tbuckley/cabot-search huggingface dataset:
Whole genome sequencing in metastatic breast cancer: Lessons learned from the BC Cancer personalized oncogenomics program.
Authors: Nathalie LeVasseur, Yaoqing Shen, Eric Yang Zhao, Sophie Sun, Janessa J. Laskin, Karen A. Gelmon, Marco A. Marra, Stephen K. L. Chia
Journal: Journal of Clinical Oncology (2018)

12065 Background: The emerging interest in precision medicine has lead to the genomic profiling of breast cancer, with the intent of identifying therapeutically targetable alterations. The clinical relevance of whole genome sequencing (WGS) and RNA-sequencing as compared to targeted next generation sequencing (NGS) remains uncertain. Moreover refined data is needed to identify which patients benefit most from molecular profiling. Methods: Informative and actionable findings from WGS in metastatic breast cancer patients between 2012-2017 were reviewed and compared to FoundationOne and MSKCC-IMPACT targeted panels. The data providing rationale for informative and actionable findings was compiled using an RNA/DNA heatmap. Comparison of signal nucleotide variants (SNVs) mutation signatures and mutational burden was compared across histological and molecular subtypes and between aging-driven and non-aging driven tumours. Results: WGS of 139 metastatic breast cancer patients revealed that 77% of actionable items arose from expression data, 60% from mutations, 45% from copy number changes, 28% from mutation signature, mutation burden, or homologous recombination deficiency (HRD) and 5% from structural variants (SV). The majority (7616/7998, 95%) of mutations were only detected by WGS, representing mostly passenger mutations, whereas driver mutations were also identified with the genes included in the FoundationOne (339/7998, 4%) and MSKCC-IMPACT panels (201/7998, 3%). No significant differences in mutation burden were identified among subtypes, although tumors whose somatic mutagenesis was driven predominantly by aging-related processes displayed lower mutation burdens. More frequent elevation of HRD-associated mutation signatures of SNV/SV were identified in triple-negative/basal-like tumors. Conclusions: While most actionable mutations were covered by pre-existing targeted panels, expression data represents a significant proportion of actionable information obtained from WGS. Mutational burden did not vary significantly among subtypes. Signature properties and their relation to molecular subtypes remains an interesting arena for clinical application.
Combination of niclosamide to target androgen receptor variant 7 (AR-V7) and abiraterone to target androgen synthesis for the treatment of castration-resistant prostate cancer (CRPC): Initial results from a phase Ib/II trial.
Authors: Chong-xian Pan, Primo Lara, Christopher P. Evans, Mamta Parikh, Marc Dall'era, Chengfei Liu, Daniel Robles, Allen Gao
Journal: Journal of Clinical Oncology (2018)

5031 Background: The androgen receptor (AR) variant AR-V7 lacks the ligand binding domain, constitutively activates the AR pathway, and confers resistance to Abiraterone (Abi) and enzalutamide (Enza). We discovered that the anti-helminthic drug niclosamide targets AR-V7 and sensitizes resistant CRPC to Enza and Abi. We hypothesize that niclosamide/PDMX1001 potentiates the efficacy of Abi against CRPC. Methods: Eligible patients (pts) have progressive CRPC with serum testosterone < 50 ng/dl. No prior Abi was allowed. In the Phase Ib cohort, pts received Abi 1000 mg PO qd, prednisone 5 mg PO bid, with intrapatient dose-escalation of niclosamide/PDMX1001 from 400 mg PO bid to 1600 mg PO tid. Trough niclosamide/PDMX1001 levels were measured. The Phase II cohort will enroll 27 patients with detectable AR-V7 in the peripheral blood. Co-primary endpoints include toxicity and response as determined by the Prostate Cancer Working Group 2 criteria. Results: Of 6 pts (age 74-83) in the Phase Ib cohort, five pts tolerated a niclosamide/PDMX1001 dose of 1,600 mg po tid without dose limiting toxicity; per protocol, this is the recommended Phase II dose. Niclosamide/PDMX1001 trough level was 0.305-0.648 µM in the three pts analyzed thus far, higher than the target level of 0.1µM required for anti-cancer activity. Of 6 pts, two pts achieved undetectable PSA ( < 0.01 ng/ml) for over 16 cycles and are still going on, compared to historical control 0/30 pts treated with Abi alone; two with partial PSA response (≥50% decrease). Of the remaining two pts, one was prematurely taken off from the study after one cycle because of rising PSA, and the other had PSA decrease of 17.1%, but biopsy of the only enlarged lymph node showed all necrotic tissue. No dose-limiting toxicity was observed. The Phase II cohort will now enroll. Molecular correlative studies will be presented. Conclusions: The combination of niclosamide/PDMX1001, Abi and prednisone is well tolerated with promising safety and efficacy data. Targeted serum trough levels of niclosamide are clinically achievable. Clinical trial information: NCT02807805.
