tbuckley/cabot-search huggingface dataset:
Ethnic variations in ARID1a expression in clear cell and endometrioid ovarian carcinoma.
Authors: Tiffany Lai, Koah Vierkoetter, Asia Ayabe, Hyeong Jun Ahn, David Shimizu, Keith Y. Terada
Journal: Journal of Clinical Oncology (2016)

e17073 Background: ARID1a is thought to function as a tumor suppressor; mutations in this gene have been associated with many cancers. Recent studies have found ARID1a mutations in atypical endometriosis as well as endometriosis associated ovarian carcinomas. Methods: The current study is a retrospective review of 91 cases of clear cell and endometrioid ovarian carcinomas diagnosed at Queens Medical Center in Honolulu, Hawaii between Janurary 1, 1995 to April 12, 2013. Tissue microarray was performed to evaluate loss of expression of ARID1a. Loss of expression was confirmed on whole slide sections. Clinical and ethnic information was obtained by review of medical records and the tumor registry. Ethnic information was able to be obtained for 69 of the 91 cases. Chi square or fisher’s exact tests were performed to compare loss of ARID1a expression between different racial groups. Results: Of the 91 cases studied, 20 cases exhibited loss of ARID1a expression and 71 had retained expression. There was no significant difference in expression of ARID1a among racial groups. 12 out of 48 (25%) of Asians and 1/10 (10%) of Pacific Islanders exhibited loss of expression, in comparison to 3/10 (30%) of Caucasians. There was also no significant difference when comparing Japanese and non-Japanese: 9/31 (29%), and 7/38 (18%) respectively (p value = 0.29). Conclusions: Hawaii represents a diverse ethnic population in which to study disease, with 47.5% being of Asian and Pacific Islander descent. An increased rate of clear cell ovarian carcinoma in Asians, in particular the Japanese population has been described in the literature previously. According to the current study, loss of ARID1a expression does not appear to account for this racial preference.
A Phase 1 study of MEDI1873 in adult patients with select advanced solid tumors.
Authors: Ani Sarkis Balmanoukian, Scott Joseph Antonia, Ross A. Stewart, Chelsea Black, Fujun Wang, Joyce Antal, Joyson Joseph Karakunnel, Jeffrey R. Infante
Journal: Journal of Clinical Oncology (2016)

TPS3099 Background: Directly activating T cells by delivering activating signals that augment those received via the T-cell receptor may enhance a patient’s response to tumor antigens. Glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) is expressed on regulatory T cells (Tregs) and up-regulated on activated effector T cells where it is involved in regulating T-cell activation. MEDI1873, a GITR agonist, is under investigation in patients with advanced solid tumors. Based on preclinical studies, a GITR agonist is expected to induce an antitumor immune response by promoting effector T-cell activation and overcoming local immunosuppression by reducing the number of intratumoral Tregs1,2. Methods: This is a first-in-human, Phase 1, multicenter, open-label, dose escalation study in adult patients with recurrent or metastatic solid tumors (NCT02583165). The primary objectives are to assess safety, describe dose-limiting toxicities, and determine the maximum tolerated dose of single-agent MEDI1873. The secondary objectives are to evaluate antitumor activity based on RECIST Version 1.1 (includes objective response rate, disease control rate, duration of response, progression-free survival, and overall survival endpoints), pharmacokinetics, and immunogenicity of single-agent MEDI1873. In addition, pharmacodynamic biomarkers will be evaluated, including changes in the number and activation status of circulating and intratumoral lymphocyte populations compared with baseline. Eligible patients ( ≥ 18 years) will have histologically or cytologically confirmed advanced solid tumors and must have received prior treatment for recurrent or metastatic disease. In this dose escalation study, a modified 3+3 design will be followed. MEDI1873 will be administered until unacceptable toxicity or disease progression occurs. Recruitment for this study is ongoing. References 1. Cohen AD, et al. PLoS One 2010;5:e10436. 2. Coe D, et al. Cancer Immunol Immunother 2010;59:1367-77. Clinical trial information: NCT02583165.
Economic evaluation for the US of venetoclax (VEN) versus ibrutinib (IBR) versus allogeneic hematopoietic stem-cell transplantation (HSCT) for patients (pts) with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) with 17p deletion (del 17p).
Authors: Nimer Alsaid, Ali McBride, Daniel Oscar Persky, Faiz Anwer, Leslie Ann Andritsos, Abhijeet Kumar, Seongseok Yun, Hani M. Babiker, Ivo Abraham
Journal: Journal of Clinical Oncology (2018)

