tbuckley/cabot-search huggingface dataset:
Phase (Ph) I study of the safety and efficacy of the cMET inhibitor capmatinib (INC280) in patients (pts) with advanced cMET+ non-small cell lung cancer (NSCLC).
Authors: Martin H. Schuler, Rossana Berardi, Wan-Teck Lim, Robin Van Geel, Maja J. De Jonge, Todd Michael Bauer, Analia Azaro, Maya Gottfried, Ji-Youn Han, Dae Ho Lee, Mira Wollner, David S. Hong, Arndt Vogel, Angelo Delmonte, Alexander Krohn, Yong Zhang, Matthew Squires, Monica Giovannini, Mikhail Akimov, Yung-Jue Bang
Journal: Journal of Clinical Oncology (2016)

9067 Background: cMET dysregulation occurs in 3–10% of NSCLC and is a negative prognostic factor. INC280 is a highly selective cMET inhibitor with preclinical and clinical antitumor activity. The dose-escalation part of this ongoing Ph I study (NCT01324479) included a cMET-dysregulated NSCLC expansion group. Preliminary efficacy was seen in NSCLC pts with high cMET expression, prompting the addition of a second expansion group of pts with EGFRwt, high cMET-expressing NSCLC. We report here on both NSCLC groups. Methods: The primary objective of this Ph I study was met; INC280 RP2D was established at 400 mg BID in a tablet formulation. Secondary objectives included exploring the antitumor activity of INC280 at the RP2D in the original and additional NSCLC groups. Eligible pts (aged ≥ 18 years; ECOG PS ≤ 2) in the original group had documented cMET+ (H-score ≥ 150 or cMET/centromere ratio ≥ 2.0 or gene copy number [GCN] ≥ 5 or IHC 2+ or 3+) NSCLC. In the additional NSCLC group, pts had documented EGFRwt and centrally assessed cMET IHC 3+. Results: As of Sep 28 2015, 43 pts were enrolled in the NSCLC expansion groups: 26 and 17 pts in the original and additional groups, respectively (median age 60 years; 74% Caucasian; 2 median prior therapies; 86% PS 0/1). 27/43 (63%) pts discontinued treatment, mainly due to disease progression (44%). The most common AEs (all grades, regardless of causality) were nausea (47%), vomiting (37%), peripheral edema (35%), decreased appetite (33%), and fatigue (33%). The most common Grade 3/4 AEs (regardless of causality) were anemia, hypokalemia, and pneumonia (all 7%). Response by expansion group and cMET status was assessed in evaluable pts. In the original group, 5/26 pts had partial responses (PR; ORR 19%); 2 pts in the original group also had cMET exon 14 mutations and both had PRs. In pts with cMET IHC 3+, 5/17 had PRs (2 unconfirmed/ongoing; ORR 29%). In pts with cMET GCN ≥ 5, 5/8 had PRs (2 unconfirmed/ongoing; ORR 63%). Conclusions: Oral INC280 at the RP2D was well-tolerated with a manageable safety profile. Strong preliminary activity was observed in pretreated pts with NSCLC and high cMET GCN or cMET overexpression. Clinical trial information: NCT01324479.
Assessment of orthotic needs in Iranian veterans with ankle and foot disorders
Authors: Kamiar Ghoseiri, Mostafa Allami, Mohammad Reza Soroush
Journal: Military Medical Research (2018)

