tbuckley/cabot-search huggingface dataset:
Assigning clinical meaning to somatic and germline whole exome sequencing data to guide cancer precision medicine.
Authors: Arezou A Ghazani, Nelly Oliver, Joseph P St. Pierre, Andrea Garofalo, Lynette M. Sholl, Neal Ian Lindeman, Judy Ellen Garber, Steven Joffe, Pasi A. Janne, Stacy W. Gray, Levi A. Garraway, Eliezer Mendel Van Allen, Nikhil Wagle
Journal: Journal of Clinical Oncology (2016)

11565 Background: Implementing cancer precision medicine requires interpretation of each potentially clinically relevant and biologically meaningful genomic alteration to aid clinical decision-making. We developed a systematic approach to this challenge through the CanSeq program, a prospective study of tumor and germline whole exome sequencing (WES) in patients with metastatic colorectal and lung cancer. Methods: WES was performed on DNA extracted from FFPE tumor biopsies and matched blood samples from 242 patients. Data were analyzed to identify point mutations, indels, and copy number alterations. Variants were ranked according to therapeutic and biological relevance using PHIAL, an analytical software tool. Levels of evidence were assigned to clinical implications associated with each variant. Decisions to return results to participants were initially made by a molecular tumor board, and ultimately evolved to a guideline-based interpretive algorithm to allow scalability. Results: 165/242 participants have had WES analyzed, interpreted, and returned to their clinical team. Of 768 somatic variants evaluated, 511 (67%) were determined to be potentially clinically relevant and reported to clinical teams. Of these, 31% classified as having clinical evidence, 21% pre-clinical evidence, and 48% theoretical/inferential rationales. Among 806 curated germline variants, only 5% were deemed clinically relevant and reported to clinical teams. Among returned germline variants, 47% were classified as pathogenic, 16% as likely pathogenic, and 37% as variants of uncertain significance in a gene related to the patient’s cancer. In total, 91% of patients had an actionable or potentially actionable somatic alteration; 21% had at least one reported germline alteration. Conclusions: This systematic interpretive framework effectively identifies clinically relevant somatic and germline alterations. There was a significant difference in the proportion of reported somatic and germline alterations. Although the majority of cases harbored at least one potentially clinically relevant somatic alteration, we observed wide variations in the strength of evidence associated with these alterations.
Comprehensive analyses of long non-coding RNA expression profiles in NSCLC identified AFAP1-AS1 as a prognostic biomarker.
Authors: Wenjia Xia, Mantang Qiu, Youtao Xu, Rong Yin, Gaochao Dong, Jie Wang, Lin Xu
Journal: Journal of Clinical Oncology (2016)