7527 Background: Prior to targeted agents, HSCT was the primary treatment for R/R CLL del 17p. VEN and IBR have been shown to improve progression free (PFS) and overall survival (OS). We performed an independent economic evaluation of VEN versus IBR versus HSCT in R/R CLL del 17p from the U.S. payer perspective. Methods: From published trial data we constructed a life-time horizon Markov model with 3 states: PFS; progression; and death. Kaplan-Meier PFS and OS curves for VEN, IBR and HSCT were digitized, and Weibull distributions fitted. The wholesale acquisition cost of VEN and IBR were sourced from RedBook. Costs of the HSCT (procedure, pre-conditioning, post-procedural adverse events [AE]) were estimated from published prediction equations and a claims database. EQ-5D utility values were sourced from literature. AE disutility values were assumed the same for the 3 interventions. Discount of 3% was applied. The life years (LY) and quality adjusted LY (QALY) for each treatment were estimated, and the incremental cost-effectiveness (ICER) and cost-utility ratios (ICUR) were determined. Results: IBR prevailed in PFS over VEN and HSCT until ~190 weeks (3.7 years) when curves crossed and VEN prevailed over both IBR and HSCT. VEN prevailed in OS over IBR and HSCT over the full life time horizon. The Table below presents the BCA and PSA estimated costs and (QA)LYs gained. VEN was cost saving over IBR and HSCT and yielded higher (QA)LY gains. IBR was cost saving over HSCT and yielded higher (QA)LY gains. The ICERs and ICURs for VEN over IBR and HSCT were cost saving per (QA)LY gained. For IBR, the ICER and ICUR revealed incremental costs per LY and QALY gained. Conclusions: Over a life time horizon, VEN showed cost savings while achieving higher (QA)LYs over IBR and HSCT. IBR achieved higher (QA)LYs over HSCT but at incremental cost. BCA/PSA ICER(cost/LY) VEN $743,840/-$705,032 IBR $564,054/-$565,080 $215,016/$259,077 HSCT ICUR(cost/QALY) VEN $1,487,680/-$1,383,951 IBR $925,628/-$946,891 $198,476/$233,170 HSCT
How well do activity monitors estimate energy expenditure? A systematic review and meta-analysis of the validity of current technologies
Authors: Ruairi O’Driscoll, Jake Turicchi, Kristine Beaulieu, Sarah Scott, Jamie Matu, Kevin Deighton, Graham Finlayson, James Stubbs
Journal: British Journal of Sports Medicine (2018)

Objective To determine the accuracy of wrist and arm-worn activity monitors’ estimates of energy expenditure (EE). Data sources SportDISCUS (EBSCOHost), PubMed, MEDLINE (Ovid), PsycINFO (EBSCOHost), Embase (Ovid) and CINAHL (EBSCOHost). Design A random effects meta-analysis was performed to evaluate the difference in EE estimates between activity monitors and criterion measurements. Moderator analyses were conducted to determine the benefit of additional sensors and to compare the accuracy of devices used for research purposes with commercially available devices. Eligibility criteria We included studies validating EE estimates from wrist-worn or arm-worn activity monitors against criterion measures (indirect calorimetry, room calorimeters and doubly labelled water) in healthy adult populations. Results 60 studies (104 effect sizes) were included in the meta-analysis. Devices showed variable accuracy depending on activity type. Large and significant heterogeneity was observed for many devices (I 2 &gt;75%). Combining heart rate or heat sensing technology with accelerometry decreased the error in most activity types. Research-grade devices were statistically more accurate for comparisons of total EE but less accurate than commercial devices during ambulatory activity and sedentary tasks. Conclusions EE estimates from wrist and arm-worn devices differ in accuracy depending on activity type. Addition of physiological sensors improves estimates of EE, and research-grade devices are superior for total EE. These data highlight the need to improve estimates of EE from wearable devices, and one way this can be achieved is with the addition of heart rate to accelerometry. PROSPEROregistration number CRD42018085016.
Seventeen percent of NGS 50 gene panel variants are not expressed in RNAseq.
Authors: Razelle Kurzrock, Rahul Parulkar, Timothy Joseph Yeatman, Wafik S. El-Deiry, Timothy J. Pluard, Chad Garner, Sandeep K. Reddy
Journal: Journal of Clinical Oncology (2018)

