tbuckley/cabot-search huggingface dataset:
Anti-mesothelin chimeric antigen receptor T cells in patients with epithelial ovarian cancer.
Authors: Janos Laszlo Tanyi, Andrew R Haas, Gregory Lawrence Beatty, Caitlin Jane Stashwick, Mark H. O'Hara, Mark Aloysuis Morgan, David L. Porter, Jan J. Melenhorst, Gabriela Plesa, Simon F. Lacey, Carl H. June
Journal: Journal of Clinical Oncology (2016)

5511 Background: We report a Phase I study of six patients with epithelial ovarian cancer treated with an intravenous infusion of autologous T cells transduced to express a chimeric antigen receptor directed against mesothelin (CART-meso). Methods: Six recurrent serous ovarian cancer patients were treated with autologous lentiviral vector transduced T cells expressing a second generation chimeric antigen receptor (CAR) construct targeting mesothelin. The CAR is composed of an extracellular anti-mesothelin single chain variable fragment derived from mouse monoclonal antibody SS1 fused to the intracellular signaling domains 4-1BB (CD137) and TCR zeta. Four patients received a single dose of 3 x 10^7 CART-meso cells/m2 and two patients received 3 x 10^8 CART-meso cells/m2, without (n = 4) or with (n = 2) lymphodepletion. Results: There were no acute AE related to the infusion and no cytokine release syndrome was experienced. Related Grade 3-4 AEs include pleural effusion, tachypnea, and dyspnea in one patient and related Grade 3 AEs include abdominal pain, ascites, and constipation in two other patients. CART-meso T cells were detectable in the peripheral blood starting 1 hour after infusion and expanded with a peak at Day 7-10 followed by a contraction phase. Higher levels were detected in patients treated with the higher dose of CART-meso cells and with lymphodepletion. Expansion of CART-meso cells was also observed in the malignant pleural effusion of one patient. Clearing of malignant cells in the pleural fluid was seen on Day 21-26 after infusion without lymphodepletion suggesting a direct anti-tumor effect. Trafficking of CART-meso cells was noted in tumor samples from three of four patients. At one month after treatment, all six patients showed stable disease on imaging per RECIST criteria. Conclusions: Phase I trial of infusion of CART-meso T cells in patients with recurrent serous ovarian cancer was found to be feasible and safe. CART-meso cells engrafted and expanded in the blood of all subjects, and trafficked to sites of tumor resulting in clearance of pleural effusion in one patient. These encouraging preliminary results may help guide future clinical trials in adoptive T cell therapy. Clinical trial information: NCT02159716.
Evolution of pancreatic cancer survival over the past two decades.
Authors: Veronica Mariotti, Ricardo Daniel Parrondo, Miguel Gonzalez Velez, Narjust Duma, Lori Ann Leslie, Martin Gutierrez
Journal: Journal of Clinical Oncology (2017)

e15722 Background: Pancreatic cancer (PaCa) is a highly lethal disease, with a 5-year overall survival (OS) rate of approximately 6%, and a median OS of only 3–6 months (m). Despite recent improvements in surgical techniques and increased use of combination chemotherapy (CT), OS remains poor. This study aims to examine the factors that led to increased OS in PaCa patients (pts) over the past two decades in a single academic institution. Methods: All medical records of pts diagnosed with PaCa at the John Theurer Cancer Center from 1990 to 2012 were reviewed, and 916 PaCa pts were included in this analysis. We compared one group of pts diagnosed from 1990 to 2003 (G1, n = 482), with a group of pts diagnosed from 2004 to 2012 (G2, n = 434) in terms of OS, demographics, tumor features and treatment (tx). Results: Median age at diagnosis was 70.5 years (range 26-96). There was no significant difference between G1 and G2 in terms of age at diagnosis, stage of disease and number of pts who received surgery. A significantly higher percentage of pts received CT in G2 compared to G1 (66.5% vs 51.0%, p = .00). Tumors of the pancreatic head were more common in G1 compared to G2 (51.8% vs 44.4% p = .02). More pts in G2 received two or more CT agents compared to G1 (49.0% vs 34.1%, p = .00). Median OS was significantly longer in G2 compared to G1 (9m vs 5m, p = .00), in pts who received CT compared to pts who did not (3m vs 9m, p = .00) and in pts who received surgery compared to pts who did not (5m vs 19m, p = .00). Pancreatic head location was associated with improved OS compared to other locations (9m vs 5m, p = .00). No OS difference was found between pts who received combination with two or more agents vs single agent CT. Conclusions: In line with multiple studies, analysis of PaCa data from our institution showed an increase OS in pts diagnosed with PaCa in more recent years, and in those who received surgery and CT. CT was administered in a larger number of pts in G2, which might account for the better OS in this group. Pts diagnosed with tumors of the pancreatic head had better survival, which could be explained by earlier presentation leading to earlier diagnosis and tx. Further research in PaCa therapeutics is needed, as long-term OS in PaCa pts remains poor despite recent advances.
Predicting survival in gastric cancer patients randomized to docetaxel with mass spectrometric quantitation of TUBB3.
Authors: Fabiola Cecchi, Daniel V.T. Catenacci, Sarit Schwartz, Shankar Sellappan, Yuan Tian, Rosalba Miceli, Filippo Pietrantonio, Alessandro Pellegrinelli, Antonia Martinetti, Maria Di Bartolomeo, Todd A. Hembrough
Journal: Journal of Clinical Oncology (2017)

