tbuckley/cabot-search huggingface dataset:
Multi-institutional European phase I/II trial of trabectedin plus radiotherapy in metastaticsoft tissue sarcoma (STS) patients. A Collaborative Spanish (GEIS), Italian (ISG) and French (FSG) Sarcoma Groups study.
Authors: Javier Martin Broto, Antonio Lopez-Pousa, Nadia Hindi, Josefina Cruz, Javier Peinado, Carlo Morosi, Josep Isern, Maria Carmen Dolado, Rosa Maria Alvarez Alvarez, Ana Alvarez, Giovanni Grignani, Marco Gatti, Pablo Luna Fra, Ignacio Alastuey, Jean-Yves Blay, Marie-Pierre Sunyach, Inmaculada Rincon, Alessandro Gronchi, Jesus Romero
Journal: Journal of Clinical Oncology (2018)

11544 Background: Patients (pts) with advanced STS who require tumor shrinkage beyond first line, have very limited options since the approved drugs exhibit less than 10% of RECIST response. Trabectedin (T) had shown preclinical synergy with radiotherapy (RT). Low-dose RT concurrent with T was conducted in a phase I/II trial as a proof-of-concept of synergy. We present here data from the phase I (pulmonary metastatic cohort) Methods: Pts received T along with RT (30 Gy) in 10 fractions (3Gy/fr). Dose Levels for T were: -1 (1.1 mg/m2), 1 (1.3 mg/m2) and 2 (1.5 mg/m2). Dose level 1 was expanded for a better cardiotoxicity assessment. Dose-limiting toxicity (DLT) were defined as grade ≥3 events excluding G3/4 neutropenia lasting < 5 days, G3 transaminitis if not led to T delay and G3-4 nausea/vomiting due to inadequate prophylaxis. Primary endpoint was response rate according to RECIST Results: From 04/2015 to 06/2017, 18 pts were enrolled. Histologies were: synovial sarcoma in 10 (56%) pts, UPS in 3 (17%), myxoid liposarcoma, dedifferentiated liposarcoma, G3 NOS sarcoma, leiomyosarcoma and MPNST in 1 pts each. Median previous lines 1 (0-3). Twelve pts received T at dose level 1 and 6 pts at level 2. Overall, G 3/4 AEs were: neutropenia (8), ALT elevation (2), GGT elevation (2), anemia (2), febrile neutropenia and pneumonitis (1 each). There were two DLTs: Transient G4 ALT elevation in level 1 and G4 neutropenia ( > 5 days) in level 2. Based on central radiological review and 17 evaluable pts, 2 pts achieved CR (12%), 3 PR (18%), 6 SD (35%), 6 PD (35%). On local review, we found 2 CR (12%), 5 PR (29%), 4 SD (24%), 6 PD (35%). On the irradiated lesions, 4 CR (24%), 8 PR (47%), 4 SD (24%) and 1 PD (5%) were found. With a median FU of 18 m, median PFS was 2.83 (2.3-3.3). Thirteen pts (72%) have died, with a median OS of 8.77 m (3.6-13.9) and 12-month OS rate of 48% Conclusions: T concurrent with RT was feasible in pts with pulmonary metastatic STS regardless of histologic subtype. T at 1.5 mg/m2 is the recommended dose for phase II part. We confirmed the synergy of T+RT, with 71% of the irradiated lesions showing long-lasting dimensional responses. Clinical trial information: NCT02275286.
TCT-442 Robotic Peripheral Vascular Intervention with Drug Coated Balloons is Feasible and Reduces Operator Radiation Exposure: Results of the Robotic-Assisted Peripheral Intervention for Peripheral Artery Disease (RAPID) Study II
Authors: Ehtisham Mahmud, Franz Hafner, Peter Rief, Chris Cain, Lawrence Ang, Marianne Brodmann
Journal: Journal of the American College of Cardiology (2018)
Correlation of PD-L1 Expression with Tumor Mutation Burden and Gene Signatures for Prognosis in Early-Stage Squamous Cell Lung Carcinoma
Authors: Hui Yu, Zhengming Chen, Karla V. Ballman, Mark A. Watson, Ramaswamy Govindan, Irena Lanc, David G. Beer, Raphael Bueno, Lucian R. Chirieac, Michael Herman Chui, Guoan Chen, Wilbur A. Franklin, David R. Gandara, Carlo Genova, Kristine A. Brovsky, Mary-Beth M. Joshi, Daniel T. Merrick, William G. Richards, Christopher J. Rivard, David H. Harpole, Ming-Sound Tsao, Adrie van Bokhoven, Frances A. Shepherd, Fred R. Hirsch
Journal: Journal of Thoracic Oncology (2018)
A phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in muscle invasive bladder cancer (ABACUS).
Authors: Thomas Powles, Alejo Rodriguez-Vida, Ignacio Duran, Simon J. Crabb, Michiel Simon Van Der Heijden, Albert Font Pous, Gwenaelle Gravis, Urbano Anido Herranz, Andrew Protheroe, Alain Ravaud, Denis Maillet, Maria Jose Mendez-Vidal, Cristina Suarez, Anja Lorch, Cora N. Sternberg, Mark David Linch, Shah-Jalal Sarker, Aaron Prendergast, Kelly Mousa, Daniel E. Castellano
Journal: Journal of Clinical Oncology (2018)

