tbuckley/cabot-search huggingface dataset:
Local drug activation technology to make cytotoxics safer for localized solid tumors.
Authors: Sangeetha Srinivasan, Nathan Yee, Filemon Dela Cruz, Andrew Kung, Ervin Gaviria, Ethan Miller, Maksim Royzen, Jose Manuel Mejia Oneto
Journal: Journal of Clinical Oncology (2018)

12082 Background: Only 1-2% of systemic chemotherapies actually reaches a localized tumor while the rest can result in severe off-target effects. There is a critical need to safely deliver cytotoxics directly to the tumor. Methods: Shasqi’s Therapy (Shasqi Tx) is a bioorthogonal chemistry-based approach consisting of 1) a drug-activating gel and 2) a systemic prodrug. The biocompatible tetrazine (Tz)-modified gel is injected at tumor site and a trans-cyclooctene (TCO)-modified prodrug of a cytotoxic agent such as doxorubicin (Dox), with attenuated activity is given systemically. The prodrug concentrates through a covalent reaction between TCO and the Tz located at the gel. The active drug is spontaneously released over multiple days, directly in the tumor compartment. Remaining prodrug is rapidly cleared by systemic routes, minimizing off-target effects. This technology is reloadable and independent of biological processes. The attenuation of prodrug activity enables an increase in therapeutic index while reducing systemic side effects, as the active drug predominantly localizes to the gel site. Results: NSG-H mice injected with Tz-modified alginate gel and systemic TCO-doxorubicin (TCO-Dox; prodrug of Dox). The maximum tolerable dose (MTD) of single dose of TCO-Dox was >12x and as 5 daily doses was >38x of single MTD of Dox (control), without any adverse effects. Preliminary bioanalysis provides a basis for the improved safety of Shasqi Tx over traditional chemotherapy. Gel-injected BALB/c mice received TCO-Dox IV. In serum 5 min after injection > 90% of the circulating anthracycline remained as intact prodrug while ~7% was converted to Dox. Finally, we tested Shasqi Tx’s safety in a pilot dog study with spontaneous local adenocarcinoma. Standard Dox therapy led to disease progression with a drastic drop in body weight. Then, multiple cycles of Shasqi Tx given at > 11x the lifetime MTD of Dox, reduced tumor size and led to stable disease for > 430d, body wt. gain without major side effects. Conclusions: Shasqi Tx enhances delivery of toxic drugs to a target site while limiting exposure in off-target tissues in small and large animals. Further, the increase in therapeutic index allows greater doses of cytotoxics to be delivered safely.
TCT-121 A Highly Predictive Model for New Permanent Pacemaker Implantation after Transcatheter Aortic Valve Replacement with Contemporary Self-Expanding Valves: Importance of the Membranous Septum Length
Authors: Zhen-Gang Zhao, Mathew Williams, Cezar Staniloae, Eleonora Vapheas, Run Du, Moyang Wang, Muhamed Saric, Peter Neuburger, Michael Querijero, Alan Vainrib, Kazuhiro Hisamoto, Nicholas Amoroso, Tara Collins, Emily Clark, Illya Pushkar, Danielle Sin, Binita Shah, Zachary Taylor, Hanah Lee, Samantha Vidal, Tonya Robin, Daniel Bamira, Ricardo Benenstein, Hasan Jilaihawi
Journal: Journal of the American College of Cardiology (2018)
p16 expression and its prognostic impact in HNSCC pts in Belém-Brazil.
Authors: Amanda Raquel da Silva Gomes, Williams Fernandes Barra, Millene A Bechara, Juliana P N da Costa, Maria Fernanda V L de Carvalho, Carlos Augusto Silva, Jose L L Magalhaes, Eliude R. Nascimento, Fernando Chalu Pacheco, Gilberto Castro
Journal: Journal of Clinical Oncology (2016)