4068 Background: No predictive biomarker for chemotherapy has been validated for clinical use. A relationship between resistance to taxanes and expression of class III β-tubulin (TUBB3) protein has been suggested by small clinical studies, but not confirmed in randomized trials. Immunohistochemical definitions of “TUBB3 positive” vary widely between studies and depend on subjective measures of strong vs weak staining. We retrospectively evaluated the relationship between survival and TUBB3 protein quantitated by mass spectrometry in the tumor samples of 247 patients from the Intergroup Trial of Adenocarcinoma of the Stomach (ITACA-S). Patients had been randomized to a docetaxel-containing adjuvant regimen or to monotherapy with fluorouracil and leucovorin (5-FU/LV). Methods: Archived tumor tissues were microdissected and solubilized for proteomic analysis. TUBB3 and 44 other protein biomarkers were quantified with a mass spectrometry-based assay. A TUBB3 protein cutoff of 750 amol/ug was predetermined based on the assay’s limit of detection. The Mantel-Cox log-rank test was used for survival comparisons. Results: Among gastric cancer (GC) patients treated with docetaxel-containing chemotherapy (n = 125), those with TUBB3 levels below the cutoff (750 amol/µg of total protein) had a longer median overall survival (mOS) than patients with TUBB3 levels above the cutoff (1563 vs 886 days, p = 0.04). TUBB3 level made no difference in survival among patients who received 5-FU/LV. Of note, among patients with high TUBB3 levels ( &gt; 750 amol), those treated with 5-FU/LV survived 3 years longer than patients in the docetaxel arm (mOS = 1991 vs 886 days, p = 0.048). Conclusions: Quantitative proteomic analysis of TUBB3 identified a subset of GC patients who benefitted from the addition of docetaxel to adjuvant chemotherapy. GC patients with TUBB3-expressing tumors had worse outcomes on a docetaxel-containing regimen than on 5-FU/LV. An ongoing study of triple-negative breast cancer patients treated with docetaxel suggests that proteomic TUBB3 may be predictive in other cancer indications. Personalized chemotherapy based on quantitated TUBB3 is promising and warrants broader evaluation.
A phase I-II study to evaluate safety and efficacy of the combination of niraparib plus cabozantinib in patients with advanced kidney/urothelial carcinoma.
Authors: Daniel E. Castellano, Miguel A. Climent, Ignacio Duran, Begona Mellado, Jesus Paramio, Francisco X. Real, Jose Luis Ramirez, Juan Luis Sanz, Albert Font Pous
Journal: Journal of Clinical Oncology (2018)