War-related traumas can lead to orthopedic and neurological disorders in victims. However, the scope of such disorders may expand months or even years after the trauma. Orthotic treatment as a rehabilitation process aims to enable people with disabilities to reach and maintain their optimal physical, sensory, intellectual, psychological, and social functional levels. This study aimed to investigate the rate of using orthoses among Iranian veterans with neuromuscular and skeletal disorders of the ankle and foot. Furthermore, the priorities of orthotic treatment in those veterans were explored.This qualitative study was a national health needs assessment conducted in 11 provinces of Iran during 2011-2016. A stakeholder research group was established to survey the veterans in respect to their demographic variables, activities of daily living, current health conditions, and rate of using orthoses.Overall, 907 of the 1124 veteran participants completed the survey (response rate: 80.7%). Most of the veterans were men (97.7%), and their age and disability rate were 52.07 ± 8.13 years and 31.92% ± 14.93%, respectively. Nearly 42% of the veterans had experience in using orthoses on a daily and weekly basis. As physical ambulation was the main problematic activity in veterans, most of them were using medical shoes and foot orthoses. Nearly 37% of veterans were in need of some type of lower limb orthoses on the contralateral side to compensate for their hip inequality. In sequential order, the most in need orthoses for veterans were foot orthoses (n = 538), medical shoes (n = 447), lower limb orthoses on the contralateral side (n = 320), spinal orthoses (n = 273), and upper limb orthoses (n = 86).In spite of the high demands for orthoses among Iranian veterans with ankle and foot disorders, the use of orthoses is insufficient. Hence, there is a discrepancy between the current rate of orthoses use and its ideal situation, and more resources should be provided for service providers to be able to serve veterans. Moreover, veterans should be educated regarding orthoses, their use, and their impacts on the user's health status. The findings of a needs assessment of orthoses can be used in strategic planning and decision making to improve health care services for Iranian veterans.
Inhibition of EphB4–Ephrin-B2 Signaling Enhances Response to Cetuximab–Radiation Therapy in Head and Neck Cancers
Authors: Shilpa Bhatia, Jaspreet Sharma, Sanjana Bukkapatnam, Ayman Oweida, Shelby Lennon, Andy Phan, Dallin Milner, Nomin Uyanga, Antonio Jimeno, David Raben, Hilary Somerset, Lynn Heasley, Sana D. Karam
Journal: Clinical Cancer Research (2018)

Purpose: The clinical success of targeted therapies such as cetuximab and radiotherapy (RT) is hampered by the low response rates and development of therapeutic resistance. In the current study, we investigated the involvement of EphB4-ephrin-B2 protumorigenic signaling in mediating resistance to EGFR inhibition and RT in head and neck cancers.Experimental Design: We used patient-derived xenograft (PDX) models of head and neck squamous cell carcinoma (HNSCC) and HNSCC cell lines to test our hypothesis. Tumor tissues were subjected to PhosphoRTK array, and Western blotting to detect changes in EphB4-ephrin-B2 targets. mRNA sequencing and microarray data analysis were performed on PDX tumors and HNSCC cell lines, respectively, to determine differences in gene expression of molecules involved in tumor cell growth, proliferation, and survival pathways. Effects on cell growth were determined by MTT assay on HNSCC cells downregulated for EphB4/ephrin-B2 expression, with and without EGFR inhibitor and radiation.Results: Our data from locally advanced HNSCC patients treated with standard-of-care definitive chemo-RT show elevated EphB4 and ephrin-B2 levels after failure of treatment. We observed significant response toward cetuximab and RT following EphB4-ephrin-B2 inhibition, resulting in improved survival in tumor-bearing mice. Tumor growth inhibition was accompanied by a decrease in the levels of proliferation and prosurvival molecules and increased apoptosis.Conclusions: Our findings underscore the importance of adopting rational drug combinations to enhance therapeutic effect. Our study documenting enhanced response of HNSCC to cetuximab-RT with EphB4-ephrin-B2 blockade has the potential to translate into the clinic to benefit this patient population. Clin Cancer Res; 24(18); 4539-50. ©2018 AACR.
Abstract 17368: Years of Life Lost Due to Heart Failure in the United States (US)
Authors: Harshali Patel, Adrian Kielhorn, Nicole Yurgin, Adrian F Hernandez
Journal: Circulation (2015)

Background: Heart failure (HF) is a complicated syndrome where ~50% of patients die within 5 years of diagnosis. Years of life lost (YLL) is a population-based mortality indicator that takes into account age at death, giving greater weight to deaths occurring at a younger age and thereby providing information on mortality that is relevant to the entire population without the bias of elderly death. A YLL analysis was applied to patients with HF to illustrate the relationship between HF and premature mortality. Further YLL for HF was compared to other common elderly diseases. Methods: Data between 1999 and 2012 on the number of deaths attributed to HF and other conditions common in the elderly were from the Centers for Disease Control and Prevention and the National Center for Health Statistics online database; standard life-expectancy data for the US were from the World Health Organization global health observatory data repository. YLL was calculated from the number of deaths multiplied by years of life remaining based on a standard life expectancy at the age at which death occurs. Total YLL over all age groups was then divided by the total number of deaths for the mean YLL per HF patient. The same calculation was made for several other conditions for comparison. Results: A total of 804,095 US deaths were attributed to HF. The mean HF YLL was 9.64 years, which was higher than YLL calculated for osteoporosis and Alzheimer’s/other dementias (7.12 and 7.67 years, respectively; Figure) and similar to Parkinson’s disease (9.73 years). Conclusions: Analysis of premature mortality by YLL suggests that patients with HF would live on average 9.64 years longer had they not developed HF.
Supporting survivorship care through comprehensive cancer control technical assistance.
Authors: Allison Harvey, Mohammad Khalaf, Aubrey Villalobos, Mandi Chapman
Journal: Journal of Clinical Oncology (2018)