e17525 Background: p16 protein overexpression is a surrogate marker of oncogenic human papillomavirus (HPV) infection and a prognostic marker in head and neck squamous cell carcinoma (HNSCC) patients (pts). Here we aim to study p16 expression and its prognostic impact in HNSCC pts in Belém, Northern Brazil. Methods: Pts with locally advanced HNSCC treated between 2009-2012 at reference cancer center, Hospital Ophir Loyola, were included in this retrospective analysis. p16 expression was evaluated by immunohistochemistry (mouse monoclonal E6H4) and p16 was considered to be overexpressed when strong and diffuse nuclear and cytoplasmic staining was detected in at least 70% of tumor cells. Survival curves were estimated using the Kaplan-Meier method and compared with log-rank test. Univariable and multivariable hazard ratios (HRs) were estimated using the Cox proportional model. Results: 80 pts, 68 men/12 women, median age 59.5 y (28-89), staged as III (31%) and IV (69%), 88% smokers were studied. Primary sites were 19 oral cavity, 18 oropharynx, 12 hypopharynx and 31 larynx. p16 overexpression (p16+) was detected in 21 patients (26 %), predominantly in oral cavity (42%) and oropharyngeal (44%) tumors. Laryngeal tumors had significantly lower overexpression (6.45%, p 0.0001). Median follow-up was 20 months (1-73). 5-year overall survival rate for all sites was 38% in p16(+) pts versus 25% in those p16-negative (HR 0.4; 95%CI 0.49-0.9; p 0.02). Among oral cavity and oropharyngeal pts, p16+ pts also presented better 5-year OS outcomes: 49% vs. 18% (HR 0.49; 95%CI 0.26-0.92; p 0.02) and 42% vs. 18% (HR 0.27; 95%CI 0.07-1.0; p 0.05), respectively. Conclusions: p16 overexpression was frequent in these HNSCC pts and presented a favorable impact in terms of overall survival.
mRECIST to predict survival in advanced hepatocellular carcinoma: Analysis of two randomized phase II trials comparing nintedanib versus sorafenib.
Authors: Tim Meyer, Daniel H. Palmer, Ann-Lii Cheng, Julia Hocke, Arsene-Bienvenu Loembe, Chia-Jui Yen
Journal: Journal of Clinical Oncology (2016)

4086 Background: Response Evaluation Criteria in Solid Tumors (RECIST) has been shown to be a poor surrogate for survival benefit with targeted therapy in advanced hepatocellular cancer (HCC). We investigated whether response evaluated using modified RECIST (mRECIST) predicted overall survival (OS) using comparable data from two Phase II trials conducted to evaluate the efficacy/safety of nintedanib versus sorafenib as first-line treatment of mainly Caucasian patients (study 1199.37; NCT01004003) or Asian patients (study 1199.39; NCT00987935) with advanced HCC. Methods: Data from patients (n=188) treated with either nintedanib or sorafenib were pooled for analyses. Cox regression and Kaplan–Meier survival analyses were used to explore differences in OS between the responders and non-responders according to RECIST 1.0 and mRECIST criteria. Two multivariate Cox proportional hazards selection models were conducted to identify baseline variables that predict survival and if RECIST response (analysis 1) and mRECIST response (analysis 2) predict survival at the 0.2 level of significance. Results: Response rates were 4.3% (n=8) by RECIST and 14.9% (n=28) by mRECIST. Discordance between RECIST/mRECIST evaluation was most common for assessment of partial response (n=22; 11.7%) and stable disease (n=24; 12.8%). OS was significantly longer in patients with response compared to patients without response; RECIST: hazard ratio (HR) 0.32 (95% CI 0.13–0.81), p=0.0113 and mRECIST: 0.53 (95% CI 0.33–0.85), p=0.0079. In both multivariate models, presence of macrovascular invasion (MVI) and presence of extrahepatic spread (EHS) at baseline were associated with worse OS. RECIST response and mRECIST response were both significant predictors of survival (see table). Conclusions: Objective mRECIST response is a surrogate for OS and as such should be considered a valid endpoint for use in HCC trials. Clinical trial information: NCT01004003 and NCT00987935. OS hazard ratio (95% CI) p-value Analysis 1 MVI absent 0.72 (0.51‒1.01) 0.0571 EHS absent 0.71 (0.49‒1.01) 0.0591 RECIST response 0.40 (0.16‒1.01) 0.0514 Analysis 2 MVI absent 0.76 (0.54‒1.07) 0.1094 EHS absent 0.72 (0.50‒1.03) 0.0721 mRECIST response 0.61 (0.37‒0.99) 0.0431
Discovery of a predictive protein biomarker for leptomeningeal disease after craniotomy and radiation.
Authors: Michael Henry Soike, Jimmy Ruiz, Emory McTyre, Stacey O'Neill, Shadi Qasem, Cristina M Furdui, Jingyun Lee, Thomas Lycan, Christopher Rodman, Kounosuke Watabe, Stephen B Tatter, Adrian W Laxton, Michael D Chan, Jing Su
Journal: Journal of Clinical Oncology (2018)