12118 Background: Next Generation Sequencing (NGS) has gained widespread clinical adoption for the determination of molecular targets for therapy in oncology. Standard NGS panels evaluate DNA only. RNAseq has shown that molecular targets identified by NGS panels are not universally expressed. We hypothesized that heterogeneous epigenomic factors may lead to low or absent RNA expression. We sought to determine the frequency of non-expressed variants that would be tested by a standard NGS panel. Methods: Retrospective analysis of a database from a commercial DNA tumor:normal and RNAseq platform was carried out. 992 samples were identified with paired DNA(WGS or WES)/RNAseq NGS. An analysis of expressed variant status for SNVs of the following type: synonymous, silent, missense, nonsense. Expressed variants are based on whether at least 2 alternate reads in the RNA are present at that variant site. A 50 gene panel (AmpliSeq HotSpot V2) was used as the reference comparison: ABL1, EGFR, GNAS, KRAS, PTPN11, AKT1, ERBB2, GNAQ, MET, RB1, ALK, ERBB4, HNF1A, MLH1, RET, APC, EZH2, HRAS, MPL, SMAD4, ATM, FBXW7, IDH1, NOTCH1, SMARCB1, BRAF, FGFR1, JAK2, NPM1, SMO, CDH1, FGFR2, JAK3, NRAS, SRC, CDKN2A, FGFR3, IDH2, PDGFRA, STK11, CSF1R, FLT3, KDR, PIK3CA, TP53, CTNNB1, GNA11, KIT, PTEN, VHL Results: A total of 225,727 SNVs were detected in the 992 samples. 669 samples had at least 1 SNV in the 50 gene panel set for a total of 1661 SNVs, of which 1375 SNVs were expressed in the RNAseq (82.8%). Across 37 tumor types the range of expression was 57% (melanoma)-100% (uterine). Conclusions: In this retrospective analysis using a 50 gene commonly used hotspot panel as a hypothetical reference comparison, 17% of detected variants were not expressed in the RNAseq. The lack of RNA expression may contribute to less than expected clinical benefit with molecularly targeted therapies. Since the distribution is non-uniform, identification of these genes can yield improved testing algorithms and treatment strategies.
Feasibility of endobronchial ultrasound fine-needle aspiration for massively parallel next-generation sequencing in cancer patients.
Authors: Simon R. Turner, Darren Buonocore, Natasha Rekhtman, Snjezana Dogan, Patrice Desmeules, Oscar Lin, Maria E. Arcila, David Randolph Jones, James Huang
Journal: Journal of Clinical Oncology (2017)

8535 Background: Next generation sequencing (NGS) is an important emerging tool in precision oncology, allowing identification of a growing number of clinically validated and investigational therapeutic molecular targets. A potential limitation is that some NGS assays require more DNA input than more limited molecular assays. Endobronchial ultrasound fine-needle aspiration (EBUS-FNA) is a minimally invasive procedure for sampling mediastinal and pulmonary lesions, but it is unknown if it provides adequate material for NGS. Methods: An IRB approved, retrospective review was performed of patients undergoing EBUS-FNA by thoracic surgeons at our institution 3/1/14 - 9/28/16. NGS was performed using an assay developed at our institution that detects mutations in up to 410 genes (MSK-IMPACT). Samples diagnostic for malignancy and with MSK-IMPACT requested were identified. Pathology and clinical data were drawn from the medical record and MSK-IMPACT results were examined. Results: 784 EBUS-FNA were done in the study period. MSK-IMPACT was requested on 115 positive samples. MSK-IMPACT was successful in 99 samples (86.1%), identifying an average of 12.7 mutations at a mean coverage depth of 806X. In 17 (17.2%) samples, tumor content was suboptimal ( &lt; 20% of nucleated cells), with fewer identified mutations than in cases with higher tumor content (6.8 vs 13.9, p = 0.01). NGS was performed on paraffin-embedded cell blocks in 93 cases (93.9%), and in 6 cases DNA extraction was performed from residual cytological material isolated from supernatant including cell-free DNA. Failures were attributable to low cell content (7), high contamination by benign cells (4) or both (1) and processing issues (4). No difference in surgical or radiologic parameters were identified for failed or suboptimal samples. Conclusions: In our practice, EBUS-FNA has a high rate of success for obtaining adequate tissue for NGS. Ability to utilize cell-free DNA for molecular studies – a new process in our lab – allows increased success of molecular testing in scant samples. Further studies may identify factors contributing to NGS failure and to improving success for samples with minimal cellularity.
Impact of concurrent chemoradiation on quality of life in Indian patients with locally advanced head and neck cancers.
Authors: Lohith G
Journal: Journal of Clinical Oncology (2016)