15 Background: In 2010, the Centers for Disease Control and Prevention (CDC) issued six priorities for Comprehensive Cancer Control (CCC) programs, including addressing needs of cancer survivors (Seeff, 2010). CCC programs identified need for technical assistance (TA), tools and resources in this area. George Washington University (GW) Cancer Center provides TA on survivorship through a 5-year agreement from CDC and contracts from 5 states. Methods: Since 2013, GW developed three online trainings for health care providers with a focus on survivorship. From 2016-2017, GW delivered four tailored in-person workshops to health care professionals (N = 137). GW also produced a survivorship report and a roadmap to implement the patient navigation standard from the Commission on Cancer: both include background information, sample metrics and implementation resources. Results: Across online trainings for oncology and primary care provider (PCP) learners, a majority of participants (N = 1,983) agreed or strongly agreed their knowledge was enhanced (94.6%) and planned to implement strategies/skills/information learned (79.6%). While content varied for workshops, patient-provider communication, survivorship care plans and patient navigation were common topics presented. The majority (n = 74) agreed or strongly agreed their knowledge was enhanced (82.4%) and planned to implement strategies/skills/information learned (86.4%). The survivorship report has been downloaded 11,000+ times in one year and the roadmap nearly 5,000 times in one month. Conclusions: Based on uptake of TA, GW is meeting a need for CCC programs. However, stakeholder feedback indicates programs continue to desire TA support to meet patient navigation and survivorship care standards. Notably, most PCPs are not familiar with survivorship care, and uptake of trainings aimed at PCPs remains low. Opportunities for further TA to troubleshoot challenges in patient navigation and survivorship care remain.
Results from molecular analysis for therapy choice (MATCH) arm I: Taselisib for PIK3CA-mutated tumors.
Authors: Ian E. Krop, Opeyemi Jegede, Juneko E. Grilley-Olson, Josh David Lauring, Stanley R. Hamilton, James A. Zwiebel, Shuli Li, Lawrence Rubinstein, Austin Doyle, David R. Patton, Edith P. Mitchell, Carlos L. Arteaga, Barbara A. Conley, David Sims, Lyndsay Harris, Alice P. Chen, Keith Flaherty
Journal: Journal of Clinical Oncology (2018)

101 Background: MATCH is a trial that assigns patients (pts) with solid tumors, lymphomas, or multiple myeloma to specific targeted therapies based on genetic alterations identified in fresh tumor biopsies. Arm I evaluated the PI3-kinase inhibitor taselisib in pts with activating mutations in PIK3CA, the catalytic subunit of PI3-kinase. Methods: Pts with KRAS mutations or PTEN mutation or loss were excluded, as were pts with breast or squamous lung cancer. Pts received taselisib 4 mg po daily on 28 d cycles until progression or intolerable toxicity. Staging was every 2 cycles. The primary endpoint was objective response (OR); secondary endpoints were PFS, 6-month PFS, and predictive biomarkers. Results: 65 pts (enrolled 3/2016-4/2017) received ≥1 dose of study therapy; 45 tumor types were represented; 38% of pts had > 3 prior lines of therapy. There were no ORs, but prolonged stable disease was observed (estimated PFS6 rate 27%, 90% CI 19%-39%), and 2 pts remain on study > 1 yr. The most common toxicities were fatigue (38%), diarrhea (38%) and nausea (34%), all predominately grade 1-2, with 2% of pts requiring dose reductions, and 11% discontinuing taselisib because of toxicity. No hyperglycemia or rash were observed. PIK3CA mutations occurred in the helical domain (HD, 69%), kinase domain (KD, 17%), or other domains (14%). There was an observed trend (non-significant) toward longer PFS in tumors with KD mutations compared to HD or other mutations (median PFS 4.6 mo vs 3.5 mo vs 1.8 mo, respectively). Co-occurring mutations were detected in 67% of tumors. In exploratory analyses, TP53/MDM2 alterations (n = 24) were associated with PFS < 6 mo, and enrichment for PFS ≥ 6 mo was observed in pancreatic-biliary tumors/cholangiocarcinoma (3/6) and adenoid cystic carcinoma (3/4). Only 1 of 9 pts with BRAF, NRAS, HRAS, MAP2K1, MAPK1, or NF1 mutations achieved PFS ≥ 6 mo. Conclusions: In a mixed histology cohort selected for activating PIK3CA mutations, taselisib did not achieve any ORs, although 27% of pts had PFS ≥ 6 mo. PIK3CA mutation independent of histology is an insufficient predictor of taselisib activity. Associations of individual histologies and PIK3CA mutation subtypes with PFS may be worthy of further study. Clinical trial information: NCT02465060.
miR-519a enhances chemosensitivity and promotes autophagy in glioblastoma by targeting STAT3/Bcl2 signaling pathway
Authors: Hong Li, Lei Chen, Jun-jie Li, Qiang Zhou, Annie Huang, Wei-wen Liu, Ke Wang, Liang Gao, Song-tao Qi, Yun-tao Lu
Journal: Journal of Hematology & Oncology (2018)

