tbuckley/cabot-search huggingface dataset:
Potential eligibility of metastatic colorectal cancer (MCRC) patients for last line therapy: Implications for drug access.
Authors: Wayne Hung, Gillian Gresham, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2015)

e17572 Background: Regorafenib is a relatively new treatment option for MCRC patients who have exhausted all other available therapies, but this agent is costly and can pose unique toxicities for patients. Characterizing the actual proportion of patients in an unselected population that would be eligible for this treatment can inform appropriate allocation of healthcare resources and facilitate clinicians in identifying patients most suitable to benefit from this drug. Methods: Patients diagnosed with MCRC from 2009 to 2014, referred to any 1 of 5 cancer centers in British Columbia, and received all available lines of therapies except regorafenib were included. We compared each patient’s characteristics against the inclusion and exclusion criteria used in the registration trial of regorafenib to determine if the patient would be considered eligible to receive the drug if it were available. At the time of this study, regorafenib was not funded for use. Overall survival was defined as the time interval between date of original stage IV diagnosis and date of death. Results: We identified 398 patients: median age was 61 years, 63% were men, 78% were White, and 58% were ECOG 0/1. Overall, 268 (67%) patients had 3 prior lines of therapy, while the rest had 4 or more. On review, only 113 (28%) patients were deemed suitable to receive regorafenib whereas the remainder would be considered ineligible. Common reasons for ineligibility included poor ECOG 2+ (43%), laboratory abnormalities (38%) particularly liver dysfunction (32%), history of arterial or venous thromboembolic events (23%), and uncontrolled cardiac disease (12%). Survival analysis demonstrated that eligibility for regorafenib itself without receiving actual treatment was associated with improved survival when compared to ineligible individuals (3.7 vs. 2.6 years, p = < 0.001). Conclusions: Only a minority of MCRC patients would be considered eligible for regorafenib and potentially proceed with treatment. As not all patients are suitable to receive the last line of therapy, this could minimize the budget impact of the drug on the healthcare system. Applying trial eligibility criteria to the population can help to inform funding decisions.
Development of myeloid-derived suppressor cells (MDSC) targeted therapy for the treatment of cisplatin-resistant bladder cancer.
Authors: Yuji Takeyama, Minoru Kato, Yasuomi Shimizu, Kosuke Hamada, Taro Iguchi, Satoshi Tamada, Tatsuya Nakatani
Journal: Journal of Clinical Oncology (2019)

415 Background: The emergence of immune checkpoint inhibitors (ICI) has brought hope for cure and survival for those suffering from various cancers, including bladder cancer. However, the response rate of ICI monotherapy is modest, and recent reports indicate that myeloid-derived suppressor cells (MDSC) might play a role in the resistant mechanism of ICI. In this study, we assess the effect of chemokine signal on the proliferation of bladder cancer and investigate whether MDSC could be a new target for the treatment of cisplatin-resistant bladder cancer. Methods: We established a cisplatin resistant strain (MB49R) of mice bladder cancer cell line MB49, and examined the alteration of the expression levels of inflammatory chemokines by chemokine array. Next, we isolated MDSCs from spleen and tumor in tumor-bearing mice to examine gene expression levels of chemokine receptors (CXCR2 and CCR2) and immunosuppression genes (Arg-1 and iNOS). Furthermore, we assessed the efficacy of CDDP, α-PD-L1 and chemokine antagonists against the proliferation of tumors in MB49 and MB49R xenograft models. Results: Expression levels of CCL2 and CXCL1/2, which are involved in the migration of MDSC, were significantly increased in the culture supernatant of MB49R compared to those in MB49 cell lines. This result was confirmed by real-time RT-qPCR of tumor extract, and this increase was also observed in human bladder cancer cell lines (T24 and T24R). CXCR2 and CCR2 were highly expressed in PMN-MDSC and M-MDSC, respectively, which were isolated from spleen or tumors in tumor-bearing mice, and gene expression levels of Arg-1 and iNOS were dramatically increased in M-MDSCs from the tumor tissues compared to those from spleen. Also, analysis by flow cytometry revealed that PMN-MDSC dramatically decreased in MB49R compared to parental MB49 tumors, while the proportion of M-MDSC was not changed in MB49R, which indicates that M-MDSC could be a target for the treatment of CDDP resistant bladder cancer. Conclusions: The results in the present study might indicate that the combination treatment with ICI and MDSC-targeting therapy could be an option for the treatment of cisplatin-resistant bladder cancer.
Engineered Human Umbilical Cord Derived Erythroid Progenitor Cells (HUDEP2) with Sickle or β-Thalassemia Mutation: An in-Vitro System for Testing Pharmacological Induction of Fetal Hemoglobin
Authors: So Hyun Park, Ciaran M Lee, Yankai Zhang, Alicia Chang, Vivien A Sheehan, Gang Bao
Journal: Blood (2018)
Growth-factors system in anti-EGFR monoclonal antibody therapy in the treatment of patients with head and neck squamous cell carcinoma (HNSCC).
Authors: Liubov Yu Vladimirova, Elena Mikhaylovna Frantsiyants, Marina Engibaryan, Aza Agieva, Natalia D. Cheryarina, Irina L Popova
Journal: Journal of Clinical Oncology (2015)