2068 Background: Leptomeningeal disease (LMD) is a common but morbid disease progression after craniotomy for resection of brain metastases (BrM). LMD has been observed most commonly with breast cancer BrM, but the cellular mechanisms facilitating LMD have not been elucidated. We sought to identify a protein associated with a higher risk of developing LMD. Methods: At our institution, patients (2005-2016) who had craniotomy for BrM followed by adjuvant radiation therapy were eligible for this IRB approved study. Frozen BrM samples were reduced with trypsin digestion, pelleted by centrifugation, and analyzed by liquid chromatography–mass spectrometry. Mass spectra were searched with Sequest HT algorithm in Proteome Discoverer v2.1 (Thermo Scientific). Patient outcomes were obtained from the medical record and overall survival (OS) and time-to-event were calculated with Kaplan-Meier and Competing Risk. To identify proteins of interest, we used empirical Bayes based linear models (limma) and the Benjamini–Hochberg false discovery rate analysis (FDR). Univariate (UVA) and multivariate (MVA) analyzed patient characteristics and proteins associated with LMD. Results: Proteomic expression data for 39 patients were included. The median OS was 13 months. Eleven (28%) developed LMD. 6407 proteins were analyzed. After FDR, only collagen type 1 alpha 1 chain (COL1A1) and collagen type I alpha 2 chain (COL1A2) were associated with a higher risk of LMD (FDR 0.045 and 0.089, respectively). On UVA and MVA analysis, COL1A2 was associated with a statistically significant higher risk of LMD (Table). Conclusions: COL1A2, a component of type I collagen, is associated with a higher risk of LMD development, even when accounting for breast histology. COL1A2 may be a protein of interest in the mechanism facilitating LMD progression. UVA and MVA for proteins of interest developing in LMD progression. Variable UVA Hazard Ratio (confidence interval) MVA Coefficient and p-value Previous systemic therapy 7.8 (1.6-38) 1.24 p = 0.15 Smoking at diagnosis 0.4 (0.1-1.3) Age 1.0 (0.9-1.0) Gender 0.3 (0.1-1.5) Breast vs other histology 4.4 (1.5-12.8) 0.08 p = 0.89 COL1A1 1.3 (1.2-1.4) -0.002 p = 0.98 COL1A2 1.3 (1.1-1.4) 0.20 p = 0.03
Analytic validation of a clinical circulating tumor DNA assay for patients with solid tumors.
Authors: Phil Stephens, Travis A Clark, Mark Kennedy, Jie He, Geneva Young, Mandy Zhao, Mike Coyne, Ginny Breese, Jeffrey S. Ross, Lauren Young, Shan Zhong, Mark Bailey, Bernard Fendler, Vincent A. Miller, Erica Schleifman, Eric Peters, Geoff Otto, Doron Lipson
Journal: Journal of Clinical Oncology (2016)

e23049 Background: With an increasing number of circulating tumor DNA (ctDNA) profiling assays available, physicians must be empowered to distinguish which assays have the high level of accuracy required to meet the diagnostic needs of their patients from those that do not. We undertook this study to establish the analytic validation of a ctDNA assay, optimized for clinical care. Methods: A highly optimized, integrated workflow including sample collection, storage and transport, plus ctDNA purification, library generation, enrichment (solution hybridization capture) and then high depth sequencing (HiSeq2500) was developed. Computational methods were developed to enable sensitive and specific detection of all alteration classes. Accuracy and reproducibility were validated using 117 reference samples with known alterations and 268 clinical ctDNA samples. A CLIA-validated NGS assay, droplet digital PCR and break-point PCR were used to validate alterations identified. Results: The ctDNA assay demonstrated unprecidented accuracy: > 99% sensitivity and > 99% positive predictive value (PPV) for base subs and indels, > 99% sensitivity and 98% PPV for rearrangements/fusions with a limit-of-detection below 0.5%, plus robust detection of high-level, focal amplifications. In addition, the assay accurately reports allele frequency. In 48 clinical ctDNA samples, 95 alterations of all classes were 100% confirmed by orthogonal testing. We also report results comparing alterations from patient-matched ctDNA and FFPE biopsies across > 500 solid tumors. Conclusions: The development of a commercially directed ctDNA assay requires rigorous analytic validation and availability of clinically relevant test metrics to assure reliable interpretation and reporting to optimize targeted treatment options. This rigorous analytic validation study demonstrates high-accuracy detection of all alteration classes even when present at low allele frequency from blood,, thereby realizing the potential of ctDNA-based molecular profiling for the management of patients with cancer. An ongoing large prospective clinical trial will provide additional initial data on appropriate clinical settings for use of this assay in patient care.
P04.15 Autophagy induction following TTFields application serves as a survival mechanism mediated by AMPK signaling
Authors: Y Porat, A Shteingauz, T Voloshin, R Schneiderman, M Giladi, E Kirson, U Weinberg, A Kinzel, Y Palti
Journal: Neuro-Oncology (2018)

