tbuckley/cabot-search huggingface dataset:
Novel domain-targeted anti-Trop-2 monoclonal antibodies to elicit therapeutic synergy against multiple human cancers.
Authors: Saverio Alberti, Marco Trerotola, Valeria Relli, Chiara Pedicone, Antonella D' Amore, Francesca Dini, Silvia Fratarcangeli, Emanuela Guerra
Journal: Journal of Clinical Oncology (2017)

e14002 Background: Trop-2 is a calcium signal transducer that drives tumor cell growth. Trop-2 is overexpressed in the majority of carcinomas, where it associates with worse prognosis. The Trop-2 extracellular domain contains a N-terminal cysteine-rich globular domain followed by a stem-like cysteine-less region that connects to the transmembrane domain. Trop-2 engages in homophylic interactions between adjacent cells and interacts with tight-junction proteins, which may severely affect accessibility by therapeutic monoclonal antibodies (mAb). Available anti-Trop-2 mAb mostly recognize a single immunodominant epitope between the globular and stem regions, and have limited or no therapeutic efficacy. In order to untap the potential of anti-Trop-2 immunotherapy we generated novel anti-Trop-2 mAb with tailored specificity towards the globular versus stem regions. Methods: Balb-C mice were immunized with soluble human Trop-2 produced in human 293 and murine L cell lines and in baculovirus expression system. Domain-targeted anti-Trop-2 mAb were selected by flow cytometry using live 293 transfectants.Therapeutic potential was assessed in human cancer xenografts in murine models. mAb mode of action was investigated by Western blot, live-cell imaging and in vitro ADCC and cancer cell growth inhibition assays. Results: mAb were identified that were differentially directed against the Trop-2 stem versus globular regions. These mAb efficiently bound Trop-2 expressing cancer cells and inhibited cell growth in vitro. In vivo, naked anti-globular OX-G64 and anti-stem OX-S55 mAb were most effective in inhibiting the growth of colon, ovary, breast and prostate cancers as xenografts in nude mice. NSG mice and in vitro mechanism profiling indicated efficient ADCC, together with efficient internalization for ADC development. Differential efficacy for established tumors versus isolated-cell models of metastatic dissemination was shown. Most remarkably, OX-G64/OX-S55 co-administration demonstrated sinergic growth inhibition in vivo. Conclusions: The OX-G64 and OX-S55 anti-Trop-2 mAb are novel domain-targeted, sinergic therapeutic mAb for game-changing anti-cancer immunotherapy.
TCT-187 Periprocedural complications and procedural effectiveness in diabetics and non-diabetics treated with percutaneous coronary interventions and rotablation
Authors: Rafał Januszek, Artur Dziewierz, Zbigniew Siudak, Tomasz Rakowski, Tomasz Kameczura, Magdalena Jędrychowska, Artur Pawlik, Dariusz Dudek, Stanislaw Bartus
Journal: Journal of the American College of Cardiology (2018)
Abstract 11980: National Trends and In-hospital Outcomes During Delivery in Pregnant Women With Heart Disease in the US
Authors: Paraskevi Koutrolou-Sotiropoulou, Fabio V Lima, Jie Yang, Jianjin Xu, Kathleen Stergiopoulos
Journal: Circulation (2016)

Background: Investigation of trends and outcomes in heart disease (HD) and pregnancy has been limited. Objective: We chose to investigate the temporal trends and outcomes of pregnancy in women with HD in the US from 2003-2012. Methods: Healthcare Cost and Utilization Project’s National Inpatient Sample was screened for hospital admissions for delivery in pregnant women with HD from 2003-2012. Maternal clinical characteristics and outcomes were identified in women with and without HD, and in HD subtypes: congenital (CHD), valvular (VHD), cardiomyopathy (CDM), and pulmonary hypertension (PH). Primary outcomes of interest were prevalence, trends, and major adverse cardiac events (MACE), a composite of in-hospital death, acute myocardial infarction, heart failure, arrhythmia, cerebrovascular event, embolic events, or cardiac complications of anesthesia. Results: We studied 81,295 patients with HD and 39,894,032 without. CHD was the most frequent type (41.8%, 33,982 of 81,295), followed by VHD (30.9%, 25,138 of 81,295), CDM (20.8%, 16,926 of 81,295) and PH (6.5%, 5,250 of 81,295). MACE was highest among women with CDM and lowest in CHD (44.0%, 7,449 of 16,926 vs 6.2%, 2,102 of 33,982 p&lt;0.0001). PH patients had the highest in-hospital death, followed by CDM (1.0%, 51 of 5,250 and 0.7%, 124 of 16,926 respectively). Pregnant women with HD significantly increased by 24.7%, related to increases in CDM, CHD, and PH. MACE significantly increased by 18.8%. Conclusions: Pregnancy in women with heart disease is increasing, particularly for high risk conditions such as CDM and PH. There is a significant and gradual increase in MACE for women with heart disease.
A phase 1b/2 study of napabucasin with weekly paclitaxel in advanced, previously treated platinum resistant ovarian cancer.
Authors: Carlos Becerra, Agustin A. Garcia, John L. Hays, Michael W. Method, Stephen Lane Richey, Adrian Langleben, Donald A. Richards, Gregory Michael Cote, Kimiko Kossler, Wei Li, Youzhi Li, Matthew Hitron, Chiang Li
Journal: Journal of Clinical Oncology (2017)

