tbuckley/cabot-search huggingface dataset:
AXL and CDCP1: A roadmap of innate resistance in EGFR mutant NSCLC.
Authors: Niki Karachaliou, Imane Chaib, Andres Felipe Cardona Zorrilla, Jordi Berenguer, Jillian Bracht, Jie Yang, Xueting Cai, Zhigang Wang, Ana Drozdowskyj, Ilaria Attili, July Katherine Rodríguez, Luis Leonardo Rojas Puentes, Santiago Viteri Ramirez, Sai-Hong Ignatius Ou, Tony Mok, Trever Grant Bivona, Mayumi Ono, Jingrong Jean Cui, Peng Cao, Rafael Rosell
Journal: Journal of Clinical Oncology (2018)

e24003 Background: Several non receptor tyrosine kinases (RTKs) activated by EGFR tyrosine kinase inhibitors (TKI) have been identified. Src family kinases (SFKs), FAK and STAT3 protein and mRNA levels are elevated after EGFR TKI, driving activation of YAP1, which, in turn, upregulates AXL, MET and CDCP1. Methods: A combination of genomic, biological, in vivo models, and clinical patient cohorts were performed. The efficacy of gefitinib or osimertinib with several inhibitors, including dasatinib and TPX-0005, was examined. Since only TPX-0005 abrogated Src, FAK, JAK2 and STAT3 activity, the assays were carried out with this drug. Nude mice bearing PC9 or H1975 cells were treated with osimertinib plus TPX-0005. Gene expression analysis was conducted in two cohorts (Cohort 1 and 2) of EGFR mutant NSCLC patients and was correlated with progression-free survival (PFS), overall survival (OS), and response. Results: An array of RTKs and non-RTKs were overexpressed before therapy and were not ablated with either gefitinib or osimertinib. TPX-0005 with an EGFR TKI abolishes AXL and CDCP1 mRNA expression. In addition, SFKs siRNA reduced YAP1 phosphorylation. AXL, CDCP1 and MET phosphorylation were diminished when YAP1 or SFKs were knocked-down. The combination of an EGFR TKI with TPX-0005 was synergistic in several EGFR mutant NSCLC cell lines. Osimertinib plus TPX-0005 caused tumor regression in PC9 and H1975 xenograft models. In Cohort 1, the Cox analysis showed CDCP1 as an independent prognostic factor for PFS (hazard ratio [HR] 1.79, p = 0.0407) and OS (HR 2.23, p = 0.0192). A two-gene model based on AXL and CDCP1 expression was strongly associated with the clinical outcome to EGFR TKIs in both cohorts of patients. Conclusions: CDCP1 and AXL warn of an aberrant activation of SFKs, FAK, STAT3 and YAP1 pathways. A Phase I trial of EGFR TKI plus TPX-0005 in EGFR mutant NSCLC is desirable.
Precision medicine for recalcitrant cancers with the patient-derived orthotopic xenograft (PDOX) mouse models for identification of effective therapy.
Authors: Takashi Murakami, Kei Kawaguchi, Tasuku Kiyuna, Kentaro Igarashi, Kentaro Miyake, Yukihiko Hiroshima, Scott D. Nelson, Sarah M Dry, Yunfeng Li, Arun S. Singh, Frederick C. Eilber, Robert M. Hoffman
Journal: Journal of Clinical Oncology (2017)