P15 TRIGLYCERIDE-CONTAINING LIPOPROTEIN SUB-FRACTIONS AND CORONARY HEART DISEASE AND STROKE RISK
Authors: R Joshi, G Wannamethee, D Rhodes, J Engmann, C Dale, T Gaunt, B Jefferis, O Papacosta, T Shah, T Tillin, A Wong, N Chaturvedi, M Kivimaki, D Kuh, M Kumari, A Hughes, Y Ben-Shlomo, J P Casas, A D Hingorani, A F Schmidt
Journal: Cardiovascular Research (2018)
International application of an online clinical informatics expert system for breast cancer.
Authors: Naresh Ramarajan, Rekha Anjali Kumbla, Sudeep Gupta, Nancy Renee Feldman, Jeffrey M. Miller, Gitika Srivastava, Yue-Ting Lau, Nita S Nair, Rajendra A. Badwe
Journal: Journal of Clinical Oncology (2016)

e18037 Background: Cancer patients have limited access to experts and evidence based treatment plans. Navya is a patented, clinical informatics system that uses clinical data as input to exhaustively search and rank applicable Randomized Control Trials and guidelines to output specific evidence based treatment options for individual patients. In a retrospective trial, Navya’s treatment options in breast cancer were concordant with experts and tumor board decisions at one of Asia’s largest tertiary care cancer centers. Currently, experts at the same center use Navya’s clinical data summary and weigh Navya’s treatment opinions to provide rapid evidence based expert opinions, online, to breast cancer patients from 15 developing countries in Asia and Africa. We prospectively study how often experts choose Navya’s options as the expert opinion for the online service. We assess reproducibility of Navya for a different population in a developed country by studying retrospective concordance with tumor board at a large academic safety net hospital in USA. Methods: Protocol specified clinical data of women with non-metastatic breast cancer were abstracted from medical reports. Navya’s output was classified into major (neo-adjuvant chemotherapy vs. upfront surgery and need for adjuvant chemotherapy, and radiation therapy, respectively) and minor (breast conservation vs. mastectomy, taxane vs. non-taxane chemotherapy and sites of nodal radiation) decisions. Primary outcome was concordance between Navya and experts (I) and tumor board (II). Results: Enrollment in RCTs, uncommon comorbidities, informed refusal, and experts’ extrapolation of results of RCTs were the reasons for discordance. Conclusions: A clinical informatics based expert system in breast cancer was highly concordant with experts and tumor boards in two large international settings. Developing the system for all cancers has significant potential to scale access to expert oncologists online and maximize global outcomes in cancer care. I. Online Expert Opinion - Asia (161 patients) II. Tumor Board - USA (145 patients) Major Minor Major Minor Decisions 275 221 450 439 Concordance 100% [99.9%- 100%] 100% [99.9%- 100%] 98% [97.98%- 98.01% 97.26% [97.25%- 97.28%]
Correlation of peripheral and intratumoral T-cell receptor (TCR) clonality with clinical outcomes in patients with metastatic urothelial cancer (mUC) treated with atezolizumab.