5548 Background: Napabucasin is a first-in-class cancer stemness inhibitor, identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al PNAS 112 (6):1839, 2015). Napabucasin has shown potent synergistic preclinical anti-tumor activity with paclitaxel (PTX). In a phase Ib dose escalation study in patients (pts) with advanced solid tumors, napabucasin plus weekly PTX was well tolerated. A phase II expansion cohort was opened for patients with platinum resistant ovarian cancer. Methods: Pts with advanced ovarian cancer who had disease progression either during or in the 6 months following platinum-based systemic therapy were enrolled. napabucasin was administered orally at a starting dose of 240, 480, or 500 mg twice daily with PTX 80 mg/m2 IV weekly on 3 of every 4 weeks. AEs were evaluated using CTCAE v4.03 and objective assessments were performed per RECIST 1.1 every 8 weeks. Results: A total of 98 pts were enrolled. The average number of prior lines of systemic treatment was 3.5, including prior taxane-based therapy in 100% of patients. Treatment was well tolerated. Related grade 3 adverse events occurring ≥ 5% of pts included diarrhea (12.2%) and vomiting (5.1%). Among pts who received RECIST evaluation (n = 76), the disease control rate (DCR, proportion with SD at 8 weeks + PR + CR) was 65%, and the objective response rate (ORR, PR+CR) was 20%, with complete response in 3 pts (4%). In all patients (ITT, n = 98), the median progression-free survival (mPFS) was 3.0 months and median overall survival (mOS) was 9.3 months. Conclusions: Clinical safety and encouraging signs of anti-cancer activity, including three complete responses, were observed in pts with pre-treated platinum resistant ovarian cancer who received treatment with napabucasin plus weekly PTX. Further clinical evaluation in controlled trials is warranted. Clinical trial information: NCT01325441.
Abstract 15361: Loss of Caveolin-3 Disrupts Mouse Sinoatrial Node Pacemaking and Stimulates Atrial Arrhythmogenesis
Authors: Di Lang, Aleah Warden, Ravi Balijepalli, Timothy J Kamp, Alexey V Glukhov
Journal: Circulation (2016)

Introduction: Caveolae represent a population of caveolin-3 (Cav3)-containing membrane microdomains housing a number of ion channels and transporters that are involved in sinoatrial node (SAN) pacemaking. Cav3 organizes these channels within macromolecular signaling complexes providing highly localized autonomic regulation of the SAN. Hypothesis: Cav3 is required for functional integrity of the SAN, synchronizing Ca release and Ca-voltage coupling. Methods: ECG telemetry, simultaneous optical mapping of voltage and Ca in whole hearts and isolated atria, and Ca imaging of isolated atrial myocyte were applied to wild type (WT, n=8) and Cav3 knockout (KO, n=8) mice, at baseline and under isoproterenol (Iso). Results: Though no difference in average heart rate (HR) was revealed between groups, KO mice showed significant beat-to-beat HR variability, both in vivo and in vitro (9.4 ± 2.4% from HR in KO vs. 2.2 ± 1.1% in WT, P<0.01). Optical mapping linked the increased HR variability to enhanced ectopic foci out...
Identifying opportunities to improve quality of cancer care: An evaluation of the use of diagnostic imaging in women curatively treated for early breast cancer (EBC).
Authors: Katherine Enright, Tejas Desai, Rinku Sutradhar, Alejandro Gonzalez, Melanie Lynn Powis, Nathan Taback, Christopher M. Booth, Maureen E. Trudeau, Monika K. Krzyzanowska
Journal: Journal of Clinical Oncology (2016)