e23164 Background: Our laboratory has developed the patient-derived orthotopic xenograft (PDOX) mouse model of all major cancer types. Methods: Sarcomas from patients were transplanted into the right bicep femoris muscle of nude mice or at a site corresponding to their metastasis. Melanomas were transplanted in nude mice at the orthotopic site corresponding to their metastasis in the patient. An HER-2-expressing cervical cancer was transplanted to the uterine cervix of nude mice. Results: A Ewing’s sarcoma with a FUS-ERG fusion and a CDKN2A-deletion was resistant to doxorubicin as was the patient and sensitive to palbociclib and linsitinib. A spindle-cell sarcoma PDOX was resistant to doxorubicin, but sensitive to pazopanib. A pleomorphic rhabdomyosarcoma PDOX was found resistant to cyclophosphamide, but sensitive to the combination of temozolomide and irinotecan. A melanoma with a BRAF-V600E mutation PDOX was resistant to vemurafenib even thought it targets the BRAF-V600E mutation and was sensitive to trametinib, but resistant to cobimetinib, although both are MEK inhibitors. The primary tumor in a cervical cancer PDOX was resistant to endostatin, but the metastasis in this model was sensitive. Conclusions: The PDOX models have distinguished differential sensitivity of primary and metastatic tumors to the same drug. PDOX models can also distinguish effective drugs when they are sensitive to first-line therapy. Most importantly, the PDOX models can find potential effective therapeutics for recalcitrant disease. Drug evaluation with the PDOX models demonstrate that mutational analysis of the patient tumor may not be sufficient to direct therapy by itself and together with PDOX testing, can result potentially in precision treatment.
TCT-801 Predictors of Immediate Success and Long-Term Clinical Outcomes After Percutaneous Mitral Balloon Valvuloplasty in Patients With Rheumatic Mitral Stenosis
Authors: Rafael Alexandre Meneguz-Moreno, Jose Costa, Nisia Gomes, Sergio Braga, Auristela Ramos, Zilda Meneghelo, Mercedes Maldonado, Alfredo Nunes Ferreira Neto, J. Italo Franca, Dimytri Siqueira, Cesar Augusto Esteves, Amanda Sousa, J. Eduardo Sousa, Alexandre Abizaid
Journal: Journal of the American College of Cardiology (2018)
Severe immune-related adverse effects (irAE) requiring hospital admission in patients treated with immune checkpoint inhibitors for advanced malignancy: Temporal trends and clinical significance.
Authors: Kerry Lynn Reynolds, Justine Vanessa Cohen, David P. Ryan, Ephraim P. Hochberg, Michael Dougan, Molly Thomas, Amanda Guidon, Colleen Channick, Steven T Chen, Sara Schoenfeld, Meghan Sise, Rebecca Leaf, Tomas G Neilan, Jacqueline N. Chu, Chin Hur, Yonina Murciano-Goroff, Alexandra C Villani, Mazen Nasrallah, Ryan J. Sullivan, Aditya Bardia
Journal: Journal of Clinical Oncology (2018)

3096 Background: Disruption of the immune system using immune checkpoint inhibitors can result in a multitude of immune-related adverse effects (irAE). While irAEs have been well-reported in clinical trials, the impact and magnitude in the real world is unclear. Methods: Data was collected on patients with advanced malignancy who experienced a suspected irAE requiring admission to an academic hospital (02/11-06/17). Each case was comprehensively reviewed by a minimum of two reviewers, including one sub-specialist. In addition, oncologists were surveyed regarding their confidence about managing irAEs. Results: From 2011-2017, there were 343 hospitalizations for suspected irAEs, and the majority (65%; N = 223) were confirmed irAEs from immunotherapy: PD1 (31.8%), CTLA4 (29.2%), CTLA4 + PD1 (15.7%), PD1 à CTLA4 (14.8%), CTLA4àPD1 (8.5%), and PDL1 (3.1%). The most common irAEs were gastrointestinal (43.9%), pulmonary (16%), hepatic (15%), neurologic (8.9%), endocrine (7.1%), rheumatologic (4%), dermatologic (3%), cardiac (3%), renal (1.8%), and allergy (1.3%). Mean length of stay was 6.4 days, readmission rate for irAE 25%, and inpatient mortality 4%. Majority of patients (92%) required continuation of immunosuppressive medication on discharge. Disposition was to home (87%), skilled facility (8.8%), or hospice (4.2%). Inpatient admissions due to irAEs has increased significantly over time (2016 vs 2011, odds ratio = 3.07; p < 0.01). However, a survey (N = 26) revealed that oncologists do not feel very comfortable managing irAEs, and 48% felt irAEs should be managed by different service. Conclusions: irAEs from immune checkpoint inhibitors can result in prolonged hospitalizations, need for immunosuppression, inpatient mortality, and high readmission rate. The number of admissions due to irAEs has increased by more than three-fold in the recent years, but comfort level in managing these complications is low. Consequently, there is a critical need for coordinated multidisciplinary approach, comprehensive provider education, and translational research programs for early detection and intervention.
Cardiac rehabilitation for the transient ischaemic attack (TIA) and stroke population? Using the Medical Research Council (MRC) guidelines for developing complex health service interventions to develop home-based cardiac rehabilitation for TIA and ‘minor’ stroke patients
Authors: Neil Heron
Journal: British Journal of Sports Medicine (2018)