e13019 Background: Increasing evidence has highlighted the critical roles of long non-coding RNAs (lncRNAs) as biomarkers and therapeutic targets for cancer. Expression profiles of lncRNAs could provide insights into the biology, prognosis, and molecular classification of non-small cell lung cancer (NSCLC). Methods: 463 tissue samples which were analyzed by Affymetrix HG-U133Plus 2.0 arrays were retrieved from the Gene Expression Omnibus database. The probe sets were annotated for lncRNA according Ref-seq database. Quantitative real-time PCR (qRT-PCR) and in situ hybridization was performed to detected lncRNAs expression in tissue microarray. Results: LncRNA expression profile remarkably differs between NSCLC and normal samples, and 856 differentially expressed lncRNAs were identified. Bioinformatics analyses showed that these lncRNAs were located nearby transcription start sites and key regulators of cancer and these lncRNAs were involved in many critical biological processes. We found AFAP1-AS1 was highly expressed in NSCLC and its expression indicated poor prognosis of NSCLC according to published microarray data. ISH and TMA validated the overexpression of AFAP1-AS1 and AFAP1-AS1 was an independent prognostic factor for NSCLC (HR = 4.128, 95% CI: 1.414-12.053, P= 0.010). Conclusions: Many lncRNAs are aberrantly expressed in NSCLC and their expression profiles, like AFAP1-AS1, may be a valuable predictive marker of clinical outcome.
A tripartite complex of suPAR, APOL1 risk variants and αvβ3 integrin on podocytes mediates chronic kidney disease
Authors: Salim S Hayek, Kwi Hye Koh, Morgan E Grams, Changli Wei, Yi-An Ko, Jing Li, Beata Samelko, Hyun Lee, Ranadheer R Dande, Ha Won Lee, Eunsil Hahm, Vasil Peev, Melissa Tracy, Nicholas J Tardi, Vineet Gupta, Mehmet M Altintas, Garrett Garborcauskas, Nikolina Stojanovic, Cheryl A Winkler, Michael S Lipkowitz, Adrienne Tin, Lesley A Inker, Andrew S Levey, Martin Zeier, Barry I Freedman, Jeffrey B Kopp, Karl Skorecki, Josef Coresh, Arshed A Quyyumi, Sanja Sever, Jochen Reiser
Journal: Nature Medicine (2017)
Glecaprevir and pibrentasvir for 12 weeks for hepatitis C virus genotype 1 infection and prior direct‐acting antiviral treatment
Authors: Fred Poordad, Franco Felizarta, Armen Asatryan, Mark S. Sulkowski, Robert W. Reindollar, Charles S. Landis, Stuart C. Gordon, Steven L. Flamm, Michael W. Fried, David E. Bernstein, Chih‐Wei Lin, Ran Liu, Sandra S. Lovell, Teresa I. Ng, Jens Kort, Federico J. Mensa
Journal: Hepatology (2017)

Although direct‐acting antiviral (DAA) therapies for chronic hepatitis C virus (HCV) infection have demonstrated high rates of sustained virologic response, virologic failure may still occur, potentially leading to the emergence of viral resistance, which can decrease the effectiveness of subsequent treatment. Treatment options for patients who failed previous DAA‐containing regimens, particularly those with nonstructural protein 5A inhibitors, are limited and remain an area of unmet medical need. This phase 2, open‐label study (MAGELLAN‐1) evaluated the efficacy and safety of glecaprevir (GLE) + pibrentasvir (PIB) ± ribavirin (RBV) in HCV genotype 1–infected patients with prior virologic failure to HCV DAA‐containing therapy. A total of 50 patients without cirrhosis were randomized to three arms: 200 mg GLE + 80 mg PIB (arm A), 300 mg GLE + 120 mg PIB with 800 mg once‐daily RBV (arm B), or 300 mg GLE + 120 mg PIB without RBV (arm C). By intent‐to‐treat analysis, sustained virologic response at posttreatment week 12 was achieved in 100% (6/6, 95% confidence interval 61‐100), 95% (21/22, 95% confidence interval 78‐99), and 86% (19/22, 95% confidence interval 67‐95) of patients in arms A, B, and C, respectively. Virologic failure occurred in no patients in arm A and in 1 patient each in arms B and C (two patients were lost to follow‐up in arm C). The majority of adverse events were mild in severity; no serious adverse events related to study drug and no relevant laboratory abnormalities in alanine aminotransferase, total bilirubin, or hemoglobin were observed. Conclusion : The combination of GLE and PIB was highly efficacious and well tolerated in patients with HCV genotype 1 infection and prior failure of DAA‐containing therapy; RBV coadministration did not improve efficacy. (H epatology 2017;66:389–397).
Assessment of a clinical and genetic algorithm to predict endoxifen concentration.
Authors: Emily Van Wieren, Kelley M. Kidwell, Zeruesenay Desta, Howard L. McLeod, Lisa A. Carey, William Johnson Irvin, Daniel Louis Hertz
Journal: Journal of Clinical Oncology (2016)