6603 Background: The overuse of imaging scans to detect recurrence in curatively treated EBC patients was recently identified as one of ASCO’s top five opportunities to improve the quality of cancer care. We undertook a population-level assessment of the current practice of imaging in women treated for EBC. Methods: EBC patients diagnosed in Ontario, Canada between 01/2006 –and 12/2010 were identified from the Ontario Cancer Registry. Patient records were linked deterministically to provincial healthcare databases to provide comprehensive follow-up. We identified any advanced imaging scans (AIS) (computed tomography, bone scans) and basic imaging scans (BIS) during the first year after completion of curative treatment. Descriptive analyses were used to assess the impact of patient and provider characteristics on the likelihood of having AIS. Results: Of the 30,006 EBC patients included, 9,186 (30.6 %) had AIS in year one (Table). In patients with AIS, the median number of scans was 2.5(IQR1-3). Older age, higher stage, comorbidity, chemotherapy (CT) exposure and having had staging investigations increased the likelihood of AIS (P < 0.001). The majority of year one scans were ordered by medical oncologists (38%) followed by primary care physicians (23%), surgeons (13%) and emergency room physicians (7%). Conclusions: While imaging is common in follow-up for EBC patients and appropriate for symptom driven investigation, the high rate of AIS use is an actionable target for quality improvement. Use of BIS and AIS in first year of follow up for EBC. Advanced N=9,186 (30.6%) Basic N=8,401 (28.0%) No Imaging N=12,419 (41.4%) Age Median (IQR) 60 (50-71) 60 (49-70) 61 (51-70) Stage 1 3,127 (34.0%) 4,018 (47.8%) 6,123 (49.3%) 2 3,978 (43.3%) 3,421 (40.7%) 4,888 (39.4%) 3 2,081 (22.7%) 962 (11.5%) 1,408 (11.3%) Comorbidity 0 8,333 (90.7%) 7,780 (92.6%) 11,695 (94.2%) 1 268 (2.9%) 183 (2.2%) 203 (1.6%) 2+ 585 (6.4%) 438 (5.2%) 521 (4.2%) Treatment Adjuvant CT 4,392 (47.8%) 3,441 (41.0%) 4,529 (36.5%) Neoadjuvant CT 743 (8.1%) 303 (3.6%) 533 (4.3%) No CT 4,051 (44.1%) 4,657 (55.4%) 7,357 (59.2%) Staging Scans 6,650 (72.4%) 5,237 (62.3%) 7,261 (58.5%)
Implementing a comprehensive translational oncology platform: From molecular testing to actionability.
Authors: Zahi Ibrahim Mitri, Swapnil Parmar, Brett Johnson, Annette Kolodzie Kolodzie, Jamie Keck, Max Morris, Alexander Guimaraes, Brooke Beckett, Uma Borate, Charles D. Lopez, Kathleen A. Kemmer, Joshi J. Alumkal, Tomasz M. Beer, Christopher L. Corless, Gordon B. Mills, Raymond C. Bergan
Journal: Journal of Clinical Oncology (2018)

e14521 Background: To implement real-time multi-omic analysis of proximal tumor biopsies to support precision-guided therapeutic intervention, a tissue acquisition and analysis trial was implemented. Here we report on anticipated findings and the unanticipated impact on patient management of this trial in the context of the broader initiative. Methods: Eligible patients presenting to Oregon Health and Science University Knight Cancer Institute were enrolled. Patients with biopsy proven metastatic or locally advanced unresectable prostate cancer, breast cancer, pancreatic cancer, or refractory acute myelogenous leukemia receiving standard of care therapy were eligible. Image guided percutaneous metastatic biopsies were collected and analyzed by the Knight Diagnostic Laboratories using CLIA/CAP-compliant next-generation DNA sequencing (GeneTrails Comprehensive Solid Tumor Panel - 124 genes) and RNA sequencing (GeneTrails Solid Tumor Fusion Gene Panel - 20 genes). Results were made available to the treating physician. Results: Between 1/26/2017 and 11/2/2017, 35 patients were enrolled, of which 25 successfully underwent biopsy. Of 23 samples yielding sufficient tumor for analysis, median biopsy cellularity and number of cores collected were 70% (15-90%) and 6 (2-20), respectively. No procedure-related complications were reported. 20 of 23 (87%) tumor samples harbored at least one potentially actionable mutation, with 18 (78%) harboring > 1 potential actionable mutation. The most common genetic alterations identified involved DNA damage repair genes, cell cycle regulating genes, the PIK3CA/Akt/mTOR pathway, and the FGFR gene family. To date, genomic results were used by treating physicians to guide next line of therapy for 4 (20%) patients. Conclusions: Real-time prospective tissue acquisition and analysis to support a successful translational oncology platform is feasible, frequently identifies potentially actionable mutations, and alters treatment selection in patients. This program is being expanded to additional clinical and research biomarker tests, and will provide the foundation to improve access and accrual to biomarker driven precision oncology trials.
Association of poor compliance with adjuvant chemotherapy with poorer survival in patients with rectal cancer: A NCDB analysis (N=14,742).
Authors: Zhaomin Xu, Supriya Gupta Mohile, Mohamedtaki Abdulaziz Tejani, Adan Becerra, Christopher Thomas Aquina, Bradley J Hensley, Reza Arsalanizadeh, Katia Noyes, John R. Monson, Fergal J Fleming
Journal: Journal of Clinical Oncology (2016)

