tbuckley/cabot-search huggingface dataset:
Association of next generation sequencing characteristics of MIBC specimens with clinical outcomes: The USC experience.
Authors: Arnab Basu, Jeremy Chang, Karen Haiber, Tanya B. Dorff, Jacek K. Pinski, David I. Quinn, Sarmad Sadeghi
Journal: Journal of Clinical Oncology (2019)

397 Background: Muscle invasive bladder cancer (MIBC) is an aggressive disease. Several molecular subtypes have been identified. Commercial next generation sequencing (NGS) panels now provide significant genetic information on tumors. We conducted an exploratory analysis on MIBC tumor samples at our institution with commercial NGS data to evaluate if these assays provide novel prognostic information. Methods: NGS data (FoundationOne) from all locally advanced and metastatic bladder specimens were collected and combined with information on demographics, tumor characteristics (stage, grade, histology). Overall Survival (OS), post-cystectomy disease free survival (DFS), and Progression Free Survival (PFS) data were also compiled. Mutations in 353 genes were examined for alterations in TP53, Rb, FGF3-RAS-RAF and PI3K-mTOR-AKT pathways. Results: 48 samples were analyzed. Most samples were pure TCC (68.8%) followed by Squamous (16.8%) , Adenocarcinoma (6.3%), Small Cell (6.3%) and Plasmacytoid variants (2.1%). Most patients (91.5%) were locally advanced at diagnosis. Pathologic alterations were found in TP53 (54.2%) , Rb (60.4%), FGF3-RAS-RAF(89.6%) and PI3K-mTOR-AKT(70.8%) pathways. Squamous variants were more likely to have TP53 pathway alterations compared with others (100% vs 45% , p &lt; 0.001) and predicted for poor overall survival. TP53 exons did not predict outcomes. In multivariable adjusted cox-regression models Rb alterations appeared to predict for improved post cystectomy DFS (p = 0.01). TP53 mutations predicted for worse PFS (p=0.01) while PI3K-mTOR-AKT pathway alterations were associated with poorer OS (p=0.02) after adjusting for all other predictors. Conclusions: In this limited single institution sample analyzed by commercial available NGS panels, some prognostic information was available. Analysis of a larger population could result in the validation of other predictive or prognostic markers.[Table: see text]
Reductionism – simplified and scientific
Authors: Leonid Perlovsky
Journal: Behavioral and Brain Sciences (2019)

Abstract In this commentary on Borsboom et al.’s target article, I address an inadequate, simplified use of the idea of “reductionism” in clinical psychology and psychiatry. This is important because reductionism is a fundamental methodology of science. Explaining mental states and processes in terms of biological and brain states and processes is fundamental for the science of psychology. I also briefly address a fundamental methodology of the goal of psychology as a hard science.
Abstract P170: High Intake of Dietary Protein is Associated With Increased Risk of Heart Failure With Preserved Ejection Fraction
Authors: Charles B Eaton, Mohamad F Barbour, Farhan Ashraf, Mary Roberts, Lisa W Martin, Matthew A Allison, Karen C Johnson, Carolina I Valdiviezo
Journal: Circulation (2017)

Background: Heart Failure with preserved ejection fraction(HFpEF) is growing and common problem in elderly women with high morbidity and mortality. The role of diet in its prevention is under-researched. Objective: To evaluate calibrated and uncalibrated dietary protein, energy adjusted animal and vegetable protein and their association with incident HFpEF. Methods: Study participants in Women’s Health Initiatve (n=14,184) with valid FFQ data, free of baseline HF or missing covariates had urinary nitrogen calibrated total protein, energy calibrated using doubly labelled water animal and vegetable protein determined. Cox models adjusted for age, education, race/ethnicity, CHD, diabetes,waist to hip ration,hypertension, physical activity, systolic blood pressure, anemia, atrial fibrillation evaluated prospective association with HFpEF. HFpEF was defined as ejection fraction &gt;45%. Results: Over 13.2 years of follow-up, there were 513 cases of HF, 268 cases of HFpEF, 162 of HFrEF and 83 of undetermined ejection fraction. Increasing levels of calibrated total protein showed a linear dose response relationship with an increased risk of HFpEF whereas uncalibrated total protein did not. Higher intake of animal protein demonstrated an increased risk , while vegetable protein showed a trend towards and inverse relationship. (see table) Conclusion: HIgher levels of calibrated total protein are associated with increased risk of HFpEF with animal protein appearing to be the most deleterious. Plant based diets with high levels of vegetable protein may be protective. Further studies should evaluate this.
Whole Genome Sequencing Identifies Single Nucleotide Variants, Structural and Copy Number Abnormalities with a High Sensitivity in Hematological Neoplasm: An All in One Diagnostic Tool Tested on 3241 Cases
Authors: Claudia Haferlach, Sven O. Twardziok, Stephan Hutter, Wencke Walter, Wolfgang Kern, Manja Meggendorfer, Niroshan Nadarajah, Torsten Haferlach
Journal: Blood (2018)
Effects of adjuvant trastuzumab with chemotherapy (ATWC) in T1N0 HER2 positive (HER2+) breast cancer.
Authors: Yada Kanjanapan, Susanna N Thomas, Desmond Yip, Jane E Dahlstrom, Nirmala Pathmanathan, Paul Stanley Craft
Journal: Journal of Clinical Oncology (2015)