4506 Background: Atezolizumab is a PD-L1 inhibitor which is licenced in metastatic urothelial cancer. This study investigates the efficacy and safety of neoadjuvant atezolizumab given prior to cystectomy in operable muscle invasive transitional cell carcinoma bladder cancer. Methods: This single arm phase 2 study investigated 2 cycles of atezolizumab (1200mg Q3) prior to cystectomy in muscle invasive transitional cell cancer (T2-4N0M0). Pathological complete response (pCR) occurring in ≥20% of patients was the primary endpoint. Biomarker analysis on sequential tissue was a co-primary endpoint. Cross sectional imaging was performed at baseline and prior to cystectomy which occurred 4 - 8 weeks after starting atezolizumab. Radiological response was assessed. Adverse events (AEs) and surgical complications were assessed using CTCAE v4.03 and the Clavien-Dindo classification. The IDMC reviewed the first 69 patients (of 85) and supported this interim presentation. Results: The median age of the 69 patients was 73 years (range 54-88). At baseline pT2, T3, T4 disease occurred in 77%, 16% and 7% of patients respectively. 14 (20%) patients had only 1 cycle (8 due to AEs). 7 patients did not have cystectomy ( 1 disease progression, 2 treatment related AE). There was 1 potential treatment related death during treatment/perioperative period (cardiovascular disease). Treatment related grade 3/4 toxicity occurred in 12% of patients. Grade 3 or 4 surgical complications occurred in 31% of pt. The pCR rate was 18/62 (29%) [95%CI: 18% to 42%] (pT0 23%, Tis 6%, T1 10% T2 21% T3 24% T4 16% stage at surgery). 39% of patients were down staged to non-muscle invasive disease. 3/18 (17%) of the pCR patients had pT3/4 disease at baseline. 30 patients had sequential imaging and radiologically measurable disease at baseline. 23% [95%CI, 10% to 42%] and 13% [95%CI, 4% to 31%] of these patients radiologically responded and progressed respectively. Biomarker results including T cell infiltration and PD-L1 status before and after therapy will be presented. Conclusions: Neoadjuvant atezolizumab is safe and associated with a meaningful pathological CR rate at this interim stage. Further exploration is justified. Clinical trial information: NCT02662309.
Use of Medical Scribes to Reduce Documentation Burden
Authors: David W. Bates, Adam B. Landman
Journal: JAMA Internal Medicine (2018)

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A phase I study of JS001, a humanized PD-1mAbin patients with advanced triple negative breast cancer.
Authors: Li Bian, Huiqiang Zhang, Tao Wang, Shaohua Zhang, Jianbin Li, Haifeng Song, Mingli Xu, Sheng Yao, Zefei Jiang
Journal: Journal of Clinical Oncology (2018)