3569 Background: Current NCCN treatment guidelines for locally advanced rectal cancer include neoadjuvant chemoradiation, followed by total mesorectal excision and adjuvant chemotherapy. The aim of this study was to identify factors associated with hospital-specific rates of adjuvant chemotherapy and examine the subsequent impact on survival among stage II/III rectal cancer patients. Methods: National Cancer Data Base was queried for clinical stage II/III rectal cancer patients (2006-2011) who underwent neoadjuvant chemoradiation followed by surgical resection. A multivariable logistic regression was used to identify patient and hospital factors associated with receipt of adjuvant chemotherapy. A Cox proportional hazards model was used to estimate the adjusted effect of receiving adjuvant therapy on 5-year overall survival (OS). Results: 14,742 patients were included. Approximately 68% of the cohort did not receive adjuvant chemotherapy. Older age, higher comorbidity score, and complete pathologic response were associated with lower odds of receiving adjuvant therapy. After risk adjustment, there was a 22-fold difference in the rate of adjuvant therapy use between the worst performing hospital and best performing hospital (3.1 to 67.7%). Use of adjuvant therapy was associated with better 5-year OS after controlling for patient confounders (HR = 0.65, 95% CI = 0.59-0.71). Conclusions: Adjuvant chemotherapy was associated with a 35% increased odds of overall survival. Despite this, only a third of eligible patients received adjuvant therapy. There is poor compliance and wide variation across hospitals in adherence to NCCN guidelines. In light of these concerning findings, new interventions such as comprehensive geriatric assessment and physical rehabilitation should be explored to see if they help address this disparity. Cox proportional hazard model: 5-year overall survival stratified by pathologic response. pCR n = 1,727 ypT0-2 n = 5,130 ypT3-4 n = 7,885 ypN0 n = 9,865 ypN+ n = 4,877 % Who received adjuvant chemotherapy 28.0 31.8 33.1 28.6 39.1 Adjuvant chemotherapy (HR) Yes 0.40 (0.23-0.67) 0.59 (0.48-0.73) 0.73 (0.66-0.81) 0.60 (0.52-0.69) 0.77 (0.68-0.87)
FDG PET/CT imaging for prognosis of metastatic non-iodine avid differentiated thyroid cancer.
Authors: Poorni Manohar, David Brandel, Emily Light Bellile, Francis P. Worden, Anca M Avram
Journal: Journal of Clinical Oncology (2016)