Authors: Samuel Funt, Alexandra Snyder Charen, Erik Yusko, Marissa Vignali, Sharon Benzeno, Mariel Elena Boyd, Meredith Maisie Moran, Brooke Elizabeth Kania, Catharine Kline Cipolla, Ashley Marie Regazzi, Harlan Robins, Gopa Iyer, Jonathan E. Rosenberg, Dean F. Bajorin
Journal: Journal of Clinical Oncology (2016)

3005 Background: The anti-programmed death-ligand 1 (PD-L1) antibody atezolizumab is active in patients (pts) with advanced mUC. We hypothesized that the TCR repertoire in tumors and blood may correlate with clinical benefit. Methods: 29 pts received atezolizumab 1200mg q3w on IMvigor 210 at MSKCC and had specimens available for analysis. High throughput DNA sequencing of the CDR3 region of the TCR beta chain was performed in baseline tumors (N=24) plus pre- and post-treatment peripheral blood mononuclear cells (PBMCs) (N=29 patients, 93 PBMC samples) using the immunoSEQ assay. Clonal dominance, clonal expansion and T-cell fraction were assessed for association with benefit (complete and partial response (CR, PR) vs. stable or progressive disease (SD, PD) and progression-free and overall survival (PFS, OS)). Results: The median number of T cells and unique TCRs sequenced in tumors was 1,402 and 1,085, respectively. The median number of T cells and unique TCRs sequenced in PBMCs was 147,493 and 81,705, respectively.Investigator reported best responses were 5 CR, 2 PR, 5 SD, and 17 PD.A combination of high T cell infiltration and clonality in tumors correlated with CR/PR compared to PD (p=0.02232, OR 11.5). The number of T cell clones in the tumor that expanded in the blood 3 weeks post-treatment was greater in CR/PR than in SD (p=0.01253) or PD pts (p=0.05565). Pts with lower baseline peripheral TCR clonality had improved PFS (p=0.0514) and OS (p=0.0116). Conclusions: In mUC patients treated with atezolizumab, high T cell infiltration and clonality in the tumor plus peripheral expansion of dominant tumor-resident TCR clones were associated with response. Low peripheral TCR clonality was associated with survival. These findings suggest that atezolizumab re-invigorates an oligoclonal population of tumor infiltrating lymphocytes and promotes their expansion in the blood. Low TCR repertoire clonality in the periphery at baseline may aid in preventing immune escape and may lead to improved OS. Similar observations have been seen in mice treated with radiation plus checkpoint blockade (Nature 520:373,2015). These findings warrant further study.
Concurrent chemoradiation (CChRT) for locally advanced stage III non-small cell lung cancer (NSCLC) with cisplatin and vinorelbine and thoracic radiotherapy: A phase II study from the Galician Lung Cancer Group.
Authors: Susana Gomez Garcia, Marinha Costa Rivas, Mª Carmen Areses Manrique, Natalia Fernández Núñez, Jorge Garcia, Manuel Caeiro, Enrrique Castro, Ines Formoso, P Calvo, Noemi De Dios Alvarez, Jl Firvida, Begoña Campos, Cristina Azpitarte, Francisco Javier Afonso, Margarita Amenedo, Joaquin Casal Rubio
Journal: Journal of Clinical Oncology (2017)

e20067 Background: Platinum-based CChRT is recommended as the evidence-based approach for the management of patients (p) with locally advanced stage III NSCLC and a good performance status, although a clearly superior regimen has not been identified. The aim of our study was to evaluate the effectiveness and toxicities of CChRT with Cisplatin (C) and intravenous and oral vinorelbine (V) and thoracic radiotherapy. Methods: 39 p with histologically confirmed inoperable locally advanced NSCLC, stage IIIA (T4 or N2)/IIIB, PS 0-1 and adequate lung function (FEV1 &gt; 1.1, V20 &lt; 30%) were included in CChRT with: C 80 mg/m2 day 1 and intravenous V 25 mg/m2 day 1 and oral V 60 mg/m2 day 8 for three cycles, during conformal radical thoracic radiotherapy (66 Gys, 180 cGy/day). The primary objective was overall survival (OS); secondary objectives were progression free survival (PFS), response rate (RR) and toxicity. Median follow-up: 20,4 months. Results: The p characteristics were: mean age 69,8 years (44-75); male/female: 33/6; ECOG PS 0/1: 7/32; adeno/squamous/large cell carcinoma: 20/13/6; stage IIIA 19 p and stage IIIB 20 p. All p were evaluable for response and toxicity. RR: 3 CR, 27 PR (RR 77%; 95% CI: 64-90), 5 SD (12.8%) and 4 PD (10.2%). The median PFS was 12 months (95% CI: 7-17) and median OS was 36 months (95% CI: 14-58). The PFS at 1/3 years were 46%/22% and the OS at 1/3 years were 75%/47%. Main toxicities (NCI-CTC 4.0) per p in CChRT (109 cycles of chemotherapy, 2.9 per p; mean doses RT: 65,3 Gys) grade 1-2/3-4 (%) were: neutropenia 32.4/25.6; anemia 32.4/10.8; thrombocytopenia 13.5/2.7; nausea/vomiting 27/2.7; fatigue 28.2/0; esophagitis 43.5/5.4 and pneumonitis 17.9/0; hospitalizations were necesary in 13 p: the most important were febrile neutropenia (6 p) and grade 3 esophagitis (2 p). Conclusions: CChRT with Cisplatin and intravenous and oral Vinorelbine during thoracic radiotherapy is a feasible treatment option for inoperable locally advanced stage III NSCLC, showing good clinical efficacy and tolerability with excellent long-term survival.