Tumor treating fields (TTFields) are an approved treatment modality for patients with glioblastoma, delivered via noninvasive application of low-intensity, intermediate-frequency, alternating electric fields. TTFields were shown to induce abnormal mitosis, aneuploidy, and increased cell granularity, which are often associated with enhancement of autophagy. In this work, we evaluated the possible effect of TTFields on regulation of autophagy in glioma cells Cells were treated with TTFields using the inovitroTM system. Cellular granularity was evaluated using flow cytometry. Autophagy was monitored by quantifying levels of lipidated Microtubule Associated Protein Light Chain 3 (LC3-II), in the presence and absence of the lysosomotropic agent and autophagy inhibitor chloroquine (CQ), using immunoblotting and immunofluorescence microscopy. Transmission Electron Microscopy (TEM) was used to visualize autophagosome-like structures. Time-lapse microscopy was utilized to follow autophagy induction in dividing cells. Endoplasmic reticulum (ER) stress markers were monitored by immunoblotting (for GRP78) and colorimetric assay (for intracellular ATP). Evaluating the roll of AMP activated protein kinase (AMPK) in autopagy induction was conducted by immunoblotting, as well as AMPK depletion by siRNA. Involvement of autophagy in cell fate after TTFields treatment was evaluated by producing Atg7 depleted glioma cell lines via shATG7 infection, as well as by combining TTFields with CQ, and monitoring cell growth and apoptosis by flow cytometry. Significant increase in cellular granularity was demonstrated in all tested cell lines. Up-regulation of autophagy in glioma cell lines treated with TTFields was demonstrated by immunoblot analysis. Fluorescence and transmission electron microscopy demonstrated the presence of LC3 puncta and typical autophagosome-like structures in treated cells. Time-lapse microscopy revealed significant increase in the formation of LC3 puncta, specific to cells which divided during treatment. Indication of proteotoxic stress in treated cells was evident based on elevated GRP78 levels and decreased cellular ATP. Pathway analysis showed that AMPK activation regulates autophagy induction by TTFields. AMPK depletion from U87-MG cells resulted in autophagy inhibition as reflected by LC3-II levels. Depletion of either AMPK or Atg7 sensitized cells to the treatment, suggesting that cancer cells utilize autophagy as a resistance mechanism to TTFields. Combining TTFields with CQ resulted in a significant dose-dependent reduction of cell growth compared with TTFields or CQ alone. These results suggest that dividing cells upregulate autophagy in response to aneuploidy and ER stress induced by TTFields application and that AMPK may serve as a key regulator of this process.
Distribution of PD-L1 expression in diverse cancer types: Experience with over 10,000 cases.
Authors: Zoran Gatalica, Ari M. Vanderwalde, Inga Rose, Sting Chen, Sandeep K. Reddy, Omid Hamid, Michael B. Atkins
Journal: Journal of Clinical Oncology (2016)

11548 Background: Blocking the programmed death-1 (PD-1) pathway has clinical benefit in metastatic cancer and has led to the approval of two mAbs for several cancer types. Expression of PD-1 ligand (PD-L1) on the tumor cell surface is associated with a higher likelihood of response to PD-1 blockade in multiple studies. We analyzed the distribution of PD-L1 in a wide variety of tumor types, studied the underlying mechanisms of expression, and compared methods of detection. Methods: 10,187 tumor samples were tested for expression of PD-L1 (SP142 antibody, Spring Biosciences). Expression (IHC) of PD-L1 in a selected number of cases was compared to 3 additional mAbs (SP263, Ventana; 22c3 and 28-8 DAKO). PD-L1 gene amplification was calculated using next generation sequencing (NGS) data. Results: Using the ≥ 2+ intensity and ≥ 5% IHC threshold, PD-L1 was detected with the highest frequency in thymic carcinoma (63%), followed by lymphomas (42%), head and neck squamous carcinoma (35%), anal carcinoma (31%), non-small cell lung cancer (30%), thyroid carcinoma (29%), bladder carcinoma (22%), cervical carcinoma (20%), melanoma (19%), and esophageal and GE junction carcinoma (15%). Significant differences between genomically defined cancer subtypes were observed (e.g. 4-fold more frequent PD-L1 expression in MSI-H colorectal and endometrial carcinomas vs. MSS counterparts). Analytical comparison of 4 different, yet well-defined Abs used in numerous clinical trials showed overall concordance of > 90%, irrespective of the thresholds employed. High copy number ( ≥ 8) of PD-L1 gene was identified in 1/2 DLBCL, 1/3 thymic carcinoma and additionally in a small percentage of breast carcinoma (4%), non-small cell lung cancer (2%) and ovarian carcinoma (1%). Conclusions: Targetable PD-L1 protein expression was identified in numerous cancer types, including some rare but highly overexpressing types not previously recognized. Threshold determination for predictive purposes remains challenging, but concordance between 4 antibodies was superb. High PD-L1 gene amplification (alone or co-amplification with JAK2 gene) is detected in a minority of carcinomas, and additional methods of detection (e.g. in-situ hybridization) may be needed.
Identifying patients for clinical trials: Evaluation of NCI-designated community cancer centers.
Authors: Christine B. Mackay, Kerry Hepler, Kirsten D Erickson, Christine Daley
Journal: Journal of Clinical Oncology (2016)