e12021 Background: Tamoxifen ineffectiveness in patients with hormone receptor + breast cancer may be attributed to subtherapeutic concentrations of its active metabolite, endoxifen. Teft et al. previously published an algorithm that integrates clinical and genetic variables to predict endoxifen concentration. The objective of this analysis was to assess the accuracy of this algorithm in two independent cohorts of tamoxifen treated patients. Methods: Two cohorts of patients taking 20 mg tamoxifen daily and not concomitantly receiving strong CYP2D6 inhibitors were enrolled in UNC LCCC 0801. Endoxifen was measured on two different assays, one measured Z- and E-endoxifen (cohort 1, n = 68), the other Z-endoxifen only (cohort 2, n = 293). Actual endoxifen concentration in the validation cohorts was compared with the Teft algorithm prediction using Pearson correlation and parameter estimates from all cohorts were visually compared. Results: Modest correlation was found for cohort 1 (concordance correlation = 0.27, 95% CI: 0.14-0.40) but there was little correlation in cohort 2 in which only active Z-endoxifen was measured (correlation = 0.04, 95% CI: 0.02-0.06). Positive coefficient estimates for CYP2D6 phenotypes confirms that higher activity is associated with increased endoxifen; however, discordant coefficients for other parameters suggest less robust associations. Conclusions: The complexity of the tamoxifen metabolism pathway lends to difficulty in constructing an endoxifen algorithm. Further analyses will be performed to develop a predictive algorithm to better inform individualized tamoxifen dosing to improve treatment efficacy. Variable Parameter Coefficient Estimate Teft Discovery Cohort Validation Cohort 1 Validation Cohort 2 # of patients 196 68 293 Intercept 1.8 1.6 3.3 Age 0.005 -0.001 0.003 Ln(BMI) 0.2 0.2 -0.8 CYP2D6 UM 1.2 1.4 0.8 EM/EM 1.0 1.6 1.2 EM/IM 0.8 1.3 1.0 EM/PM 0.7 1.0 0.9 IM/IM 0.5 0.7 0.5 IM/PM 0.04 0.4 0.5 CYP3A4*22 -0.2 0.09 0.3 CYP2D6 inhibitor Mild -0.4 -0.7 1.0 Moderate -0.5 N/A 0.07 Venlafaxine -0.2 0.06 -0.2 Season Summer 0.2 N/A -0.1 Spring 0.2 0.03 -0.08 Fall 0.1 -0.4 0.3
DNMT3A mutant transcript levels persist in remission and do not predict outcome in patients with acute myeloid leukemia
Authors: V I Gaidzik, D Weber, P Paschka, A Kaumanns, S Krieger, A Corbacioglu, J Krönke, S Kapp-Schwoerer, D Krämer, H-A Horst, I Schmidt-Wolf, G Held, A Kündgen, M Ringhoffer, K Götze, T Kindler, W Fiedler, M Wattad, R F Schlenk, L Bullinger, V Teleanu, B Schlegelberger, F Thol, M Heuser, A Ganser, H Döhner, K Döhner
Journal: Leukemia (2017)
Distribution and impact of research in hematology and oncology in Latin America (LATAM): A decade of uncertainty (ONCOLGroup).
Authors: Andres Acevedo, Andres Felipe Cardona Zorrilla, Paola Rios, Henry A. Becerra, Alexandra Gomez, Carranza Hernan, Carlos A. Vargas, Jorge M. Otero, Carlos Castro, Ludovic Reveiz
Journal: Journal of Clinical Oncology (2012)