TPS4593 Background: Niraparib (N) is an orally available and selective poly(ADP-ribose) polymerase (PARP)-1/-2 inhibitor approved for maintenance treatment of patients (pt) with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer after complete or partial response to platinum-based chemotherapy (CT). Cabozantinib (C) is a tyrosine kinase (TK) inhibitor with activity against TKs including VEGFR2, MET and AXL, approved on kidney cancer pt after TK failure, that has demonstrated clinical activity in heavily pretreated, advanced UC pt. c-Met receptor TK is activated in urothelial carcinoma (UC) cells. c-Met activity can decrease response to PARP inhibitors, whereas treatment with c-Met inhibitors renders cells more sensitive to PARP inhibition. UC pt with tumors overexpressing c-Met may benefit from the combination of c-Met and PARP inhibitors. This multicenter, open-label phase (ph) I-II study (NCT03425201) is to explore the maximum-tolerated dose (MTD) of N + C combination in pt with advanced genitourinary malignancies (UC and kidney cancer) follow by a preliminary efficacy of the combination in advanced UC. Methods: Eligible pt have confirmed histopathology of UC or clear cell renal cell carcinoma, advanced or metastatic disease, age ≥18 years, ECOG PS ≤1, progressive disease after platinum-based CT, measurable lesions, no prior therapy with PARP or c-Met inhibitors and adequate bone marrow, liver and renal functions. The ph I portion is enrolling ≈24 pt to identify the MTD proposed to use in a ph II (RP2D). Pt will receive N and C p.o. once daily in 28-day cycles: Dose level 1 (DL1) N/C 100/20 mg; DL2 200/20 mg; DL3 200/40 mg; DL4 200/60 mg. Pt will be accrued to each dose level in cohorts of 6 pt until the MTD is achieved (the highest dose at which ≤1 out of 6 pt experience a dose-limiting toxicity [DLT]). DLT will be evaluated during the first 2 cycles. The ph 2 portion will enroll 51 UC pt to receive the RP2D. Tumors will be assessed per RECIST v1.1. Endpoints of the ph 2 are 6-month PFS (primary), overall response rate, disease control rate, duration of response, PFS and OS. Tissue and plasma sample will be collected for translational study. Clinical trial information: NCT03425201.
Measuring cost in the value equation using time-driven activity-based costing (TDABC) at The University of Texas MD Anderson Cancer Center, Division of Radiation Oncology.
Authors: Nicholas D. Olivieri, Benjamin D. Frank, John D. Calhoun, Alexis B. Guzman, Justin N. Onwenu, Isela De La Cerda, Mallika Sharma, Aidan Loggenberg, Simona Flora Shaitelman, Bruce D. Minsky, Melenda Jeter, Robert Ghafar, Thomas W. Feeley, Stephen M. Hahn
Journal: Journal of Clinical Oncology (2017)

e18305 Background: The cost of a full cycle of radiation therapy at MD Anderson Cancer Center has not been determined using a bottom-up measurement approach. Due to the complexity and variation in clinical processes, typical costing strategies do not provide the level of detail necessary to evaluate the value equation, defined as outcomes over cost. To address this limitation, we designed and implemented a practice-wide Time-Driven Activity-Based Costing (TDABC) strategy to capture our total direct cost of care for all treatment modalities within each of 9 disease site-specific services. Methods: Process maps were created for each of the 9 disease site-specific services. Care delivery times were captured by treatment modality for each service as determined by multidisciplinary teams routinely performing each step of the process. The data were entered into a standardized tool, which calculated step costs based upon capacity cost rates for each human resource. The costing tool also calculated total direct labor costs for specific treatment plans based on modality, complexity, and fractionation. Results: The analysis took six months to complete and required the use of approximately 1,000 administrative hours, 250 physician hours, 250 clinical staff hours and 100 medical physics hours. Approximately 17 process maps were created for each of the 9 services with each process map receiving further analysis based upon radiation treatment modality. As a result of observed variation in costs between disease-site services, best practices were identified and 15 standardization opportunities were discovered. Additionally, the cost-benefit analysis between high profile modalities within each disease-site service, such as Proton Therapy and Intensity Modulated Radiation Therapy (IMRT) on the Head and Neck service, were easier to complete. Conclusions: Time-Driven Activity-Based Costing is a valid method for calculating direct costs in a large academic radiation oncology practice. Standardized clinical outcome data can be used to complete the value equation and ultimately provide insight for better clinical and administrative decision making.
Increase Of Circulating Endothelial Progenitor Cells Following E-Cigarette Inhalation In Human Subjects
Authors: J. Bosson, L. Antoniewicz, J. Kuhl, S. A. Halim, F. Mobarrez, M. Lundback
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Increase Of Circulating Endothelial Progenitor Cells Following E-Cigarette Inhalation In Human Subjects
Impact of adjuvant chemotherapy in appendiceal adenocarcinoma.
Authors: Bhaskar Chandu Kolla, Madhuri Chengappa, Wolfgang Gaertner, Anne Hudson Blaes
Journal: Journal of Clinical Oncology (2018)