e17555 Background: There are no standardized prognostication algorithms for metastatic differentiated thyroid cancer (DTC). We hypothesized that [18F]-FDG PET/CT can be used to predict progression vs. stability of disease based on semi-quantitative analysis of metabolic activity within metastatic lesions. Methods: We performed a retrospective study of 64 patients (pts) with non-iodine avid metastatic DTC, of which 19 pts (30%) were treated with tyrosine kinase inhibitors. Clinical (age, gender), histopathology and radiological data were reviewed. Baseline PET/CT scan was obtained upon diagnosis of non-iodine avid metastatic DTC. Semi-quantitative analysis of metabolic activity within metastatic lesions determined the number of FDG-avid metastases, SUVmax in each lesion, and ratio of SUVmax/SUVmean blood pool activity. Progression was determined by follow-up CT scans performed every 3 - 6 months. We correlated the data collected from subsequent CT scans regarding progression or stability of lesions with the FDG avidity of metastatic lesions on baseline PET/CT scans. Data was analyzed as continuous measures to identify association between baseline FDG avidity of metastatic lesions and progression free survival (PFS) and overall survival (OS) in univariate Cox proportional hazards models. Each hazard ratio (HR) represents the relative hazard for a 10 unit increase in SUV measure. Results: After median follow up time of 47 months, 32 pts (50%) died, 19 pts (30%) had disease progression and 13 pts (20%) had stable disease. Higher SUVmax and higher SUV ratios at baseline were associated with worse PFS (HR 1.19 (CI 1.004 -1.42) p 0.04) and (HR 1.40 (CI 1.00-1.95) p 0.05), respectively. In our study, higher SUVmax and SUV ratio did not demonstrate statistically significant outcomes in overall survival (HR 1.07 (CI 0.89 -1.29) p 0.49) and (HR 1.08 (CI 0.75-1.55) p 0.70), respectively. Conclusions: With the advent of molecular targeted therapies and improved progression free disease, there is a need to develop better prognostication tools. PET scan may be used to predict progression earlier than anatomical CT and therefore may stratify patients into high risk and low risk categories to guide appropriate therapy selection.
Is third-line chemotherapy routine practice in recurrent or metastatic gastric cancer?
Authors: Hyun Woo Lee, Yong Won Choi, Mi Sun Ahn, Seok Yun Kang, Jin-Hyuk Choi
Journal: Journal of Clinical Oncology (2017)

e15558 Background: Patients (pts) with recurrent or metastatic gastric cancer eventually experience disease progression during or after completion of first-line chemotherapy. Second-line therapy is generally recommended in the current guidelines. Although third-line therapy is often performed in daily practice in some countries, there are few reports about the benefit of third-line therapy. Methods: A retrospective review was conducted on 683 pts who underwent at least first-line palliative chemotherapy for recurrent (n = 297) or primary metastatic (n = 386) gastric cancer. Clinicopathological characteristics and overall survival (OS) were analyzed according to the lines of chemotherapy as well as for all study pts. Results: One hundred and forty-nine pts (21.8%) underwent third- or further-line therapy. Third- or further-line therapy was more frequently performed in pts with young age ( &lt; 70) (p &lt; 0.0001), ECOG PS 0 or 1 (p &lt; 0.0001) at the initiation of first-line therapy, first-line combination regimen (p = 0.006), and palliative surgical resection before first-line therapy (p = 0.029). The median follow-up duration was 62 months (24-151 months) for the survivors. The median OS for pts after first- and third-line therapy was 10 and 6 months, respectively. The median OS of pts who received third-line therapy was significantly longer than that of pts who received second- or lesser-line therapy (18 vs. 8 months, p &lt; 0.0001). Multivariate analysis revealed that third- or further-line therapy was independently associated with favorable OS (hazard ratio = 0.56, p &lt; 0.0001) along with surgical resection (p &lt; 0.0001) and first-line combination regimen (p = 0.008), whereas signet ring cell histology (p = 0.002) and peritoneal metastasis (p = 0.027) were independent prognostic factors of poor OS. Conclusions: This study suggests that recurrent or metastatic gastric cancer pts may benefit from third-line chemotherapy, although careful selection is essential.
Early retirement after return to work among cancer survivors: A population based study.
Authors: Yakir Rottenberg
Journal: Journal of Clinical Oncology (2018)

e22064 Background: Long term working maintenance among cancer survivors is important for patients, their families, and society. This study compares the risk early retirement following return to work at 2 years after cancer diagnosis to a reference population free of cancer. Methods: Cohort inception and baseline measurements for this historical prospective study were drawn from the Israeli Central Bureau of Statistics 1995 National Census, followed up until 2011. Cancer incidence was obtained from the Israel Cancer Registry and employment status was obtained from the Tax Authority. Patients who died before the end of 2011 were excluded from the study. Results: 5,475 cancer patients who worked 2 years after diagnosis and 17,322 persons without a history of cancer were included in the study. Cancer was associated with early retirement following return to work at 2 years after cancer diagnosis from 3 years after diagnosis (HR = 1.19, 95% CI: 1.06-1.33) up to 9 years after diagnosis (HR = 1.29, 95% CI: 1.38-1.48), after adjusted for age, sex, ethnicity, years of education, and socioeconomic position. Conclusions: Cancer survivorship is associated with subsequent early retirement up to 9 years after diagnosis. These results emphasize the need for evaluation of unemployment status and development of tailored intervention in order to enhance working maintenance even among cancer survivors who return to work at 2 years after cancer diagnosis.