, Sarika Jain, William John Gradishar, Charles V Clevenger, Virginia G. Kaklamani
Journal: Journal of Clinical Oncology (2017)

e12568 Background: The prolactin receptor can be overexpressed in breast cancer, and pre-clinical data indicate that it contributes to the pathobiology of breast cancer. Cabergoline is a potent dopamine receptor agonist of D2 receptors and has a direct inhibitory effect on pituitary prolactin secretion resulting in reduced serum prolactin levels. Methods: A pilot phase II study of cabergoline in patients with metastatic breast cancer was conducted with primary end point of best overall response rate (ORR) among patients with measurable disease. Eligible patients had metastatic breast cancer, any receptors status was allowed, and there was no limit of prior lines of therapy. Both measurable and unmeasurable diseases (RECIST 1.1) were allowed. Cabergoline 1mg orally, twice weekly (1 cycle = 4 weeks) was given until disease progression or unacceptable toxicity. Immunohistochemistry prolactin receptor staining was performed on available baseline tumor tissue, and serum prolactin levels were serially assessed. Results: A total of 20 women were enrolled, 19 of whom were evaluable for response (one patient died on C1D7 of unrelated causes). Mean age was 62 (range 42-83); 15 (75%) were Caucasian; mean number of prior lines of therapy 5 (range 0-14). Tumor receptor statuses were distributed as follows: HR+/HER2+ 1(5%), HR+/HER2- 18 (80%), HR-/HER2+ 1 (5%). Analysis was performed after a median follow-up of 6.8 months (0.2-26.2). Best ORR was 8.3% among 12 patients with measurable disease. Results for secondary endpoints were as follows: 4-month CBR = 26% (including patients with measurable and non-measurable disease), median PFS = 1.9 months, and median OS = 10.4 months. Most common treatment related AEs were nausea (30%), fatigue (25%), and elevation in alkaline phosphatase (15%). The highest-grade AE was a single grade 3 treatment-related pain in extremity. Nine patients had sufficient baseline tissue for analysis, there was no correlation between baseline tumor prolactin receptor expression and clinical benefit ( p= 0.24). Additional correlative work is ongoing. Conclusions: Cabergoline was well tolerated and associated with modest anti-tumor activity. Clinical trial information: NCT01730729.
Update on anti-tumor necrosis factor agents and other new drugs for inflammatory bowel disease
Authors: Benjamin L Cohen, David B Sachar
Journal: BMJ (2017)

The treatment of inflammatory bowel disease (IBD)—ulcerative colitis (UC) and Crohn's disease (CD)—has evolved beyond surgery with the introduction of biologic agents, primarily antibodies against mediators of inflammation and cell attraction. Anti-tumor necrosis factor (TNF) agents have been the first line treatment for moderate to severe ulcerative colitis and Crohn's disease for more than 15 years. During that time much has been learnt about how best to use these agents. This review will assess the evidence on how to optimize the use of anti-TNF agents; when and how to start treatment; how to monitor treatment and when to de-escalate it; and the potential adverse effects of these drugs. New and emerging treatments such as anti-attractants, anti-interleukins, and Janus kinase (JAK) inhibitors will also be discussed.
Racial disparities among patients with metastatic lung disease.
Authors: Nauman Saleem Siddiqui, Zarmina Khan, Cherian Verghese, Toseef Javaid, Jamal Saleh, Syed Hasan, Iman Mohamed, Sadik Khuder
Journal: Journal of Clinical Oncology (2016)

e13070 Background: Lung cancer is the most common cause of cancer related mortality worldwide. The majority of patients present with advanced disease and significant number of patients develop metastases during the course of their disease. We wanted to evaluate metastatic lung disease (MLD) across different racial groups in patients admitted nationwide. Methods: We conducted a retrospective analysis using the 2010–2012 Healthcare Cost and Utilization Project –Nationwide Inpatient Sample (HCUP-NIS). Lung cancer patients were identified by CCS diagnosis 19. MLD was identified from the NIS Disease Severity Measures File. We used SAS survey logistic regression procedure to examine MLD differences among racial groups and adjusting for the confounding effect of age, gender, smoking, and median house hold income. Results: Our analysis consisted of 236521 lung cancer admissions over three years. About 25.2% were found to have metastatic disease. The percentage of MLD was significantly higher in male (P < 0.0001). Compared to White, Hispanics and Asians had significantly higher of MLD (OR = 1.05, P = 0.0297 and OR = 1.12 P < 0.0001 respectively). A similar but not significant trend was noted for Blacks. Patients who were reported to be smokers were found to have greater risk of MLD (OR = 1.24, P < 0.0001). Conclusions: The finding of this study indicates differences in MLD by race and gender. Higher frequencies of MLD in Hispanic and Asian individuals may indicate health care disparities among racial groups. The gender differences may be explained by different patterns of smoking in male and female. Health care access issues as it relate to lung cancer management need to be evaluated further.