e12039 Background: Brazil provides 1% of the worldwide scientific output registered in ASCO. However, contribution made by other LATAM countries remains unknown. The main objective is to evaluate LATAM countries’ scientific output regarding hematology and oncology and their global impact. Methods: Astructured search was made in ASCO, ASH, ESMO and ASTRO databases to identify abstracts recorded between 2000 and 2010 referring to any author, institution or population from LATAM. The search was expanded using Internet to find indexed or non-indexed publications referring to each selected reference. Simple random sampling was used to check 10% of the references and verify the quality of the data. Results: 1,858 of the 2,625 references that were identified fulfilled the inclusion criteria. Sixteen of 19 countries evaluated had at least one record during the 10 year target period; five countries represented 93.6% of scientific output (Brazil 51.1%/Argentina 19.9%/ México 14.1%/Peru 6.2%/Chile 2.4%) whilst Colombia only contributed 1.3%. Two-thirds of the work had been presented as abstracts, a third as posters and less than 2% orally; 17% of the abstracts had been published in a scientific journal (90% in international journals, with a mean impact factor and average citations rate of 3.5 and 14.2 respectively), 1.6 years after the meeting. Conclusions: Latin America’s contribution to scientific knowledge regarding hematology, oncology and radiotherapy is growing. The geographical distribution of such production depends on 5 countries; nevertheless, abstracts’ publication rate in journals is low.
Spatiotemporal profile of postsynaptic interactomes integrates components of complex brain disorders
Authors: Jing Li, Wangshu Zhang, Hui Yang, Daniel P Howrigan, Brent Wilkinson, Tade Souaiaia, Oleg V Evgrafov, Giulio Genovese, Veronica A Clementel, Jennifer C Tudor, Ted Abel, James A Knowles, Benjamin M Neale, Kai Wang, Fengzhu Sun, Marcelo P Coba
Journal: Nature Neuroscience (2017)
Risk of HER2-positive breast cancer among germline CHEK2 mutation carriers with breast cancer.
Authors: Chethan Ramamurthy, Raji Shameem, Andrea Forman, Jill S Dolinsky, Virginia Speare, Rachel E. McFarland, Wafik S. El-Deiry, Michael J. Hall, Mary Beryl Daly, Lori J. Goldstein, Elias Obeid
Journal: Journal of Clinical Oncology (2016)

1539 Background: Checkpoint Kinase 2 (CHEK2) germline mutations have been linked to hereditary cancers, particularly breast cancer, with data suggesting a lower risk of cancer susceptibility for the I157T CHEK2 mutation. There are no data regarding the subtypes of breast cancer including HER2 expression/gene amplification in breast tumors associated with germline CHEK2 mutations. Methods: We retrospectively reviewed genetic testing records performed in a single laboratory (Ambry Genetics) of women with a history of breast cancer referred for multi-gene panel testing between March 2012 and December 2014. Demographic features analyzed included age and race/ethnicity. Pathological characteristic of HER2 status according to descriptive diagnosis by the ordering physician was compared in women with germline CHEK2 mutation (gCHEK2-m) vs. other germline mutations (gOTHER-m). Cases with multiple germline mutations were excluded. The gCHEK2-m cases included p.I157T moderate risk mutation, the c.1100delC founder mutation, and other CHEK2mutations. Fisher's exact test and odds ratio (OR) were utilized to ascertain for any significant difference between gCHEK2-m and gOTHER-m cases. Results: A total of 6,046 cases were included in the analysis. Mean age at testing was 53 years. Regarding race/ethnicity, the majority of cases were Caucasian (70.1%) followed by African American (5.9%) and Ashkenazi Jewish (5.5%). The gOTHER-m mutations were 66% in BRCA1, BRCA2, PALB2, TP53, PTEN, and ATM, and 34% in other low-moderate risk genes. HER2 positivity was seen more frequently in gCHEK2-m (n = 158) than gOTHER-m (n = 420) (OR, 1.52; 95% CI, 0.95-2.43, p = 0.07). When gCHEK2-m was refined to exclude those with the lower risk of cancer susceptibility I157T CHEK2 mutation (n = 127), compared to gOTHER-m, there was a significant increase in likelihood of HER2 positive breast cancer (OR, 1.69; 95% CI, 1.02-2.77, p = 0.03). Conclusions: Our results suggest a possible association between germline CHEK2 mutation and HER2 positive breast cancer. If confirmed in larger data sets, these results could prompt further investigation in the molecular pathway linking CHEK2 and HER2 overexpression/amplification in breast cancer.
Setting National Policy Agendas in Light of the Denmark Results for Well-being
Authors: Ingeborg Farver-Vestergaard, Kai Ruggeri
Journal: JAMA Psychiatry (2017)