e11595 Background: Adjuvant trastuzumab with chemotherapy (ATWC) reduces recurrence and death in prospective trials of HER2+ breast cancer (BC). T1N0 ( ≤ 2cm node-negative) patients were however mostly excluded. As smaller tumours have a more favourable natural history, the question arises whether the absolute benefit from ATWC justifies the associated risks and toxicities. We examine ATWC-use in T1N0 HER2+ BC and estimate the likely absolute benefit of treatment in specific subgroups. Methods: Subjects consented to enrolment in databases of the Australian Capital Territory and South-East New South Wales Breast Cancer Treatment Group, Breast Cancer Tissue Bank and Westmead Breast Cancer Institute, Australia. Eligible patients were females with T1N0 HER2+ invasive BC diagnosed between January 2005 and December 2013. We defined a clinically meaningful benefit from ATWC as a 3% or more gain in 5-year DFS. A hazard ratio of 0.6 for recurrence risk from ATWC-use over chemotherapy alone in a meta-analysis of ATWC trials; was applied as a conservative estimate of expected benefit from ATWC in patients who did not receive this treatment. DFS was estimated by the Kaplan-Meier method. Results: There were 230 women, mean age 57yo, with 60% T1c, 67% ER+ and 63% grade 3 carcinomas. All ER+ patients received endocrine therapy. ATWC was given in 68%. ER- and grade 3 tumours were associated with poorer outcome. With median follow-up of 38 months, 14 patients had disease recurrence (9/14 had ATWC), of whom 11 died (6/11 had ATWC). There was no significant difference in the unadjusted 5-year DFS between ATWC-treated and untreated patients (89% and 91% respectively, p = 0.89). The estimated absolute 5-year DFS benefit from ATWC was 4.2%. Subgroup analyses found patients with ER+, grade 1-2, ≤ 1cm tumours had 5-year DFS of 97.2%, 100% and 100% respectively, without ATWC. Conclusions: ER- status and higher grade are associated with inferior outcome in T1N0 HER2+ BC. Overall in this group, there was an estimated 4.2% gain in 5-year DFS from ATWC. Exploratory analyses identified ER+, Grade 1-2 and ≤ 1cm tumours have a favourable natural history; suggesting a clinically meaningful benefit from ATWC is limited to subgroups within T1N0 HER2+ BC.
One and done?: Utility of PSA density as a predictor of number of cores needed to detect clinically significant prostate cancer.
Authors: Graham Hale, Jonathan Bloom, Amir H Lebastchi, Samuel A Gold, Sherif Mehralivand, Joanna H. Shih, Baris Turkbey, Peter A. Pinto
Journal: Journal of Clinical Oncology (2019)