I developed a novel home-based rehabilitation programme, including ‘ The Healthy Brain Rehabilitation Manual ’, for patients with a first transient ischaemic attack (TIA) or ‘minor’ stroke of atherosclerotic origin, using the core components of home-based cardiac rehabilitation (CR) and conducted a pilot randomised controlled trial (RCT) to evaluate its effectiveness.

CR is an effective form of secondary prevention for cardiovascular disease. CR after myocardial infarction results in reduced reinfarction risk and all-cause mortality.1 However, despite sharing similar pathology with coronary heart disease and the 90-day risk of further vascular events after a TIA or ‘minor’ stroke being as high as 18%,2 3 the value of CR for patients with a TIA or ‘minor’ stroke is unclear.

I followed the Medical Research Council guidelines for developing complex health service interventions. First, I conducted a systematic review (SR) of secondary prevention lifestyle interventions initiated within 90 days of a TIA or ‘minor’ stroke and then a SR on the use of behaviour change techniques (BCTs) in home-based CR. I used the SRs’ findings to adapt a …
Impact of pathological stratification of advanced well differentiated/dedifferentiated (WD/DD) liposarcoma (LPS) on the response to trabectedin (T).
Authors: Roberta Sanfilippo, Elena Fumagalli, Paola Collini, Giovanni Fucà, Salvatore Lorenzo Renne, Marta Barisella, Rossella Bertulli, Salvatore Provenzano, Carlo Morosi, Alessandro Gronchi, Angelo Paolo Dei Tos, Paolo Giovanni Casali
Journal: Journal of Clinical Oncology (2018)

11566 Background: Recently, we showed that the FNCLCC grading system can prognosticate the outcome of retroperitoneal LPS. We aimed to explore the impact of pathological stratification using the FNCLCC grading system on the response to Trabectedin (T) of advanced/metastatic WD/DD LPS. Methods: We analyzed patients (pts) with advanced WD/DD LPS and treated with T at our Institution for whom formalin-fixed paraffin-embedded (FFPE) tumor samples were available. Histologically, samples were categorized according to the 2013 WHO classification, complemented by Evans’ refinements. The “cellular subvariant” (CS) was diagnosed in the presence of a non-lipogenic area with a mitotic count < 5/10HPF. In cases in which the mitotic count was ≥5/10 HPF, the diagnosis was DDLPS and graded as 2 or 3 according to the FNCLCC grading system. Patients were divided into two subgroups: WDLPS/CS and G2/G3 DDLPS. Response rate (RR) and progression-free survival (PFS) were compared using the Fisher’s exact test and the log-rank test, respectively. Results: We included a total of 39 pts with advanced WD/DD LPS treated with T from April 2003 up to present. In 21 pts the sample analyzed was the primitive tumor prior to starting any systemic treatment. In 18 pts we analyzed the sample obtained at the closest date to T initiation. Four patients had a WDLPS, 7 a CS, 21 a G2 DDLPS and 7 a G3 DDLPS. In the subgroup of 11 WDLPS/CS, 5 partial responses, two minor responses and two stable diseases were observed, while in the subgroup of 28 G2/G3 DDLPS we observed one PR and 13 SD. RR was 45% for WDLPS/CS versus 4% for G2/G3 DDLPS (p = 0.0165). Median PFS was 14 months for WDLPS/CS and 3 months for G2/G3 DDLPS (HR 0.28; 95% CI 0.14-0.59; p = 0.0006). Conclusions: In this series, sensitivity to T was higher in WDLPS/CS. If what suggested by this limited retrospective case series analysis were confirmed on larger series, WD/CS vs G2/G3 DD histologies could serve as predictive factors for T in advanced WD/DD LPS.
Measuring concordance with head and neck cancer survivorship algorithms.
Authors: Maria Alma Rodriguez, Guadalupe R. Palos, Katherine Ramsey Gilmore, Patricia Chapman, Paula A. Lewis-Patterson
Journal: Journal of Clinical Oncology (2017)