e17014 Background: AntiEGFR monoclonal-antibody cetuximab (C) is proved to increase the efficacy of the treatment of patiens with HNSCC. Meanwhile not all the patients have the tumor response. The study was carried out to reveal the possible mechanisms of resistance to C. Methods: 27 pts (77,7% (21) male and 22,3% (6) female, mean age 57,5+1,7 years,T3-4N0-1M0) were recruited. C was administered 400 mg/m2 D1 and 250 mg/m2 q1w with Carboplatin AUC5 in D1 and Fluorouracil 1000 mg/m2 D 1-4 of 21 day cycle.EGF, EGFR, VEGFA, VEGFR1, VEGFD, TGF were investigated in the blood samples, tumor tissue, its perifocal zone and intact tissue line of tumor resection samples by ELISA. Blood and the tissue samples of the pts treated without C were used as the control. Results: In patients with tumor response EGFR in the tumor tissue was decreased by 40,8%, EGF-by 22,6%, VEGFR1- by 41,6%, TGF-by 28% compared to the control (p < 0,05) and 4,6-fold decrease in VEGFA was observed (p < 0,05). Changes in EGF, EGFR, VEGFA, VEGFR1, TGF in tissues around the tumor (perifocal and intact tissues) were similar but more expressed. In the blood samples 1,7-fold increase in EGFR and 1,4-fold decrease in TGF were discovered, while the rest were not changed (р < 0,05)In pts with tumor progression EGFR and TGFin the tumor tissue had no statistically significant changes compare to the control, meanwhile EGF level increased by 26,6%, VEGFR1 by 44,2% and 4,5-fold decrease in VEGFD was discovered (p < 0,05). Changes in EGF, VEGFA, VEGFR1, TGFin tissues around the tumor were different from those in the tumor and only EGFR and VEGFD were changed similarly. In the blood samples 1,5-fold increase in EGFR and 3-fold decrease in EGF, 1,5-fold decrease in VEGFA, and 2,1-fold decrease in TGFwere found after the treatment (p < 0,05). VEGFR1 and VEGFD have not changed. Conclusions: The study discovered that the changes in the the growth-factors in the blood reflects the disregulation in signal transduction in the tumor and tissues around the tumor that is the possible reason for cases when the therapy with C is ineffective.
Clinical utility of a circulating cell-free DNA assay for clinical trial enrollment in refractory metastatic colorectal cancer patients.
Authors: Van Karlyle Morris, M. Pia Morelli, Filip Janku, Michael J. Overman, Bryan K. Kee, David R. Fogelman, Eduardo Vilar Sanchez, Imad Shureiqi, Chris R. Garrett, Kanwal Pratap Singh Raghav, Cathy Eng, Shanequa Manuel, Robert A. Wolff, Helmy Eltoukhy, Richard Burnham Lanman, AmirAli Talasaz, Scott Kopetz
Journal: Journal of Clinical Oncology (2015)