e17531 Background: Concurrent chemo radiation remains the standard of care, in the management of patients with loco-regionally advanced head and neck cancers. Conventionally, the endpoints for head and neck cancer patients focused on objective tumor response, local control and overall survival,. These endpoints are assessed from the physician’s point of view.and in view of increased number of longtime survivors, the need for understanding patients experience, their perceptions of treatment effects and their priorities have to be well recognized, Hence a prospective study was conducted to evaluate the quality of life in Indian patients of locally advanced head and neck cancer patients undergoing concurrent chemo radiation. Methods: Single arm prospective observational study of 53 patients receiving concurrent chemo-radiation were assessed for changes in quality of life using EORTC QLQ-C30 and the EORTC –H&N35 questionnaires at baseline before treatment ,4th week during treatment,on completion of treatment,4weeks and 12 weeks after treatment.Data analysis was done using paired t test for each variable comparing each of the assessments done during treatment, on completion of treatment,1 month post completion of treatment and 3months post completion of treatment comparing with baseline values . Results: Mean age of the study population was 52.48 ± 11.6 years (Age range 28-72 years). There were 33.3% females and 66.7% males.There was a significant decrease in Global health related quality of life during treatment(P < 0.001) and on completion of treatment(p < 0.001) when compared to baseline scores but showing upward trends in scores post 1month and 3 month of treatment compared to baseline scores. Conclusions: There was significant deterioration in Quality of life during and after curative intent concurrent chemo-radiotherapy in Indian patients that gradually but definitely improves over time. Incorporation of quality of life assessments in daily clinical practice and with a close monitoring of acute side effects with implementation of appropriate symptomatic treatments, quality of life of Indian patients during treatment can be increased.
Intra-tumoral heterogeneity in the expression of programmed-death (PD) ligands in isogeneic primary and metastatic lung cancer (LC): Implications for immunotherapy.
Authors: David James Pinato, Robert J Shiner, Solomon D T White, James M Black, Pritesh Trivedi, Justin Stebbing, Rohini Sharma, Francesco A Mauri
Journal: Journal of Clinical Oncology (2016)

11601 Background: There is inconclusive evidence to suggest the expression of programmed cell death (PD) ligand 1 (PD-L1) is a putative predictor of response to PD-1/PD-L1 targeted therapies in LC. We evaluated the heterogeneity in the expression of PD-1 and its ligands in isogeneic primary and metastatic LC specimens from 12.580 post mortem samples. Methods: We identified 214 patients with untreated metastatic LC, of which 98 had adequately preserved tissues to construct a syngeneic primary LC/metastasis tissue microarray. Immunostaining for PD-1, PD-L1 & 2 was evaluated in primary and metastatic lesions and correlated with patient demographics, tumour histology and pattern of metastatic spread. Results: 98 patients with a median age of 70 years, 77 (75%) with Stage IV disease were included. Non-small cell LC (NSCLC) cases (n = 65, 66%) included 32 adenocarcinomas, 30 squamous cell and 3 mixed carcinomas. 29 (30%) extensive-stage SCLC and 4 (4%) atypical carcinoids (AC) were included. No staining for PD-1 was detected in the peritumoral stroma. In total, 8/65 (12%) primary NSCLC were PD-L1 positive, with the majority of matched metastases (14/17, 82%) being PD-L1 negative. SCLCs were universally PD-L1 negative across primary and metastatic disease. We found PD-L2 immunostaining in 11/65 NSCLC (17%), 2/29 SCLC (7%) and 1/4 AC (25%). Only 2/30 (7%) of matched metastatic deposits were PD-L2 positive. We found no correlation between the expression of PD ligands and stage, however PD-L2 expressing primaries had more frequently metastasized to the kidneys (43% versus 11%, p = 0.003). Conclusions: Intratumor heterogeneity in the expression of PD ligands is common in NSCLC, whilst PD-L1 is homogeneously undetectable in primary and metastatic SCLC. This holds implications in the clinical development of immune response biomarkers in LC.
A phase II study of pazopanib with oral topotecan in patients with metastatic and non-resectable soft tissue and bone sarcomas.
Authors: Mark Agulnik, Nisha Anjali Mohindra, Mohammed M. Milhem, Steven Attia, Steven Ian Robinson, Alfred Rademaker, Susan E. Abbinanti, Rasima Cehic, Catherine Humphreys, Bethany Prudner, Scott H. Okuno, Brian Andrew Van Tine
Journal: Journal of Clinical Oncology (2018)