e21602 Background: We developed institutional algorithms for cancer survivors that are site specific. However, little data exists regarding concordance with these clinical management tools. Our aim was to evaluate concordance rates with our Head and Neck (H/N) survivorship algorithms. Methods: We reviewed electronic health records (EHR) of patients seen in the H/N Survivorship Clinic between 9/01/2011 and 8/31/2014. Eligibility included: diagnosis of primary head and neck cancer, ≥ 18 years of age, no active disease, and alive at time of abstraction. Data were collected at baseline (V1) and visits 9-15 months after prior visits (V2 and V3). Data were obtained from tumor registry, a departmental database and the EHR. Twelve data elements were grouped as: 1) lab/diagnostic tests, 2) physical and psychological late effects, and 3) history and physical exams. Concordance rate (%) for each element was defined as a clinical action or recommendation aligned to the standards outlined in the H/N algorithms. Descriptive statistics were used to summarize clinical, demographic, and concordance rates. Results: Included in this analysis were patients with primary H/N malignancies of oropharynx, oral cavity, larynx, and hypopharynx, and who had completed 3 visits (V1-3). 53 patients were evaluable for concordance analyses. Compliance ranged from 55% to 100%, with lowest rates for: CT scans (55.6%), distress screening (75.5%), T4/TSH level (78.4%) and laryngoscopy (79.2%). Highest rates were noted for full physical exam (100%), chest x-ray (97.5%), dental exam (95.9%), and dysphagia evaluation (95.1%). Assessments for lymphedema and xerostomia were similar (91.8%). Conclusions: High compliance ( &gt; 90%) occurred when elements of the algorithm relied on the clinician’s assessment, whereas lower levels of compliance were seen with elements that required orders (CTs and labs), or reliance on others’ actions (i.e. distress screening by nursing). Concordance can be improved using best practice advisories in the EHR to remind providers of orders, and by fostering strong inter-professional communication on the elements of care.
Activity of an oral hyroxysterol.
Authors: Nabil Habib, Hamid Elia Daaboul, George Hage, Abdo Jabbour, Hind Zeitouni, Ryiad Khalife
Journal: Journal of Clinical Oncology (2017)

e20587 Background: Hydroxysterols are oxygenated derivatives of cholesterol. They have been shown to interfere with proliferation and cause the death of many cancer cell types, such as leukaemia, glioblastoma, colon, breast and prostate cancer cells. They control the transcription and the turnover of the key enzyme in cholesterol synthesis. Hydroxysterols interfere with PI3K/AKT, MAPK/ERK, hedgehog and Wnt pathways of proliferation and differentiation. When administered in vitro to cancer cell lines, hydroxysterols invariably both slow down proliferation and provoke cell death. Many of these compounds show antitumor activity in experimental models and most of them are very toxic. (24-ethyl-cholestane- 3β,5α,6α-triol) is the first oxysterol being tested in the clinic. It is also one of the safest in this class of compounds. Methods: We have treated with this new drug 18 patients suffering from Non-small cell lung cancer (NSCLC); sixteen males and two females. Thirteen had adenocarcinomas and five had squamous-cell carcinoma. The median age was 65. Sixteen patients had a stage IV disease and two had a stage III disease. Seven had a PS: 1, seven had a PS: 2 and four had a PS:3. Seventy-five percent were symptomatic and fifty percent were taking pain killers. Six patients only did not receive previous chemotherapy and five received radiotherapy. Patients received daily 10 mg/Kg of oral (24-ethyl-cholestane- 3β,5α,6α-triol) divided in 3 equal doses, until disease progression. Results: Twelve patients had a partial response (PR), three patients had a stable disease (NC) and three patients had a disease progression (PD). The median duration of response was 8 months but 2 patients are still under treatment. No toxicity was observed so ever. Seventy-five percent of symptomatic patients had a remarkable symptom control. Conclusions: These encouraging results make this new and safe drug a good candidate for further clinical trials either alone or in association with other drugs for the treatment of NSCLC.
TCT-293 Incidence, procedural aspects and prognosis of percutaneous coronary intervention of Unprotected Left Main Coronary Artery disease in patients with ST-segment elevation Myocardial Infarction.
Authors: Victoria Vilalta, Oriol Rodriguez Leor, Jose Linares, Gerard Roura Ferrer, Xavier Carrillo, Eduard Fernández-Nofrerias, Jose Luis Ferreiro, Joan Antoni Gomez-Hospital, Josepa Mauri, Angel Cequier, Antoni Bayes-Genis
Journal: Journal of the American College of Cardiology (2018)
ATLAS: A phase 2, open-label study of rucaparib in patients (pts) with locally advanced or metastatic urothelial carcinoma (mUC).
Authors: Petros Grivas, Dale L. Nepert, Kenton Wride, Daleen Thomas, Andrea Loehr, Andrew Simmons, Simon Chowdhury
Journal: Journal of Clinical Oncology (2018)