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Cell‐Engineered Nanovesicle as a Surrogate Inducer of Contact‐Dependent Stimuli
Authors: Junho Kim, Chugmin Han, Wonju Jo, Sehong Kang, Siwoo Cho, Dayeong Jeong, Yong Song Gho, Jaesung Park
Journal: Advanced Healthcare Materials (2017)

Heterotypic interactions between cells are crucial in various biological phenomena. Particularly, stimuli that regulate embryonic stem cell (ESC) fate are often provided from neighboring cells. However, except for feeder cultures, no practical methods are identified that can provide ESCs with contact-dependent cell stimuli. To induce contact-dependent cell stimuli in the absence of living cells, a novel method that utilizes cell-engineered nanovesicles (CNVs) that are made by extruding living cells through microporous membranes is described. Protein compositions of CNVs are similar to their originating cells, as well as freely diffusible and precisely scalable. Treatment of CNVs produced from three different stromal cells successfully induces the same effect as feeder cultures. The results suggest that the effects of CNVs are mainly mediated by membrane-associated components. The use of CNVs might constitute a novel and efficient tool for ESC research.
48 Time to tap? an audit of diagnostic paracentesis in inpatients with cirrhosis at a university teaching hospital
Authors: S O’Brien, S O’Hanlon, O El Sherif, S McKiernan, M Iqbal
Journal: Gut (2017)

Background  Spontaneous bacterial peritonitis (SBP) is a diagnosis associated with significant mortality. It has previously been shown that delayed paracentesis is associated with increased inpatient mortality in patients with SBP.  Aim  The aim of this audit was to identify time elapsed between patient presentation and the performance of diagnostic paracentesis at a University teaching hospital.  Method  We included all patients who presented to the emergency department with ascites in the setting of cirrhosis and who had a diagnostic paracentesis. In all, 122 patients over 12 months were included in our study. Data was collected retrospectively from electronic patient records. Samples were categorised according to 3 time ranges: 24 hours.  Results  Time to paracentesis is outlined in Table 1. 29.5% of patients didn’t have a white cell count sent as part of their ascites tap. 13 of the 86 patients (15.1%) with WCC sent were diagnosed with SBP, 5 of these were diagnosed >24 hours after presentation. Mortality was higher in patients whose diagnostic paracentesis were delayed until >24 hours after presentation (3/5) compared to those with paracentesis performed at   Conclusions  A significant number of patients experienced delayed paracentesis. Recommendation: Education of NCHDs in the importance of diagnostic paracentesis to guide management and reduce mortality. Further training in the skill of performing paracentesis. Re-audit following these proposals.
PALB2 mutations in high-risk women with breast or ovarian cancer.
Authors: Kelly A. Metcalfe, Mohammad R Akbari, Steven Narod, Jordan Lerner-Ellis
Journal: Journal of Clinical Oncology (2017)