104 Background: MRI/US fusion guided prostate biopsy (FBx) has been shown to detect clinically significant prostate cancer (csCaP) at higher rates and with fewer cores than standard prostate biopsy. However, the number of targeted cores needed to accurately characterize lesions identified on multiparametric MRI (mpMRI) is unknown. This study sought to determine factors that predict the number of cores needed to accurately characterize lesions during FBx of patients on active surveillance. Methods: A retrospective analysis of a prospectively maintained database of all patients undergoing FBx at an academic referral center between May 2014 and January 2018 was conducted. At least two FBx cores were taken from each lesion identified on mpMRI. Patient and lesion specific factors were analyzed to determine factors that predict the necessity to obtain additional cores to detect csCaP. GEE-based univariate logistic regression model with exchangeable correlation was used to estimate the effects of clinical characteristics including race, BMI, PSA, PSA density (PSAD), lesion location, and PI-RADS score on the proportion of positive and negative agreement. Predictability of a significant continuous predictor was quantified by AUC. The most significant patient-level predictor (PSAD) was further analyzed to determine thresholds at which multiple cores per lesion are needed to avoid missing csCaP. Results: An analysis of a total of 1141 FBx were performed during the study time interval. PSA (OR=1.57, 1.20-2.05, p&lt;0.01) and PSAD (OR=1.43, 1.11-1.85, p&lt;0.01) significantly predicted positive agreement of csCaP. AUC for positive and negative agreement was 57.4 and 61.0 for PSA and 56.4 and 72.3 for PSAD, respectively. Using these thresholds, only 56% lesions would need double core targeted biopsy. In other words, up to 44% of lesions would be accurately characterized with a single biopsy core of the targeted lesion. Conclusions: These data indicate that in patients with a PSAD less than 0.11 ng/ml 2 or greater than 0.26 ng/ml 2 , lesions may be acceptably characterized with a single targeted biopsy core.
A multibiomarker approach to predict prostate cancer pathology outcomes.
Authors: Pamela Paris, Matthew R. Cooperberg, Janet Cowan, Karla Lindquist, Yasuko Kobayashi, Jeff Simko, Henrik Bengtsson, Khushboo L Singh, Lisa F. Newcomb, Daniel W. Lin, Peter Carroll
Journal: Journal of Clinical Oncology (2019)

58 Background: Distinguishing indolent from aggressive prostate cancer remains a key challenge for prostate cancer management decision-making. A growing number of biomarkers are now on the market to help address this need, but have rarely been examined together in the same patients to determine their relative value. Methods: We identified men with low-risk cancers defined by biopsy Gleason score ≤3+3, PSA ≤10ng/ml, and clinical stage ≤T2 who underwent immediate prostatectomy. We collected archived prostate tissue and pre-surgical plasma samples from N = 381 cases from UCSF and N = 279 cases from UW. Plasma was analyzed for TGFb1 and IL6SR, previously validated markers for prostate cancer prognosis, using ELISA. From prostate tissue, DNA and RNA were extracted and analyzed for the GEMCaP copy number variation score and the cell cycle progression (CCP) score, respectively, both well-validated and previously reported scores. Pathologic outcomes were minor (pGS 3+4 or pT3a) or major (pGS ≥4+3 or ≥pT3b) upgrading/upstaging (UGUS), and multinomial regression was performed to determine putative markers’ ability to predict these outcomes, controlling for PSA, percent of biopsy cores positive, age, and clinical site. Results: Overall, 357 men had no UGUS event at prostatectomy, 236 had a minor event, and 67 had a major event. Neither TGFb1 nor IL6SR statistically significantly predicted any UGUS or major UGUS. On the other hand, both CCP and GEMCaP were directly associated with minor UGUS on univariate analysis. On multivariable multinomial analysis including both scores, the CCP score predicted minor UGUS (OR 1.70, 95% CI 1.07-2.72, p = .03) and GEMCaP also predicted minor UGUS (OR 1.04, 95% CI 1.01-1.07, p &lt; .01). Neither CCP nor GEMCaP predicted major UG/US, but the number of events was small. Noteworthy, both GEMCaP and the CCP score were statistically significant predictors of outcomes in the same model, suggesting they can complement each other by offering additional information. The other clinical parameters were not significant in this model. Conclusions: Biomarker signatures based on analysis of DNA and RNA significantly and independently predict adverse pathology among men with clinically low-risk prostate cancer undergoing prostatectomy.
What is “normal” antibiotic prescribing?
Authors: Martin Gulliford, Dorota Juszczyk, Lucy Yardley
Journal: BMJ (2019)