TPS4592 Background: There are limited treatment options for pts with mUC that has progressed during or after platinum-based chemotherapy and/or immune checkpoint inhibitors (ICIs), emphasizing the need for new therapies. Analysis of The Cancer Genome Atlas bladder cancer dataset suggests that approximately 60% of bladder cancer tumors have homologous recombination deficiency (HRD). Poly(ADP-ribose) polymerase inhibitors (PARPis) have demonstrated activity in tumors with HRD. In the United States, the PARPi rucaparib is approved for the treatment of pts with deleterious BRCA mutation (germline/somatic) associated advanced ovarian cancer treated with ≥2 chemotherapies. We hypothesize that PARP inhibition may have antitumor activity in mUC, particularly in tumors with HRD. The ATLAS (NCT03397394) trial will evaluate the efficacy and safety of rucaparib in pts with locally advanced or mUC previously treated with platinum-based chemotherapy and/or ICIs. Methods: Eligible pts must have measurable disease per RECIST v1.1, adequate organ function, and radiographic progression after 1–2 prior standard-of-care regimens. Confirmation of HRD status before enrollment is not required, but fresh tumor tissue or recently obtained archival tissue is mandatory for HRD profiling. Prior PARPi treatment is an exclusion. All pts will receive 600 mg rucaparib orally BID until disease progression or other reason for discontinuation. The primary endpoint is confirmed objective response rate (investigator-assessed per RECIST v1.1) in both HRD-positive (signature based on tumor genomic loss of heterozygosity) and intent-to-treat populations. Secondary endpoints include overall survival, progression-free survival, response duration, safety, and pharmacokinetics. Exploratory endpoints include evaluation of molecular biomarkers associated with response and resistance to rucaparib, including changes in plasma and tumor samples, and circulating tumor DNA. Patients are being enrolled in 6 countries, with a target enrollment of 200 pts. The study has > 90% power to reject the null hypothesis (P= 0.10) at a 5% significance level if the true response rate for rucaparib is 20%. Clinical trial information: NCT03397394.
Impaired Cardiac Reserve and Abnormal Vascular Load Limit Exercise Capacity in Chronic Thromboembolic Disease
Authors: Mathias Claeys, Guido Claessen, Andre La Gerche, Thibault Petit, Catharina Belge, Bart Meyns, Jan Bogaert, Rik Willems, Piet Claus, Marion Delcroix
Journal: JACC. Cardiovascular imaging (2018)
Intensive 4-weeks’ mindfulness therapy in the treatment of chronic pain in patients with cancer: Pilot study.
Authors: Anna Kieszkowska-Grudny, Katarzyna Pratnicka, Jerzy Jarosz, Dorota Jasinska
Journal: Journal of Clinical Oncology (2018)