3601 Background: Circulating cell-free DNA (cfDNA) isolated from the plasma of cancer patients has been shown to accurately reflect the genomic mutation profile of the tumor, and assays are now available for clinical use. However, physician and patient assessment of clinical utility of these assays in patients has not been previously evaluated. Methods: Patients (pts) were prospectively consented as part of the Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) protocol, with collection of 20mL of blood for cfDNA extraction and sequencing on a 54-gene panel in a CLIA-certified lab (Guardant360, Guardant Health). FFPE tissue from prior resections or biopsies underwent 50-gene sequencing (Ion Torrent, Life Technology). Results from both assays were returned to the treating physicians for patient care and clinical trial selection. Follow up surveys and chart reviews assessed clinical utility. Results: 120 mCRC pts were enrolled between 6/1/2014 and 1/7/2015, with a median of 3 prior lines of therapy. With cfDNA sequencing, 83% (99/120) of samples had a detectable genomic alteration (including 26% with detectable amplifications in EGFR, MET, or ERBB2), with an average of 4.2 mutations/pt. Sequencing of tissue provided detectable mutations in 88% of cases (106/120), with an average of 2.9 mutations /pt. cfDNA testing provided results within a median of 11 days, 14-days faster than tissue testing. 54% of cfDNA cases had potentially actionable alterations, and 66% of cases could be genomically matched to at least one clinical trial in the institution. 52% of these pts were able to be enrolled in the identified trial, with the remainder limited by eligibility criteria (9%), lack of patient interest (22%), or no current trial openings (17%). Physicians felt that the cfDNA testing improved the quality of care they were able to provide in 75% of the cases, and improved patient satisfaction with the efforts to personalize experimental options in 92% of cases. Conclusions: cfDNA sequencing can provide timely information on potentially actionable mutations and amplifications, thereby facilitating clinical trial enrollment and improving the perceived quality of care.
Cellular mechanisms mediating the anticancer activity of a novel polyherbal formulation.
Authors: Nadav Menahem Shraibom, Manu Jaggi, Anu T Singh, Ritu Verma, Alka Madaan, Pratibha Singh, Anshumali Awasthi, Vidushi Joshi, Amitesh Kishore, Sheetal Dobhal, Ronodip Kar, Kalpana Meena
Journal: Journal of Clinical Oncology (2015)