Nanoparticles for diagnosis and therapy of atherosclerosis and myocardial infarction: evolution toward prospective theranostic approaches
Authors: Julian Bejarano, Mario Navarro-Marquez, Francisco Morales-Zavala, Javier O Morales, Ivonne Garcia-Carvajal, Eyleen Araya-Fuentes, Yvo Flores, Hugo E Verdejo, Pablo F Castro, Sergio Lavandero, Marcelo J Kogan
Journal: Theranostics (2018)

Cardiovascular diseases are the leading cause of death worldwide. Despite preventive efforts, early detection of atherosclerosis, the common pathophysiological mechanism underlying cardiovascular diseases remains elusive, and overt coronary artery disease or myocardial infarction is often the first clinical manifestation. Nanoparticles represent a novel strategy for prevention, diagnosis, and treatment of atherosclerosis, and new multifunctional nanoparticles with combined diagnostic and therapeutic capacities hold the promise for theranostic approaches to this disease. This review focuses on the development of nanosystems for therapy and diagnosis of subclinical atherosclerosis, coronary artery disease, and myocardial infarction and the evolution of nanosystems as theranostic tools. We also discuss the use of nanoparticles in noninvasive imaging, targeted drug delivery, photothermal therapies together with the challenges faced by nanosystems during clinical translation.
Predictors for survival after radium-223 (R223) treatment for castration-resistant metastatic prostate cancer.
Authors: Eric Anderson, William Wong, Homan Mohammadi, Thomas Backus Daniels, Katherine S. Tzou, Steven E. Schild, Sameer R Keole, Richard Choo, Alan H. Bryce, Thai Huu Ho, Fernando Quevedo, Sujay A. Vora
Journal: Journal of Clinical Oncology (2016)

e16521 Background: R223 has been shown to improve survival of patients with castration resistant metastatic prostate cancer. The purpose of our study is to identify factors that predict survival after R223 treatment (tmt). Methods: The records of 64 patients at Mayo Clinic were reviewed. Data on patient and disease characteristics, and tmtresponse were collected. Kaplan-Meier estimate of survival time was calculated. Univariate analysis with log-rank test and multivariate analysis with Cox Proportional Hazards Model were performed to evaluate factors associated with survival. Results: The median age of patients was 74. At last follow up, 32 patients had died. Median survival time was 12.9 months (mo). Table 1 summarizes the survival of patients based on different parameters. Conclusions: In our study, several factors were associated with better survival on univariate analysis, including no prior chemotherapy, ≤5 bone metastases, baseline PSA≤36ng/ml, baseline ALP<115U/L, baseline hemoglobin≥12g/dl, ALP response, PSA decrease during treatment, and PSA increase less than 25% from baseline during treatment. In multivariate analysis, ≤5 bone metastasis, baseline ALP<115U/L, and ALP response remained significant predictors of survival. Median survival (mo) 12-mo survival Univariate analysis (p-value) Multivariate analysis (p-value) 0,1 12.9 67% 0.62 2,3 11.3 43% Yes 12.6 53% 0.028 0.17 No Not reached 71% Yes 16 76% 0.47 No 12.8 60% Yes 12.8 63% 0.62 No 12.9 57% ≤ 5 lesions Not reached 100% 0.0023 0.0096 > 5 lesions 12.6 56% ≤36ng/ ml Not reached 77% <0.0001 0.93 >36ng/ ml 11.5 43% <115U/L Not reached 87% 0.0004 0.0076 ≥115U/L 9.2 30% <12g/dl 10 40% 0.0026 0.75 ≥12g/dl 16 78% Yes Not reached 80% 0.015 0.02 No 12.5 52% Yes Not reached 91% 0.0095 0.49 No 12.8 60% Yes 12.6 56% 0.0061 0.24 No Not reached 100%
Combination of CT derived radiomic features and lymphovascular invasion status to predict disease recurrence following trimodality therapy in non-small cell lung cancer.