e16193 Background: The impact of using adjuvant chemotherapy following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with appendiceal adenocarcinoma is not known, and the practice is variable and based on results from colorectal cancer studies. The aim of this study was to assess the impact of adjuvant chemotherapy following complete cytoreduction in patients with appendiceal adenocarcinoma. Methods: Retrospective medical record review of all patients with appendiceal adenocarcinoma treated at the University of Minnesota Medical Center between 2006 and 2015. Results: A total of 103 patients with appendiceal adenocarcinoma received care at our institution during the study period, and 90 underwent cytoreductive surgery. Complete cytoreduction (cytoreductive score 0-1) was achieved in 68 patients (65%). Of these 68 patients, 28 received adjuvant chemotherapy. The most common regimens were capecitabine (n = 11), capecitabine plus oxaliplatin (n = 7), and 5-FU plus oxaliplatin (n = 6). Tumor histopathology and grade, and ability to achieve complete cytoreduction were significant predictors of overall survival (Table). The median recurrence-free (RFS) and overall survivals (OS) for non low-grade & well-differentiated tumor patients who received adjuvant chemotherapy following complete cytoreduction were 3.3 (1.3-5.5) and 5.8 (1.5-10.2) years, respectively, compared to 1.1 (0-2.5) and 2.8 (1.5-4.2) years for patients who did not receive adjuvant chemotherapy (p = 0.27 [RFS] & p = 0.03 [OS]). Conclusions: Although the impact of adjuvant chemotherapy was not statistically significant, there was a trend for improved RFS and OS. Histopathology n Median OS (95% CI) Low grade mucinous neoplasm and well-differentiated adenocarcinoma 46 7.9 (2.5-13.4) Moderately differentiated adenocarcinoma 20 9.0 (2.2-15.8) Poorly differentiated or undifferentiated adenocarcinoma 9 2.3 (0.4-4.2) Adenocarcinoma with signet ring features ( < 50%) 13 2.0 (0.7-3.3) Signet ring cell adenocarcinoma. 15 1.4 (0.0-3.5) Cytoreduction Median OS (95% CI), p < 0.001 Incomplete cytoreduction 35 2.2 (1.2-3.2) Complete cytoreduction 68 5.8 (2.9-8.7)
Development of diagnostic method for bone and soft tissue sarcomas of various histological subtypes using serum microRNA profiles.
Authors: Naofumi Asano, Juntaro Matsuzaki, Junpei Kawauchi, Satoko Takizawa, Eisuke Kobayashi, Robert Nakayama, Morio Matsumoto, Masaya Nakamura, Tadashi Kondo, Ken Kato, Naoto Tsuchiya, Akira Kawai, Takahiro Ochiya
Journal: Journal of Clinical Oncology (2018)

12019 Background: Diagnosis of sarcomas is considered to be quite difficult because of the rarity and diversity of the disease. The development of a novel diagnostic test for sarcoma is eagerly awaited. The aim of this study is to address whether serum miRNA profiles can be used to detect only malignant cases (sarcomas) of bone and soft tissue tumors regardless of histological subtypes. Methods: The case-control study included 1,002 patients with bone and soft tissue tumors representing more than 43 histological subtypes, including sarcomas, intermediate, and benign tumors. As controls, 275 healthy and 240 patients with other cancers were enrolled. MiRNA levels were measured using microarray. Patients were divided into three cohorts: a discovery to identify differentially expressed miRNAs; a training to establish a diagnostic index; and a validation to validate the utility of the index. An exploratory cohort was used to evaluate the index in recurrent sarcomas, intermediate tumors, and other cancers. Results: Circulating serum miRNA profiles, determined by microarray analysis, in malignant cases of bone and sarcomas, were clearly distinct from those in benign and healthy controls. A promising molecular detector, diagnostic index II, was developed using the serum levels of three miRNAs. Diagnostic index II also clearly separated sarcomas from benign and healthy controls with remarkable high sensitivity (94%), specificity (90%), and accuracy (91%). Conclusions: Comprehensive analysis of serum miRNA profiles in approximately 1000 cases of bone and soft tissue tumors identified a promising classifier, diagnostic index II, calculated using the serum levels of three miRNAs with remarkable performance for the detection of sarcoma. The present data overcome a serious problem associated with sarcoma diagnosis and provide the basis for the development and implementation of miRNA-based strategies for diagnostic purposes in the clinic.
A gene expression signature to characterize human lung adenocarcinoma cancer stem cells.
Authors: Alejandro Herreros-Pomares, Juan Diego de Maya, Héctor Amado, Cristóbal Aguilar-Gallardo, Eva Escorihuela, Ana Blasco, Silvia Calabuig-Fariñas, Miguel Martorell, Ricardo Guijarro, Eloisa Jantus-Lewintre, Rosa Farras, Carlos Camps
Journal: Journal of Clinical Oncology (2018)