e13590 Cellular mechanisms mediating the anticancer activity of a novel polyherbal formulation Background: There is an increased interest in understanding the molecular mechanisms by which herbal mixtures elicit their effects with the hope that they can be translated into new anticancer therapies. A novel herbal decoction 3HX was formulated that exerted excellent anticancer activity in preclinical models, specifically AML and melanoma. The present study explored the anticancer mechanism of 3HX. Methods: Cell lines SK-MEL-2 and THP-1 were treated with 3HX followed by analysis of apoptotic markers. Angiogenesis was evaluated by proliferation, migration and VEGF estimation in human endothelial cells EA.hy926. Kinase inhibition was assessed by Z' Lyte assays. Topoisomerase II activity was determined by Kinetoplast DNA Cleavage assay. NFkB signaling assay was done using NFkB-bla THP-1. Immunostimulatory assays were done by estimation of MIP-1-α, TNF-α and IL-1-β in murine splenocytes. Anti-metastatic activity was assessed by lung colonization assay. Results: 3HX induced strong apoptotic signaling in tumor cell lines mediated by ROS generation, PS externalization, mitochondrial membrane depolarization, caspase-3 activation, DNA fragmentation and cell cycle arrest. Considerable inhibition of proliferation, migration and VEGF release was recorded in treated endothelial cells. Further inhibitory effect was observed on all the 8 kinases - AKT1 (PKB alpha), ERBB2 (HER2), FLT3, MAPK1 (ERK2), PRKCA (PKC alpha), BRAF, BRAF V599E and MAP2K1 (MEK1) with > 50% inhibition at 1:10 dilution in all except MAPK1 (ERK2). Inhibition of Topoisomerase II and NFkB signaling was also observed. 3HX also increased the levels of cytokines especially MIP-1-α and TNF-α. Metastatic assays revealed inhibition of melanoma nodule count and decrease in melanin content at 2 doses of 500 mg/kg and 250 mg/kg respectively administered orally. Conclusions: 3HX exerts anticancer action by multi-target and multi-signal pathways involving apoptosis; anti-angiogenesis; anti-metastasis; inhibition of signaling kinases, topoisomerase II and modulation of tumor microenvironment by enhancement of immune function and suppression of inflammation.
Prospective head-to-head comparison of 18F-fluciclovine and 68Ga-PSMA-11 PET/CT for localization of prostate cancer biochemical recurrence after primary prostatectomy.
Authors: Jeremie Calais, Francesco Ceci, Kathleen Nguyen, Jeannine Gartmann, Matthias Eiber, Robert Evan Reiter, Amar Upadhyaya Kishan, Hossein Jadvar, Wolfgang P Fendler, Johannes Czernin
Journal: Journal of Clinical Oncology (2019)

15 Background: 18F-Fluciclovine PET/CT (FACBC) is standard-of-care in US for localization of prostate cancer (PCa) biochemical recurrence (BCR) after definitive therapy. 68Ga-PSMA-11 PET/CT (PSMA) detects PCa BCR even at low prostate-specific antigen (PSA) levels (&lt;2.0 ng/mL). We conducted a single-center prospective head-to-head comparison of these 2 PET/CT imaging tracers for localizing PCa BCR after radical prostatectomy (RP) in patients with PSA &lt; 2.0 ng/ml. Methods: Patients with PCa BCR after RP and PSA levels ranging from ≥0.2 to ≤2.0 ng/mL without any prior salvage therapy were eligible. All patients underwent FACBC and PSMA scans within ≤15 days. Images analysis was performed a) by on-site clinical reading and b) by 3 blinded international expert readers for each modality. Detection rates on per-patient and per-region based analysis served as primary study endpoints. Based on literature data we hypothesized a detection rate difference of 22% in favor of PSMA. A power analysis determined a sample size of 50 patients. Results: The 50 patients were enrolled from March to September 2018. Median PSA level was 0.50 ng/ml. Median time interval between the 2 scans was 6 days. We present here the preliminary results from the non-blinded clinical reads. Detection rate on a per-patient basis was 69% for PSMA and 34% for FACBC. Concordant findings were observed in 30/49 patients (61%): 16/49 (32%) with both positive scans and 14/49 (29%) with both negative scans. Discordant findings were observed in 19/49 patients (39%): 18/49 (37%) had a positive PSMA but a negative FACBC scan while 1/49 (2%) had a positive FACBC with a negative PSMA (local recurrence). Detection rates were consistently lower for FACBC than for PSMA for all regions: Prostate bed (12% vs 20%), pelvic nodes (14% vs 37%), extra-pelvic nodes (2% vs 8%), skeleton (2% vs 8%) and visceral organs (2% vs 6%). Conclusions: This preliminary analysis from the non-blinded on-site clinical reads demonstrates prospectively that PSMA detection rates is more than double the FACBC detection rate in patients with PCa BCR after RP and with PSA ≤2.0 ng/ml. Clinical trial information: NCT03515577.
Direct impact of clinical research in metastatic renal cell carcinoma (mRCC): A cost-effectiveness analysis of patient care outcomes and cost savings in a real-life scenario of a large public university hospital in Spain.
Authors: Silvia Garcia-Garro, Pablo Gajate, Esther Gómez-de-Salazar, Teresa Alonso Gordoa, Miguel Angel Rodriguez-Sagrado, Javier Molina CerrilloMD, Luis Manzano, Teresa Bermejo, Alfredo Carrato, Enrique Grande
Journal: Journal of Clinical Oncology (2019)