Authors: Mohammadhadi Khorrami, Prantesh Jain, Monica Khunger, Usman Ahmad, Kevin L. Stephans, Sudish C. Murthy, Vamsidhar Velcheti, Anant Madabhushi
Journal: Journal of Clinical Oncology (2018)

e24314 Background: Currently there are no clinically validated biomarkers to identify which locally advanced non-small cell lung cancer (NSCLC) patients (pts) will benefit from trimodality therapy (i.e. neoadjuvant chemoradiation (NAT) followed by surgery, TMT). In this study, we evaluate radiomic (i.e. computer extracted imaging) features of tumor phenotype as potential predictors of disease recurrence following TMT. Methods: 123 pts with stage III NSCLC treated with TMT were included. Of these, 33 pts with either distant metastasis at presentation and/or those without baseline pre-NAT CT scans were excluded. Lung tumors were retrospectively annotated by an expert reader. 1542 radiomic features (textural and shape) were extracted from intra and peritumoral regions. multivariate Cox regression analysis was performed to evaluate radiomic and clinico-pathologic factors predictive of recurrence post-surgery. Results: Pathological response was achieved in 36 (40%) pts and the rest 54 (60%) were labeled non-responders. 90 pts were randomly allocated to equally sized (n = 45) training and validation sets. The recurrence rate after surgery was 42.2% (n = 38) and the mean duration of recurrence was 20.28 ± 16.43 months. Multivariate Cox regression model revealed that a combination of two radiomic features (intratumoral and peritumoral Laplacian Laws features that capture micro-gradients and patterns of heterogeneous enhancement) from a baseline non-contrast CT scan as well as lymphovascular invasion (LVI) signature status was predictive of time to recurrence after TMT (p-value = 0.0283, 0.0129, 0.0454 respectively). Three-fold cross validation was used for training a Support Vector Machine (SVM) classifier with three features on the training set and subsequently evaluated on the validation set. The classifier successfully distinguished pts based on time to recurrence post-TMT, which was statistically significant (log-rank test, p-value < 0.014). Conclusions: Combination of LVI status and texture features extracted from within and around the tumor on baseline CT images was predictive of disease recurrence in NSCLC pts treated with TMT.