e15093 Background: Triple negative breast cancer (TNBC), as defined by ER, PR and HER2 negative expression in tumor,has limited treatment options beyond traditional chemotherapy.Immunotherapy is a new breakthrough in advancedTNBC.JS001,a humanized IgG4 antibody specific for human PD-1, has demonstrated acceptable safety profile and preliminary anti-tumor activity in other solid tumors. Methods: This Phase I open-labelstudy is designed to evaluate safety and tolerability of JS001 in advanced TNBC patients who are refractory to systemic therapy. The study has a 3+3 dose escalation design with planned cohorts at 1, 3, and 10 mg/kg Q2W followed by a dose expansion. (Clinical Trial ID: NCT02838823). Results: From August 04,2016 to October 26, 2017,20 heavily-treated advanced TNBC patients were enrolled into three dose cohorts (6 in 1 mg/kg, 8 in 3 mg/kg and 6 in 10 mg/kg) with median age of 49. Median systemic lines of treatment received prior to JS001 is 4. All patients have been treated with taxanes and 18 patients (90%) have prior platinum-based chemotherapy.75% patients have metastasis in internal organs with poor prognosis. As of Jan 30, 2018, No DLT was observed and no MTD was reached in the study. The most common treatment related AEs were all grade 1/2,including hypo-(25%) or hyper- (15%) thyroidism, AST increase (20%), ALT increase (20%), anemia (20%), hyperglycemia (15%),hypertriglyceridemia(15%), pruritus (10%), and fatigue (10%).Treatment related grade 3 AEs include1 rash and 1 bronchospasm. The emergence of AEs is not dose related.Among 20 evaluable subjects, no patients obtained CR or PR, while 7 patients achieved stable disease,for a disease control rate (DCR)of 35%. 4 patients had stable disease over 6 months, with the longest at 8 months and still ongoing.50% subjects are PD-L1 positive (≥1% cutoff) in tumor biopsy, among whom a 40% DCR was observed. Conclusions: JS001 exhibited a favorable safety profile in advanced TNBC patients.Treatment related AEs are in line with approved drugs in the same class and no additional safety signal was observed.Combination of JS001 with traditional chemotherapy and/or anti-angiogenesis therapy are being evaluated for future clinical development in advanced TNBC patients. Clinical trial information: NCT02838823.
Association of the adoption of immune checkpoint inhibitor therapy (ICT) with prevalence of tumor mutation burden (TMB) in sixteen cancer types.
Authors: Leigh Baumgart, Sandeep K. Reddy, Chad Garner, J Zachary Sanborn, William A. Flood
Journal: Journal of Clinical Oncology (2018)

e18557 Background: Tumor Mutation Burden (TMB) is an emerging biomarker for response to immune checkpoint inhibitor therapy (ICT). PDL1 is still the only companion diagnostic test for ICT. We sought to examine the relationship between the use of ICT based on real world prescription data relative to key FDA approval dates to TMB prevalence data based on whole exome sequencing (WES). Methods: Treatment plans submitted through a proprietary web-based application to obtain automated precertification for first, second, and third line therapies for 16 tumor types were retrospectively reviewed for ICT use before and after key ICT approval dates. These usage rates were then compared to the frequency of high TMB in respective tumor types as determined by a retrospective analysis of data from a commercial DNA tumor:normal and RNAseq platform where 992 samples were identified with paired DNA(WGS or WES)/RNAseq NGS. “High” vs “low” mutation burden was assigned with a threshold of 200 non-synonymous mutations. Results: High TMB frequency ranged between 5%(ovary)-52%(melanoma). ICT usage ranged between 0%-2%(melanoma) from 2011 through 2014, 0%-56%(melanoma) between 2015 and May 2017, and 0%-66%(melanoma) from May 2017 to February 2018. The rate of ICT usage increased by more than 15% since 2015 in head and neck, kidney, liver, lung, and melanoma. However, in kidney, liver, and melanoma, the usage rates since May 2017 are 18%, 10%, and 13% greater than the frequency of high TMB in those tissue types. Conversely, usage rates are 11-23% lower than high TMB frequency in bladder, breast, colon, lung, rectal, and uterine cancer. Conclusions: In this retrospective analysis using WES data to evaluate the correlation of high TMB frequency tumor types and ICT use, we found ICT use increased across most tumor types after 2014. However, the rate of use is lower than the prevalence of high TMB in many cancers (including lung). As ICT therapy is associated with better quality of life and equal to better overall survival than chemotherapy, more aggressive identification of prospective ICT patients through NGS exome assessment of TMB could be warranted.
P18 PRAVASTATIN AND MINOCYCLINE TREATMENT AFFECTS VESSEL WALL REMODELING IN A MURINE MODEL OF VASCULAR INJURY
Authors: B Lavin, A Phinikaridou, M E Andia, I Rashid, M Potter, René M Botnar
Journal: Cardiovascular Research (2018)