637 Background: Public health sustainability is a major concern worldwide. Clinical research is considered to leverage patient care outcome but also can lead costs savings and, subsequently, to maintain public health system. Thus, we analyzed the direct impact of clinical research in terms of improvement in clinical outcomes and costs related to research in patients with mRCC in real-life setting. Methods: We retrospectively collected data related to overall survival (OS) and direct health care costs from all mRCC patients who were treated with oral anti-tumour medication and followed at the Medical Oncology Department of Ramón y Cajal University Hospital in Madrid, between January 2010 and February 2017. A statistical analysis comparing the outcomes of patients included in clinical trials versus those not included was conducted. Results: In the study period, 65 patients were newly diagnosed with mRCC and received treatment. Those patients included in clinical trials showed higher median OS (91 vs. 29 months. HR 0.389; 95% CI: 0.150: 1.000; p=0.04). Median direct cost per mRCC patient in ‘real-life’ was €67,376. Median cost for a patient enrolled in at least one clinical trial was €53,673 vs. €63,834 for those who were never recruited for a trial. Participation in clinical trials contributed to a decrease in total health expenditure by 9.02% (€362,367), mainly due to reduction in the cost of medications and diagnostic tests (91.46% vs. 8.54%, respectively). Furthermore, clinical trial participants have required less number of hospitalizations (0.08 vs. 1.75) and emergency visits (0.39 vs. 3.2) per patient. Conclusions: Under the public health system perspective, participation in clinical trials is related to an improvement in overall survival as well as direct and indirect cost savings in mRCC patients.
Abstract 18235: Plasma miRNAs Are Related to Atrial Fibrillation Recurrence After Catheter Ablation: Longitudinal Findings From the miRhythm Study
Authors: Aditya Vaze, Kahraman Tanriverdi, Matthew Spring, Timothy Fitzgibbons, Kevin Donahue, John F Keaney, Cynthia Ennis, Clifford Browning, Lawrence Rosenthal, Kevin Floyd, Patrick T Ellinor, Steven Lubitz, Jane Freedman, David McManus
Journal: Circulation (2016)

Introduction: Catheter ablation for atrial fibrillation (AF) has emerged as a mainstay of therapy for reducing arrhythmia burden for symptomatic AF patients. Nevertheless, AF recurrence after ablat...
Abstract MP46: Fasting Glucose Variability in Young Adulthood and Incident Diabetes, Cardiovascular Disease, and Mortality: The Coronary Artery Risk Development in Young Adults (CARDIA) Study
Authors: Michael Bancks, April Carson, Cora Lewis, Erica Gunderson, Jared Reis, Pamela Schreiner, Yuichiro Yano, Mercedes Carnethon
Journal: Circulation (2019)