Abstract 17892: Strain Rate is Affected by Heart Rate in Younger Heart: A Simultaneous Invasive and Noninvasive in vivo Piglet Model
Authors: Etienne Fortin-Pellerin, Lisa K Hornberger, James Y Coe, Lindsay Mills, Jesus Serrano-Lomelin, Po-Yin Cheung, Nee S Khoo
Journal: Circulation (2015)

Introduction: In adult human and pig hearts, left ventricular (LV) systolic strain rate (SR) has been shown to be independent of heart rate (HR) in atrial tachycardia. It has been hypothesized that any increase in contractility related to the force-frequency relationship is balanced by a decrease in contractility due to reduced filling time and preload at higher HRs. In this study, we explore the impact of atrial tachycardia on SR of the young infant heart using a simultaneous invasive and noninvasive piglet model to determine whether SR of the immature heart is similarly not influenced by increasing HR. Methods: Under general anesthesia (propofol, isoflurane), 1 - 15 day old piglets were instrumented intravascularly with Millar high-fidelity and pacing catheters in the left ventricle and right atrium, respectively. After stabilization, invasive hemodynamic and echocardiography parameters were acquired at baseline, and at 200, 230 and 260bpm. Basal circumferential SR was analyzed off-line by speckle tracking (frame rates 247±7 Hz). Each animal was its own control and repeated measure ANOVA was used for comparison, data is expressed as mean ± SE. Results: Fourteen piglets of mean age 8.5±1.8 days, weight 3.6±0.5kg and baseline heart rate of 152±5bpm were assessed. Baseline LV systolic SR was -1.53±0.13 1/s and dP/dt 1656±115mmHg/s. With pacing, LV SR increased significantly (p = 0.002). The increase in SR mirrored the increase in contractility assessed invasively by dP/dt (p&lt;0.001). M-mode LV end diastolic dimension decreased from baseline to 260bpm (73±9.9% of baseline value, p &lt; 0.001) consistent with reduced preload with tachycardia. Conclusion: Our study suggests that in the younger heart, SR is augmented by atrial tachycardia itself even in the presence of decreased preload. This is in keeping with preservation of the force frequency relationship. Given our findings, HR should be taken into account when assessing contractility using SR in young patients.
Occupational exposure to pesticides and prognosis of diffuse large B-cell lymphoma: A cohort study.
Authors: Sylvain Lamure, Camille Carles, Quam Aquereburu, Philippe Quittet, Emmanuelle Tchernonog, Franciane Paul, Eric Jourdan, Agathe Waultier, Christine Defez, Laurence Sanhes, Sara Burcheri, Daniel Donadio, Carole Exbrayat, Alain Saad, Jean-Luc Labourey, Isabelle Baldi, Guillaume Cartron, Pascale Fabbro-Peray
Journal: Journal of Clinical Oncology (2018)

1564 Background: Professional use of pesticides is a risk factor for non-Hodgkin lymphoma. The main biological mechanisms of both pesticides and chemotherapy are genotoxicity and reactive oxygen species generation. Cellular adaptation among patients exposed to low doses of genotoxic and oxidative compounds may hinder chemotherapy efficiency in lymphoma patients. We aim to determine the influence of occupational exposure to pesticides on response to immuno-chemotherapy and survival of patients treated for Diffuse Large B Cell Lymphoma (DLBCL). Methods: The ProLyPhy study is a retrospective cohort of patients treated between 2010 and mid-2015, for DLBCL, with a least 2-year follow-up. The study took place in 6 hospitals of central southern France. We screened 404 patients with newly-diagnosed DLBCL treated with anthracycline-based immuno-chemotherapy (R-CHOP like). Occupational history was reconstructed for 244 patients. Occupational data were analysed with the Pestipop French job-exposure matrix to determine probability of occupational exposure to pesticides. We have compared treatment failure rate, 2-year event-free survival (EFS) and overall survival (OS) between exposed and non-exposed patients, after adjustment. Results: Mean age was 61.3 years (range 19-90), 62.7% of patients were male, 67 had occupational exposure to pesticides, of which 38 from farming activities. Occupational exposure did not impact clinical and biological characteristics at diagnostic. We observed that exposed patients had significantly higher treatment failure rate: 22.4% versus 11.3% (p = 0.027), OR = 3.2 (1.8-11.5, p = 0.007); this difference was higher among farmers: 31.4% CR versus 12.8%, p = 0.005, OR = 4.6 (1.8-11.5, p = 0.001). Two-year EFS was 70% in the occupationally-exposed group versus 82%, HR = 2.1 (CI 95% 1.2-3.6, p = 0.008). Among farmers, the difference was more pronounced: 2-year EFS was 56% versus 83%, HR = 3.1 (CI 95% 1.7-5.6, p < 0.001). Similarly 2-year OS was lower in the farmer group: 81% versus 92%, HR = 3.9 (CI 95% 1.5-10.0, p = 0.005). Conclusions: This retrospective study suggests that agricultural occupational exposure to pesticides is an independent risk factor for treatment failure, EFS and OS in DLBCL.