e18174 Background: The University of Kansas Cancer Center achieved NCI designation in 2012, and the year prior, acquired 5 outpatient cancer clinics, which contributed to nearly a doubling of the tumor registry cases. Prior to this merger, these practices were part of one of the nation’s largest site management organization networks of community-based oncology practices and were consistently listed as top accruing sites for many of the trials that were conducted. Soon after the merger, clinical trial enrollment dropped significantly, providing a unique opportunity to analyze the reasons for this drastic change in accrual patterns. The primary aim of this study was to identify what factors influence how patients are identified for possible clinical trial participation. Methods: This was a cross-sectional qualitative design. Individual interviews were conducted with 27 physicians and nurse practitioners. Six focus groups included 26 clinical and research staff. Descriptive summary statistics and standard text analysis were performed to summarize responses. Results: The top three factors reported to affect patient identification included: 1) absence of research staff in the clinic, 2) low physician engagement in the clinical trial process, and 3) a general lack of awareness of clinical trials by providers, clinic and research staff. 100% of the providers interviewed agreed that clinical trials are beneficial for patients as well as the practice, and most (98%) agreed the physician is primarily responsible for patient identification. Conclusions: The results from this project support the literature which suggests that physicians are the most significant factor in successful recruitment of patients to cancer clinical trials but adequate organizational support is necessary. Centers considering expanding their network to include community locations should be aware of how organizational changes may affect physician ability to accrue.
Enhancing bladder cancer (BC) care through clinician and patient education.
Authors: Hamsa Jaganathan, Anne Roc, Wendy Turell, Matt D. Galsky
Journal: Journal of Clinical Oncology (2018)

e18834 Background: Management of bladder cancer (BC) requires a patient-centered, multidisciplinary team approach, which has been advocated by ASCO. To understand healthcare provider (HCP) and patient perspectives on the quality of BC care in navigating the treatment course, we offered 1 hour of continuing medical education (CME) to HCPs and 1 hour of education to patients and analyzed self-reported survey responses. Methods: PlatformQ Health and Bladder Cancer Advocacy Network produced: a CME activity that aired live online on August 2017 and on-demand for 6 months, and a corresponding patient activity that aired live online September 2017 and on-demand for 12 months. Survey-based evaluations measured HCP responses on how they conduct quality of life (QOL) conversations with their patients and if multidisciplinary teams are used when making treatment decisions. Patient surveys asked similar themes to assess their perspectives on quality of care of their HCPs. Results: After the CME activity, 33% (n = 102) of HCPs reported discussing QOL (e.g. daily tasks, exercise, nutrition) with their patients in every visit, and 27% (n = 49) reported making greater efforts to ensure a multidisciplinary approach in their treating patients with BC. After the patient activity, only 19% (n = 59) of patients reported discussing QOL issues in every visit with their HCPs, and more than half (55%) discuss QOL issues only when specific questions or issues are raised. Patients also reported that: communication or collaboration with their HCP improved (50%, n = 60), they felt more in control of their health care decisions (54%, n = 48), and their health-related behaviors improved (36%, n = 59). Moreover, 51% (n = 59) of patients reported receiving care from a urologist and primary care provider to manage their disease, and 44% reported seeing a primary care provider, urologist, oncologist, and other HCPs, suggesting that team-based approaches are being applied to their care. Conclusions: While results indicate that multidisciplinary team approaches are being implemented in BC practice, there is an overall need for HCPs and patients to receive more education that encourages both groups to be actively involved in cancer care.