The United Kingdom has a culture of high antibiotic prescribing.1 Although the National Institute for Health and Care Excellence recommends that most self limiting respiratory tract infections be managed without antibiotics, some 50% of primary care consultations for this condition are associated with an antibiotic prescription.2 For some international …
Cancer-cell-secreted CXCL11 promoted CD8+ T cells infiltration through docetaxel-induced-release of HMGB1 in NSCLC
Authors: Qun Gao, Shumin Wang, Xinfeng Chen, Shaoyan Cheng, Zhen Zhang, Feng Li, Lan Huang, Yang Yang, Bin Zhou, Dongli Yue, Dan Wang, Ling Cao, Nomathamsanqa Resegofetse Maimela, Bin Zhang, Jane Yu, Liping Wang, Yi Zhang
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Chemotherapy combined with immunotherapy becomes the main trend in lung cancer intervention; however, how chemotherapy promotes the immune function remains elusive. Therefore, we sought to determine how chemotherapy promotes the immune function. <h3>Methods</h3> We determined in 100 NSCLC patients the expression of CD8, functional markers (IFN-γ, Granzyme B, and Perforin) and specific chemokines by quantitative real-time reverse transcriptase-PCR. Functional experiments were carried out to check whether docetaxel (DOC), a chemotherapeutic agent, modifies the expression of HMGB1 and CXCL11, and influences the infiltration properties of CD8<sup>+</sup> T cells to the tumor microenvironment. The mechanism of the release of HMGB1 and CXCL11 was determined by flow cytometry, immunofluorescence and western blotting. In in vivo experiment, we confirmed how DOC enhanced the recruitment of HER2-CAR T cells to tumor sites. <h3>Results</h3> We found that DOC upregulated the expression of chemokine receptor ligand CXCL11 in tumor microenvironment and subsequently enhanced CD8<sup>+</sup> T cell recruitment. DOC treatment significantly increased HMGB1 release in an ROS-dependent manner. Recombinant protein HMGB1 stimulated the secretion of CXCL11 via NF-κB activation in vitro. Tumors from DOC-treated mice exhibited higher expression of HMGB1 and CXCL11, more HER2-CAR T cell infiltration, and reduced progression, relative to control. Increased HMGB1 and CXCL11 expressions were positively correlated with prolonged overall survival of lung cancer patients. <h3>Conclusions</h3> Our results demonstrate that DOC induces CD8<sup>+</sup> T cell recruitment to the tumor microenvironment by enhancing the secretion of HMGB1 and CXCL11, thus improving the anti-tumor efficacy, indicating that modulating the HMGB1-CXCL11 axis might be helpful for NSCLC treatment.
Myc and Loss of p53 Cooperate to Drive Formation of Choroid Plexus Carcinoma
Authors: Jun Wang, Diana M. Merino, Nicholas Light, Brian L. Murphy, Yong-Dong Wang, Xiaohui Guo, Andrew P. Hodges, Lianne Q. Chau, Kun-Wei Liu, Girish Dhall, Shahab Asgharzadeh, Erin N. Kiehna, Ryan J. Shirey, Kim D. Janda, Michael D. Taylor, David Malkin, David W. Ellison, Scott R. VandenBerg, Charles G. Eberhart, Rosalie C. Sears, Martine F. Roussel, Richard J. Gilbertson, Robert J. Wechsler-Reya
Journal: Cancer Research (2019)

Abstract Choroid plexus carcinoma (CPC) is a rare brain tumor that occurs most commonly in very young children and has a dismal prognosis despite intensive therapy. Improved outcomes for patients with CPC depend on a deeper understanding of the mechanisms underlying the disease. Here we developed transgenic models of CPCs by activating the Myc oncogene and deleting the Trp53 tumor suppressor gene in murine neural stem cells or progenitors. Murine CPC resembled their human counterparts at a histologic level, and like the hypodiploid subset of human CPC, exhibited multiple whole-chromosome losses, particularly of chromosomes 8, 12, and 19. Analysis of murine and human CPC gene expression profiles and copy number changes revealed altered expression of genes involved in cell cycle, DNA damage response, and cilium function. High-throughput drug screening identified small molecule inhibitors that decreased the viability of CPC. These models will be valuable tools for understanding the biology of choroid plexus tumors and for testing novel approaches to therapy. Significance: This study describes new mouse models of choroid plexus carcinoma and uses them to investigate the biology and therapeutic responsiveness of this highly malignant pediatric brain tumor.
Catheter Ablation for Atrial Fibrillation
Authors: Christine M. Albert, Deepak L. Bhatt
Journal: JAMA (2019)

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Intratumoral Genetic and Functional Heterogeneity in Pediatric Glioblastoma
Authors: Mary Hoffman, Aaron H. Gillmor, Daniel J. Kunz, Michael J. Johnston, Ana Nikolic, Kiran Narta, Mehdi Zarrei, Jennifer King, Katrina Ellestad, Ngoc Ha Dang, Florence M.G. Cavalli, Michelle M. Kushida, Fiona J. Coutinho, Yuankun Zhu, Betty Luu, Yussanne Ma, Andrew J. Mungall, Richard Moore, Marco A. Marra, Michael D. Taylor, Trevor J. Pugh, Peter B. Dirks, Douglas Strother, Lucie Lafay-Cousin, Adam C. Resnick, Stephen Scherer, Donna L. Senger, Benjamin D. Simons, Jennifer A. Chan, A. Sorana Morrissy, Marco Gallo
Journal: Cancer Research (2019)