Introduction: Preclinical studies have demonstrated that myocardial infarction and necrosis accelerate atherosclerotic plaque progression due to sympathetically-driven systemic inflammation 1 .We assessed the impact of focal vascular injury on remote endothelial function and atherosclerotic plaque progression in vivo, using molecular magnetic resonance imaging with albuminbinding (gadofosveset) and elastin-specific gadolinium-based (Gd-ESMA) contrast agents.The impact of pravastatin and minocycline in this model were evaluated.Methods: Apoe -/-mice underwent gadofosveset (0.03mmol/kg) and Gd-ESMA (0.2mmol/kg) enhanced MRI (3T, Philips Achieva) of the brachiocephalic artery (BCA) at baseline and at 4, 8 and 12 weeks following high fat diet (HFD), HFD-injury, HFD-injury-Pravastatin and HFD-injury-Minocycline (n ¼ 6 in all groups).Aortic injury was performed as described 2 .Pravastatin (40mg/kg/ day) and minocycline (3mg/kg/day) treatments were provided in water.Results: Administration of gadofosveset (1A-B) resulted in a sustained and significant increase in BCA wall enhancement [(late-gadolinium enhancement (LGE) area and relaxation rate (R1)] in HFD-injury compared to HFD mice, consistent with prolonged endothelial dysfunction remote to the site of injury.This was associated with a marked increase in atherosclerotic plaque area (41%) in HFD-injury mice on Gd-ESMA MRI (1A-C) and histological analysis.Ex-vivo analysis showed increased serum IL-6 and monocyte recruitment in the BCA of the HFD-injured mice.Administration of pravastatin or minocycline attenuated remote endothelial dysfunction and atherosclerotic plaque progression, however, pravastatin alone increased fibrous cap thickness and lesion collagen content.In contrast to minocycline, pravastatin did not affect the number or phenotype of circulating monocytes, suggestive of lesion-level therapeutic effects.Conclusions: Focal vascular injury causes sustained remote endothelial dysfunction and atherosclerotic plaque progression in a systemic response driven by monocytes and IL-6 that can be attenuated with statin therapy or minocycline.
VIEKIRA PAK associated drug-induced interstitial lung disease: Case series with systematic review of literature
Authors: Yu Jun Wong, Si Yuan Chew, John Chen Hsiang, Prem Harichander Thurairajah, Rahul Kumar, Eng Kiong Teo, Roshni Sadashiv Gokhale, Imran Bin Mohamed Noor, Jessica Tan
Journal: Clinical and Molecular Hepatology (2018)
In Vivo Fate and Activity of Second- versus Third-Generation CD19-Specific CAR-T Cells in B Cell Non-Hodgkin’s Lymphomas
Authors: Carlos A. Ramos, Rayne Rouce, Catherine S. Robertson, Amy Reyna, Neeharika Narala, Gayatri Vyas, Birju Mehta, Huimin Zhang, Olga Dakhova, George Carrum, Rammurti T. Kamble, Adrian P. Gee, Zhuyong Mei, Meng-Fen Wu, Hao Liu, Bambi Grilley, Cliona M. Rooney, Helen E. Heslop, Malcolm K. Brenner, Barbara Savoldo, Gianpietro Dotti
Journal: Molecular Therapy (2018)

Second-generation (2G) chimeric antigen receptors (CARs) targeting CD19 are highly active against B cell malignancies, but it is unknown whether any of the costimulatory domains incorporated in the CAR have superior activity to others. Because CD28 and 4-1BB signaling activate different pathways, combining them in a single third-generation (3G) CAR may overcome the limitations of each individual costimulatory domain. We designed a clinical trial in which two autologous CD19-specific CAR-transduced T cell products (CD19.CARTs), 2G (with CD28 only) and 3G (CD28 and 4-1BB), were infused simultaneously in 16 patients with relapsed or refractory non-Hodgkin's lymphoma. 3G CD19.CARTs had superior expansion and longer persistence than 2G CD19.CARTs. This difference was most striking in the five patients with low disease burden and few circulating normal B cells, in whom 2G CD19.CARTs had limited expansion and persistence and correspondingly reduced area under the curve. Of the 11 patients with measurable disease, three achieved complete responses and three had partial responses. Cytokine release syndrome occurred in six patients but was mild, and no patient required anti-IL-6 therapy. Hence, 3G CD19.CARTs combining 4-1BB with CD28 produce superior CART expansion and may be of particular value when treating low disease burden in patients whose normal B cells are depleted by prior therapy.
Single agent activity of ZW25, a HER2-targeted bispecific antibody, in heavily pretreated HER2-expressing cancers.
Authors: Funda Meric-Bernstam, Murali Beeram, Jose Ignacio Mayordomo, Diana L. Hanna, Jaffer A. Ajani, Mariela A. Blum Murphy, Rashmi Krishna Murthy, Sarina Anne Piha-Paul, Todd Michael Bauer, Johanna C. Bendell, Anthony B. El-Khoueiry, Heinz-Josef Lenz, Michael F. Press, Nels Royer, Diana Felice Hausman, Erika Paige Hamilton
Journal: Journal of Clinical Oncology (2018)