Chemoresistance to temozolomide (TMZ) is a major challenge in the treatment of glioblastoma (GBM). We previously found that miR-519a functions as a tumor suppressor in glioma by targeting the signal transducer and activator of transcription 3 (STAT3)-mediated autophagy oncogenic pathway. Here, we investigated the effects of miR-519a on TMZ chemosensitivity and autophagy in GBM cells. Furthermore, the underlying molecular mechanisms and signaling pathways were explored.In the present study, two stable TMZ-resistant GBM cell lines were successfully generated by exposure of parental cells to a gradually increasing TMZ concentration. After transfecting U87-MG/TMZ and U87-MG cells with miR-519a mimic or inhibitor, a series of biochemical assays such as MTT, apoptosis, and colony formation were performed to determine the chemosensitive response to TMZ. The autophagy levels in GBM cells were detected by transmission electron microscopy, LC3B protein immunofluorescence, and Western blotting analysis. Stable knockdown and overexpression of miR-519a in GBM cells were established using lentivirus. A xenograft nude mouse model and in situ brain model were used to examine the in vivo effects of miR-519a. Tumor tissue samples were collected from 48 patients with GBM and were used to assess the relationship between miR-519a and STAT3 expression.TMZ treatment significantly upregulated miR-519a in U87-MG cells but not in U87-MG/TMZ cells. Moreover, the expression of miR-519a and baseline autophagy levels was lower in U87-MG/TMZ cells as compared to U87-MG cells. miR-519a dramatically enhanced TMZ-induced autophagy and apoptotic cell death in U87-MG/TMZ cells, while inhibition of miR-519a promoted TMZ resistance and reduced TMZ-induced autophagy in U87-MG cells. Furthermore, miR-519a induced autophagy through modification of STAT3 expression. The in vivo results showed that miR-519a can enhance apoptosis and sensitized GBM to TMZ treatment by promoting autophagy and targeting the STAT3/Bcl-2/Beclin-1 pathway. In human GBM tissues, we found an inverse correlation between miR-519a and STAT3 expression.Our results suggested that miR-519a increased the sensitivity of GBM cells to TMZ therapy. The positive effects of miR-519a may be mediated through autophagy. In addition, miR-519a overexpression can induce autophagy by inhibiting STAT3/Bcl-2 pathway. Therefore, a combination of miR-519a and TMZ may represent an effective therapeutic strategy in GBM.
Is Oncotype DX test necessary for T1b grade 1, hormone receptor positive HER-2 negative breast cancer? A single institution retrospective analysis.
Authors: Vinay K. Gudena
Journal: Journal of Clinical Oncology (2018)