Pediatric glioblastoma (pGBM) is a lethal cancer with no effective therapies. To understand the mechanisms of tumor evolution in this cancer, we performed whole-genome sequencing with linked reads on longitudinally resected pGBM samples. Our analyses showed that all diagnostic and recurrent samples were collections of genetically diverse subclones. Clonal composition rapidly evolved at recurrence, with less than 8% of nonsynonymous single-nucleotide variants being shared in diagnostic-recurrent pairs. To track the origins of the mutational events observed in pGBM, we generated whole-genome datasets for two patients and their parents. These trios showed that genetic variants could be (i) somatic, (ii) inherited from a healthy parent, or (iii) de novo in the germlines of pGBM patients. Analysis of variant allele frequencies supported a model of tumor growth involving slow-cycling cancer stem cells that give rise to fast-proliferating progenitor-like cells and to nondividing cells. Interestingly, radiation and antimitotic chemotherapeutics did not increase overall tumor burden upon recurrence. These findings support an important role for slow-cycling stem cell populations in contributing to recurrences, because slow-cycling cell populations are expected to be less prone to genotoxic stress induced by these treatments and therefore would accumulate few mutations. Our results highlight the need for new targeted treatments that account for the complex functional hierarchies and genomic heterogeneity of pGBM. SIGNIFICANCE: This work challenges several assumptions regarding the genetic organization of pediatric GBM and highlights mutagenic programs that start during early prenatal development.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/9/2111/F1.large.jpg.
The impact of intratumoral heterogeneity on prognostic biomarkers in localized prostate cancer.
Authors: Harry Brastianos, Jure Murgic, Adriana Salcedo, Melvin Lee Kiang Chua, Alice Meng, Michael Fraser, Michael Donald Brundage, Neil Eric Fleshner, Theodorus van der Kwast, Robert G. Bristow, Paul Christopher Boutros, Alejandro Berlin
Journal: Journal of Clinical Oncology (2019)

46 Background: Genomic biomarkers can identify patients that harbour aggressive disease. The utility of these biomarkers is uncertain due to genomic variation between prostate biopsy specimens. To quantify the robustness of genomic biomarkers, we performed spatio-genomic characterization of distinct tumor foci. We scored three validated DNA-based biomarkers of early biochemical recurrence: percentage of genome with a copy number aberration (PGA), a 100-loci biomarker, and an optimized 31- loci biomarker derived from the previous. For each biomarker, we determined their robustness to intratumoral heterogeneity in association with predicting early biochemical recurrence (eBCR; ≤18 months) and long term control (LTC; ≥48 months). Methods: We queried a registry of 1054 patients with high-risk prostate cancer who underwent a radical prostatectomy (RP). We developed a cohort (n = 42) risk matched by clinicopathologic prognostic indices. Half of the patients had eBCR, while the other half had LTC. We profiled multiple tumor foci per patient, analyzing 119 tumor foci. For each focus, CNA profiles were generated, and three biomarker scores were calculated. For each patient and biomarker, we calculated the score of the lowest-score region, the highest-score region, or sampling of all foci and use the mean score. Results: All three biomarkers distinguished LTC from eBCR. PGA scores separated the two groups with an area under the receiver operator curves (AUC) ranging from 0.75-0.80. The 100- and 31-loci signatures, had AUCs ranging from 0.76-0.85 and 0.76-0.80 respectively. Using Cox proportional hazards modeling, we found that PGA was associated with LTC (Hazard ratio (HR) range: 2.56-6.22; p &lt; 0.05. This was replicated for the 100-loci signature (HR range: 3.55-5.23; p &lt; 0.05). The 31-loci detected associations with eBCR independent of how different foci were summarized (log-rank p-value range: 5.1 x 10 -4 - 5.9 x 10 -3 ). Conclusions: Despite divergence in biomarker scores, all three predicted eBCR. Our study suggests that genomic biomarkers can overcome intratumoral heterogeneity, making discrete samples potentially adequate in patients with high-risk disease to determine the risk of eBCR after radical treatment.
Patient Adherence and Persistence to Oral Targeted Therapies for Hematologic Malignancies: A Retrospective Cohort Study Among Managed Care Enrollees
Authors: Krish Patel, Vinjamuri Sai Sudhir, Shaum Kabadi, Joanna C Huang, Sanchita Porwal, Kushan Thakkar, John M. Pagel
Journal: Blood (2018)