2500 Background: ZW25, a novel Azymetric bispecific antibody, targets HER2 domains ECD2 and ECD4, resulting in multiple differentiated mechanisms of action including increased tumor cell binding, blockade of ligand-dependent and independent growth, and improved receptor internalization and downregulation relative to trastuzumab (T). In vivo studies demonstrate anti-tumor activity in HER2-low to high expressing models. This Phase 1 study evaluated ZW25 single agent safety and anti-tumor activity. Methods: Part 1 (P1) evaluated ZW25 5, 10 and 15 mg/kg weekly and 20 mg/kg biweekly using a 3+3 design to identify a recommended dose (RD) for further study. Part 2 (P2) is ongoing and evaluating safety and efficacy in separate expansion cohorts, including HER2-high (IHC 3+ or 2+/FISH+) breast (BC), gastric/esophageal (GE), and other cancers. Pts had to have progressive disease after standard of care, including HER2-targeted agents. Adverse events (AE), PK, and response per RECIST 1.1 (every 8 wks in pts with measurable disease) were assessed. Results: 33 pts have been treated in P1 and P2: 17 BC, 11 GE and 5 other cancers. HER2-high BC pts had prior T and T-DM1 (100%), pertuzumab (82%) and lapatinib (53%), with a median of 6 HER2-targeted regimens for metastatic disease. All GE pts had received prior T, with a median of 4 systemic tx. Safety and anti-tumor activity were similar across dose levels with no DLTs. The RD for Part 2 was 10 mg/kg weekly or 20 mg/kg biweekly. The most common AEs were diarrhea and infusion reaction, all Gr 1 or 2, with no tx-related discontinuations. Time on study is 14-348 days with 9 pts still active. 23 pts are response evaluable, with 3 pts not yet restaged. Conclusions: ZW25 has been well tolerated with promising single agent anti-tumor activity in pts with heavily pretreated HER2-expressing cancers that have progressed after standard of care, including multiple HER2-targeted regimens. These data support the therapeutic potential of ZW25 and suggest that its unique MOA may overcome mechanisms of resistance to other HER2-targeted agents. Clinical trial information: NCT02892123.Partial response (PR) and disease control rates DCR = PR or SD anytime on study. PR DCR BC n=13 46% 54% GE n=7 43% 57% Other n=3 — 33% Total n=23 39% 52%
Early markers of anthracycline сardiotoxicity in treatment of patients with breast cancer.
Authors: Liubov Yu Vladimirova, Oleg I. Kit, Nailya Guskova, Natalya Mikhailovna Tikhanovskaya, Elena A. Sycheva, Anastasia Nozdricheva, Svetlana V. Abakumova, Natalya A Abramova, Anna E Storozhakova, Irina L. Popova, Ludmila A. Ryadinskaya, Aza A. Lyanova, Kristina A. Novoselova, Zinaida P. Lisunova, Kristina Avanesova, Ineya I. Zekhtser, Svetlana V. Belgova, Viktoria Zakharchenko, Irina V. Tselishcheva, Izabella Torpudzhyan
Journal: Journal of Clinical Oncology (2018)

e14506 Background: The purpose of the study was to assess changes in biochemical markers of cardiotoxicity in anthracycline chemotherapy for breast cancer. Methods: The study included 30 pts (32-72 years, 50%<50 years) with stage II-III breast cancer (BC) receiving 4 cycles of anthracycline (AC) chemotherapy (CT). N-terminal pro-brain natriuretic peptide (NT-proBNP), troponin I (TI), creatine kinase (CK), creatinine and urea were determined (Vitros 5600, USA) in the blood serum before AC administration and on days 2 and 5 after it. The results were compared with electrocardiography and echocardiography (EchoCG) data. The data were processed using the Statistica 6.0 program. Results: No clinical or instrumental data on an acute myocardial infarction were registered. NT-proBNP˃64.0 pg/mL was considered as high. Before treatment, 15 (50%) pts showed increased NT-proBNP (on average 144.3±38.8 pg/mL), which correlated with EchoCG results and indicated initial cardiovascular pathology. The initial level of NT-proBNP in other pts was 48.2±14.7 pg/mL. Correlation between the age and NT-proBNP was not found (p > 0.05). Day 2, NT-proBNP increased by 2.6 times (p < 0.01) in 26 (86.7%) pts: 15 (50.0%) with initially high levels and 12 (40.0%) with initially normal ones. Day 5, NT-proBNP increased in 7 (23.3%) pts and decreased in 6 (20.0%). NT-proBNP levels restored to initial values by the 4th CT cycle. The changes after the 1st AC injection and on days 2 and 5 were similar in direction. TI and CK did not change at all stages even in pts with high NT-proBNP, indicating the development of reversible cardiotoxic effect. Levels of creatinine and urea were within the reference range which excluded their impact on NT-proBNP. Conclusions: NT-proBNP is bound to be the most sensitive marker of cardiotoxicity and could serve as an earlier marker in patients with breast cancer undergone chemotherapy with anthracyclines.