1527 Background: In Canada, genetic testing for BRCA1 and BRCA2 is available free of charge to women who meet eligibility criteria, based on personal and family history of cancer. Less than 10% of women are identified with a BRCA mutation, despite features of hereditary cancer. PALB2 has been identified as a moderate penetrance gene in various populations. In the current study, we examined the frequency of PALB2 mutations in women with breast or ovarian cancer who met criteria for genetic testing for BRCA1 and BRCA2and tested negative. Methods: DNA samples from women with breast or ovarian cancer, who met criteria for provincial BRCA1 and BRCA2 genetic testing and tested negative between the years of 2007 and 2014 were included in this study. All 13 coding exons of PALB2 plus 20 base pairs from the exon boundaries were amplified using Wafergen SmartChip technology. The amplified DNA were paired-end sequenced at 2x250 cycles using an Illumina MiSeq sequencer. Results: 2,225 women with breast cancer and 429 women with ovarian cancer were tested for PALB2 mutations. No PALB2 mutations were found in women with ovarian cancer. Seventeen deleterious PALB2 mutations were detected in women with breast cancer (0.8%). The frequency of PALB2 mutations was significantly higher in women with bilateral breast cancer (2.4%) compared to women with unilateral breast cancer (0.6%) (p = 0.01). There was no significant difference in age at diagnosis between those with and without a PALB2mutation (50.9 years vs 53.8 years; p = 0.34). Conclusions: Genetic testing for PALB2 should be considered for high-risk women with breast cancer, especially those who present with bilateral breast cancer. However, PALB2 does not appear to contribute to ovarian cancer which has implications for counselling women who are identified with a PALB2 mutation.
Phase I study of mTORC1/2 inhibitor BI 860585 as single agent or with exemestane or paclitaxel in patients with advanced solid tumors.
Authors: Filippo G. De Braud, Jean-Pascal H. Machiels, Marcello Tiseo, Sylvie Rottey, Matteo Duca, Marie Laruelle, Stefania Salvagni, Lore Lapeire, Laura Manfreda, Céline Veau, Daniela Fischer, Mahmoud Ould-Kaci
Journal: Journal of Clinical Oncology (2016)

2545 Background: BI 860585 is a potent, selective ATP-competitive mTOR serine/threonine kinase inhibitor which has shown preclinical activity against various cancer types. This Phase I trial (NCT01938846) aims to determine the maximum tolerated dose (MTD) of BI 860585 as a single agent or combined with exemestane or paclitaxel in patients (pts) with advanced solid tumors. Methods: This study used a 3+3 design in 3 treatment arms (all in 28-day cycles): single-agent BI 860585 (5–300 mg/day; Arm A), BI 860585 (40–220 mg/day) combined with fixed-dose exemestane (25 mg/day; Arm B), and BI 860585 (80–160 mg/day) combined with paclitaxel (60 or 80 mg/m2/week; Arm C). MTD is defined as the highest dose at which ≤ 1 out of 6 pts experience a dose-limiting toxicity (DLT) during cycle 1. Results: To date, 41 pts have been treated in Arm A, 24 in Arm B and 17 in Arm C. DLTs have been observed in (n DLTs/n evaluable): 4/36 pts, and 4/20 pts in Arm A and B, respectively. No DLT has occurred in 12 pts in Arm C. DLTs (all grade 3) were diarrhea, rash and alanine/aspartate aminotransferase increased in Arm A; and stomatitis and rash in Arm B. The MTD was determined as 220 mg/day in Arm A. The most frequent treatment-related adverse events (AEs) have been: hyperglycemia (54%), diarrhea (39%) and nausea (37%) in Arm A; hyperglycemia (38%), diarrhea and rash (both 33%) in Arm B; and hyperglycemia (53%) and fatigue (47%) in Arm C; the majority of AEs were Grade ≤ 2. No Grade 5 treatment-related AEs were observed. Preliminary best response data showed stable disease (SD) in Arm A (n = 18), SD (n = 6) and partial response (PR; n = 4) in Arm B, including a breast cancer pt pretreated with an mTORC1 inhibitor and exemestane, and SD (n = 8) and PR (n = 1) in Arm C. Disease control rates (PR+SD) were 44% in Arm A, 46% in Arm B and 59% in Arm C. Preliminary PK analysis showed linear PK with no food effect and no drug-drug interaction with exemestane or paclitaxel. Conclusions: MTD was determined as 220 mg/day for BI 860585 monotherapy. At MTD, AEs were mild-to-moderate and consistent with the mode of action of the compound. Early signs of efficacy were observed in varied tumor types with BI 860585 monotherapy and in combination. The study is ongoing. Clinical trial information: NCT01938846.