10121 Background: Cancer pain can occur at any stage of disease and occurs on average in 51% of patients (pts) with cancer. Badly managed pain in cancer patients causes suffering and a significant reduction in the quality of life. Chronic pain (ChP) pts expect quick improvement in pain reduction. This pilot study was designed to check whether shortened and modified version of mindfulness training and therapy (MFNT) can help in ChP decrease in cancer patients’ group. Methods: 83 (63%F) oncological pts with ChP (21-90y,M = 52,4y; SD = 18,7y) took part in this longitudinal study. Patients were invited to 4-weeks MFNT (1session/w), which was 2times shortened than standard Mindfulness Based Stress Reduction Therapy. Each session (90 min) included 30min of psychoeducation and 60min of practice. In addition, pts participated in 4h MFN day (only practice) and practiced MFN 30min every day. Participants based on questionnaires rated the pain intensity 4x (each session), psychological functioning and quality of life (QoL) 2x (before and after 4w). Results: There was a significant change in the intensity of pain symptoms recorded in the morning (F(3, 81) = 7,86;p< 0,001,η2= 0,23), evening (F(3, 81) = 10,72;p < 0,001;η2 = 0,28)and average during the day (F(2,82) = 24,02;p < 0,001;η2 = 0,37). Additionally, pts observed depression (t (83) = 9,95; p< 0,001)and anxiety (t (83) = 9,88; p< 0,001) reduction, as well as improvement in QoL (t (83) = 9,24; p< 0,001). Pts assessed a whole participation in MFNT at 7,9 (scale0-10) and at 9 as a recommendations for other ChP pts. Conclusions: Intensive 4w MFNT seems to be an interesting supportive treatment option in ChP reduction, but also an effective alternative for 8w MBSR. It could be a way for better pain management, depression and anxiety symptoms decreasing and QoL increasing among cancer pts. In addition, MFNT meets the needs of patients in terms of length of therapy.
Preliminary toxicity data from the combination of pembrolizumab and definitive-dose radiotherapy for locally advanced head and neck cancer with contraindication to cisplatin therapy.
Authors: Jared Weiss, Jessica Ruth Bauman, Allison Mary Deal, Siddharth Sheth, Bhishamjit S. Chera, Colette Shen, Chris Hilliard, Tanguy Y. Seiwert, Ranee Mehra, Juneko E. Grilley-Olson
Journal: Journal of Clinical Oncology (2018)

6069 Background: Bolus cisplatin in combination with radiation therapy is a standard of care for the treatment of locally advanced SCCHN, but contraindications such as hearing loss, tinnitus, inadequate renal function or neuropathy are common. Pembrolizumab is a PD1 inhibitor with FDA approval for the treatment of platinum-refractory recurrent SCCHN. Methods: This is a phase II study (NCT02609503) for patients with locally advanced SCCHN who are not optimal candidates for the standard therapy of cisplatin and radiation. The primary endpoint is PFS. Patients are treated with 3 cycles of pembrolizumab concurrent with radiation followed by 3 adjuvant cycles. Planned accrual is 29 subjects and 18 patients have been accrued. Because of rapid advance in studies combining PD1-axis agents with radiotherapy, we report early toxicity data on the first 12 patients who have completed six cycles of pembrolizumab and at least 30 days of followup from last pembrolizumab dose. Results: All patients completed 70 Gy radiation. 11 patients completed 6 cycles of pembrolizumab and 1 patient completed 5 (discontinued due to PD, not toxicity). The most common primary reason for cisplatin ineligibility was abnormal hearing (4) followed by tinnitus (3), nephropathy (2), neuropathy (2) and diabetes with poor control (1). The most common toxicities were mucositis and lymphopenia. Pneumonitis and auto-immune toxicity were absent. All toxicities that occurred more than once and listed as possible, probable or definitely related to pembrolizumab and radiation are listed in the table. PEG tubes were placed in 3 patients. Conclusions: Early data suggest low toxicity and high feasibility of pembrolizumab combined with radiotherapy. Clinical trial information: NCT02609503. Grade 1 Grade 2 Grade 3 Grade 4 Oral mucositis 0 7 2 0 Decreased lymphocyte count 1 1 6 1 Radiation dermatitis 4 1 0 0 Dysgeusia 5 1 0 0 Fatigue 5 0 1 0 Dry Mouth 2 4 0 0 Weight loss 1 3 1 0 Nausea 2 1 0 0 Dysphagia 2 2 0 0 Maculopapular rash 2 1 0 0 Anemia 3 0 0 0 Oral pain 1 1 0 0 Anorexia 0 1 1 0 AST increased 1 1 0 0 Bili increased 2 0 0 0 Hypothyroidism 0 2 0 0 Pain 2 0 0 0 Decreased WBC 1 1 0 0