e20547 Background: Treatment resistance is linked to cancer stem cells (CSCs), a highly tumorigenic subpopulation of cells with the ability to grow as spheres in non-adherent conditions. The aim of this study was to isolate and analyse CSCs from tumor samples of resected non-small cell lung cancer (NSCLC) patients and cell lines, comparing their expression pattern with their paired-differentiated cells. Methods: The study was performed on cells from 8 NSCLC patients and 12 NSCLC cell lines (A549, NCI-H1395, NCI-H1650, NCI-H1975, NCI-H1993, NCI-H2228, NCI-H23, NCI-H358, NCI-H460, HCC827, PC9 and SW900) grown in monolayer and as spheres. A panel of 60 genes (CSC-markers, pluripotency inducers, cell cycle regulators, invasion promoters and components of Notch, Wnt and Hedgehog pathways) was analysed by RTqPCR. Gene expression results were validated at a protein level by immunoblot and IF. Results: 8 out of 20 primary NSCLC cultures were successfully established and formed tumorspheres. Patients’ median age was 67 years [57-74], 50% were male, and 62.5% were adenocarcinomas (ADC). Gene expression analysis in primary cultures and cell lines revealed that lungspheres had significantly higher expression of CSC-related genes (ALDH1A1, KLF4, NANOG, CD44, CD90, CDKN1A, JUNB, MDM2), invasion promoters (MMP9, SNAI1, ITGA6), ligands and receptors of Notch (NOTCH1, NOTCH3, DLL4, JAG1) and Wnt components (CTNNB1, GSK3B) compared to adherent cells. A logistic regression analysis indicated that a signature composed by CD44, NANOG, CDKN1A, SNAI1, ITGA6 and NOTCH3, was able to distinguish tumorspheres from differentiate-adherent cells (AUC = 0.95). Protein expression analyses showed overexpression of proteins encoded by the gene signature on tumorspheres from ADC patients, but spheres from SCC patients were more heterogeneous regarding the expression of these markers when compared to their paired-adherent cells. Conclusions: Lung tumorspheres are a useful platform for CSCs characterization. We propose a gene expression signature that could provide the basis for developing novel therapies for the treatment of lung ADC. Supported by grants from RTICC-FEDER, PI12-02838 and PI15-00753 from ISCIII and from the Arnal Planelles Foundation.
Abstract 17707: Urgent And Emergency Cardiac Surgery Can Safely be Performed by Residents-in-training Without Compromising Long-term Survival
Authors: priyadharshanan ariyaratnam, Mahmoud Loubani
Journal: Circulation (2016)

Introduction: The long term effects of urgent and emergency surgery performed by cardiothoracic trainees are largely unknown Hypothesis: Trainee-led and consultant-led emergency/urgent cardiac surgery have equivocal short and long-term outcomes Methods: We retrospectively analysed prospectively collected data on 13,655 patients who underwent cardiac surgery between June 1999 and June 2015 at our institution. We divided operations into Consultant-led (Group A), Trainee-led without consultant scrubbed (Group B) and Trainee-led with consultant scrubbed (Group C). We compared in-hospital outcomes using multivariate logistic and linear regression. We compared long-term outcomes using cox-regression. Results: There were 82.9% of patients in Group A, 9.0% in Group B and 8.1% in Group C. Elective cases were 76.9%, Urgent cases were 20.7% and Emergency cases were 2.4% of all procedures performed. From multivariate analysis, trainee-led procedures had longer cross-clamp and bypass times for elective and urgent/emer...