e12598 Background: NCCN (National comprehensive cancer network) recommends to consider Oncotype DX testing for patients diagnosed with stage IA breast cancers between 0.5- 1 cm that are hormone receptor positive and HER-2 negative. This study is a retrospective review of patients diagnosed with T1b stage IA breast cancers diagnosed at Cone Health Cancer Center between 2012 and 2017 who had Oncotype DX testing. Methods: Patients with T1b hormone receptor positive and HER-2 negative breast cancer, who had Oncotype DX testing performed were queried from tumor registry from 2012 to 2017. The registry also provided information regarding the grade and whether these patients received chemotherapy. Results: A total of 73 patients with T1b N0 (stage IA ) invasive breast cancers that were ER and PR positive and HER-2 negative between 2012 and 2017, had Oncotype DX test performed. Along these, 12 patients received adjuvant chemotherapy. Among those patients receiving adjuvant chemotherapy, 9 patients had Oncotype DX score ≥25. There were 3 patients with Oncotype DX score ≤24 (22, 23 and 24) who also received chemotherapy. Among those who received chemotherapy, there were no patients with grade 1 disease. All of them were grade 2. Analysis of data on grade 1 T1b breast cancer patients (n = 43), revealed that all of them had Oncotype DX scores ≤ 24 and none of them received adjuvant chemotherapy. Conclusions: This retrospective analysis suggests that patients with T1b grade 1 ER/PR positive HER-2 negative breast cancers will have Oncotype scores ≤ 24 and hence will not require chemotherapy. It brings up the question of whether Oncotype DX testing for this select group of patients can be safely omitted. Limitations: This is not a prospective study and the sample size is not large enough to make any definitive conclusions. The decision regarding whether to order Oncotype DX testing for this clinically low risk group of patients should be left with individual providers. It will be helpful to do a large data analysis of Oncotype DX results from patient’s who had T1b grade 1 ER/PR positive HER-2 negative disease to see if these results are consistent across different institutions.
Outcome of patients with multiple myeloma (MM) relapsing after front-line autologous stem cell transplantation (ASCT): Impact of reduced intensity allogeneic transplantation (RICALLO).
Authors: Reza Tabrizi, Gerald Marit, Chaterine Mohr, Axelle Lascaux, Stephane Vigouroux, Kamal Bouabdallah, Arnaud Pigneux, Thibaut Leguay, Marie-Sarah Dilhuydy, Cedric Duclos, Sophie Dimicoli-Salazar, Noel Jean Milpied
Journal: Journal of Clinical Oncology (2014)

e19564 Background: The aim of this single centre study was to assess the outcome of pts with MM following the relapse after ASCT, according to whether or not a RICALLO was performed. Methods: Records of the patients were reviewed and the criteria for entering the study were: Symptomatic MM treated frontline with a program including single or double ASCT, relapse at any time following ASCT, up to 65 y.o at relapse, response (CR, VGPR or PR) to a second line treatment. RICALLO was proposed to pts with no significant co-morbidities, having either sibling or MUD and who gave their consent after precise information on the risk of the RICALLO. Results: 125 pts, between 04/2002 and 10/2012 fulfilling the inclusion criteria were identified. 32 pts received a RICALLO within a median of 7 months (2-35) after relapse. The RIC consisted of fludarabine plus either 2Gy ICT or busulfan and ATG. The graft was PBSC from sibling in 12 pts and from MUD in 20 pts. Ninety three pts (CT group) received therapies according to ongoing protocols or available standard of cares. The main characteristics of the patients in each group: median age (57.4 yo for Allo and 60 yo for CT group), MM prognostic factors at diagnosis, type of 1stline therapy, single or double ASCT, time to relapse after ASCT and 2d line treatment were similar between the 2 groups. The initial treatment for relapse consisted of VD (36 pts), RD (36), TD (37), VTD (12) or MPV, MPT, Bendamustin or ASCT (1 for each). With a median FU of surviving pts of 46 months, the 3y OS from the time of relapse for the entire cohort was: 56% (CI95%, 52-60). It was of 48% (CI95% 39-57) and of 59% (CI95% 54-64) for the Allo group and the CT group respectively (p= ns). The causes of death were, relapse in 10 and 49 pts, or treatment toxicity in 11 and 0 pts in the Allo group and CT group respectively. The 3y EFS from the time of relapse was 33% (CI95%, 25-41) and 20% (CI95%, 16-24) for the Allo and the CT group respectively (p=0.01). Conclusions: The better disease control following RIC allo did not result in an improvement of overall survival due to a higher TRM mainly related to GVH disease. Future protocols should aim at reducing GVHD without impairing disease control.