Introduction: Whether long-term variability in fasting glucose (FG) independent of incident diabetes mellitus (DM) is associated with incident cardiovascular disease (CVD) and mortality is unclear. Hypothesis: Higher variability of FG would be associated with higher risk for incident CVD and mortality as compared with lower FG variability, independent of increases in FG over time and the development of DM. Methods: We studied 4210 black and white CARDIA participants, ages 18 to 30 years (1985-1986) at baseline and calculated 2 measures of long-term glucose variability, the coefficient of variation about the mean (CV-FG) and the absolute difference between successive FG measurements (average real variability; ARV-FG) before the onset of DM. We estimated hazard ratios (HR) for incident CVD and mortality over 30 years of follow-up with adjustment for time-varying CVD risk factors. Results: There were 417 incident cases of DM, 195 incident CVD events (122,279 person-years) and 237 deaths (123,505 person-years). The HR for incident CVD per 1-standard deviation (1-SD) higher CV-FG was 1.24 (95% confidence interval [CI]: 1.08, 1.42) and for ARV-FG was 1.14 (95% CI: 1.01, 1.28) after adjustment for demographics, baseline FG, change in FG, and time-varying education, smoking, alcohol consumption, body mass index, physical activity, systolic blood pressure (BP), BP medications, low-density lipoprotein cholesterol, cholesterol medications, incident DM, and DM medications (Figure 1A and 1B). HRs for mortality were similar in magnitude for 1-SD ARV-FG (HR: 1.22, 95% CI: 1.10, 1.35) and slightly weaker for CV-FG (HR: 1.12, 95% CI:0.98, 1.27) after adjustment for time-varying CVD risk factors. The majority of mortality and the variability-mortality association was due to non-CVD mortality. Associations were similar in magnitude when restricted to individuals without incident DM. Conclusion: Higher intra-individual FG variability during young adulthood before the onset of DM was associated with incident CVD and mortality.
Inhibition of the Interleukin-36 Pathway for the Treatment of Generalized Pustular Psoriasis
Authors: Hervé Bachelez, Siew-Eng Choon, Slaheddine Marrakchi, A. David Burden, Tsen-Fang Tsai, Akimichi Morita, Hamida Turki, David B. Hall, Michael Shear, Patrick Baum, Steven J. Padula, Christian Thoma
Journal: New England Journal of Medicine (2019)

Interleukin-36 Blockade in Pustular Psoriasis Seven patients with pustular psoriasis, three with mutations in IL36RN, were treated with a monoclonal antibody against interleukin-36 receptor and had...
Author Correction: Lung regeneration by multipotent stem cells residing at the bronchioalveolar-duct junction
Authors: Qiaozhen Liu, Kuo Liu, Guizhong Cui, Xiuzhen Huang, Shun Yao, Wenke Guo, Zhen Qin, Yan Li, Rui Yang, Wenjuan Pu, Libo Zhang, Lingjuan He, Huan Zhao, Wei Yu, Muxue Tang, Xueying Tian, Dongqing Cai, Yu Nie, Shengshou Hu, Tao Ren, Zengyong Qiao, Hefeng Huang, Yi Arial Zeng, Naihe Jing, Guangdun Peng, Hongbin Ji, Bin Zhou
Journal: Nature Genetics (2019)
Abstract 17459: Maturation of Early Diastolic Left Ventricular Function is Largely Complete in the First Month of Life: Insights From Semiautomated Analysis of Color M-Mode Echocardiographic Filling Velocities
Authors: Collin T Erickson, Ling Li, Brett Meyers, Mary Craft, Andreas Schuster, Pavlos Vlachos, Shelby Kutty
Journal: Circulation (2017)

Introduction: Clinical applicability of pulsed Doppler transmitral filling is limited by several factors including pseudonormalization. We analyzed left ventricular (LV) diastolic performance using numerically processed color M-mode flow data. Hypothesis: LV filling mechanics and diastolic function have predictable maturational progression. Methods: Normal infants were enrolled prospectively for a series of 5 research echocardiograms at age 1 week, 1 month, 6 months, 1 year, and 2 years. Color M-mode images were collected from 4-chamber view, and a semiautomated, previously validated MATLAB algorithm was utilized for analysis of diastolic filling. The propagation velocity (Vp), strength of filling (Vs, calculated as Vp X length between mitral valve and Vp deceleration point), and intraventricular pressure difference (IVPD) in 3 segments along apex-to-mitral valve scan line were measured. Comparisons were made between age groups. Results: In 70 infants (mean ± SD age 237.0 ± 254.2 days, weight 7.4 ± 3.5 kg...