11550 Background: Topotecan and pazopanib (PAZ) individually have clinical benefit in patients (pts) with sarcomas. PAZ is a multi-tyrosine kinase inhibitor and topotecan affects endothelial cells, and inhibits HIF-1, an upstream regulator of VEGF expression. The utilization of PAZ with topotecan is anticipated to produce anti-tumor synergism in pts with sarcomas. Methods: A phase II study of PAZ/topotecan in pts with metastatic and non-resectable bone and soft tissue sarcomas (STS) was conducted by the Midwest Sarcoma Trials Partnership. Age > 18, ECOG ≤1, adequate organ function, measurable disease and 1 prior therapy were required. Pts were treated with PAZ 800mg oral daily, Topotecan 8mg orally day 1, 8, 15 on a 28-day cycle until disease progression or unacceptable toxicity. Pts enrolled in 3 cohorts: 1. STS non-liposarcoma 2. osteosarcoma 3. liposarcoma. Primary endpoint: progression-free rate (PFR) at 12 weeks in cohort 1. Secondary endpoints: overall response rate (ORR), clinical benefit rate (CBR), OS, median progression free survival (PFS), PFR at 12 weeks in cohort 2 and 3, and safety and tolerability. Lab correlates evaluated PFR and OS to levels of VEGFR2 and PDGF. Simon 2-stage design was used for cohort 1. Results: A total of 139 pts were enrolled at 6 sites, with 121 evaluable for response. Data per cohorts 1,2, and 3: # of pts- 103, 17 and 19; mean age- 56, 41, 57; % female- 63, 53, 32%; 1-2 prior therapies- 75, 65, 84%. PFR at 12 weeks is 57.5%, 62.5%, 31.3% with a median PFS of 4.4, 4.5, 1.4 months and OS of 9.8, 11.1, 12.3 months. ORR is 8,6,0 % and CBR is 74, 88, 38%. Grade 3-4 adverse events (%): neutropenia (42), thrombocytopenia (29), hypertension (16) and anemia (12). Pts in cohort 1 who progressed within 6 weeks received 61% of prescribed PAZ dose vs. 67% for those with did not progress. Histologies in cohort 1- LMS (49%), UPS (15%), synovial (10%). Correlative data will be presented. Conclusions: The combination of PAZ/topotecan produced identical results to historical data for PAZ alone in pts with STS, except with a worse toxicity profile. For pts with osteosarcoma, the combination proved extremely promising and cohort 2 will be expanded. The combination was ineffective in liposarcoma. Clinical trial information: NCT02357810.
TCT-4 Reduction of stroke with use of the double-filter cerebral embolic protection device in patients undergoing transfemoral aortic valve replacement with self-expandable, mechanically implantable and balloon-expandable aortic valves
Authors: Julia Seeger, Birgid Gonska, Markus Otto, Wolfgang Rottbauer, Jochen Wöhrle
Journal: Journal of the American College of Cardiology (2018)
The impact of generics on drug volume and expenditures in oncology: A 2005-14 MIDAS analysis.
Authors: Victoria Divino, Katharine Coyle, Satyin Kaura, Michael Kleinrock, Rolin L. Wade, Mitch DeKoven
Journal: Journal of Clinical Oncology (2016)

e18254 Background: The Hatch-Waxman Act of 1984 facilitated the market entry of generic drugs while protecting innovator patent rights, encouraging continued biopharmaceutical investment in research and development (R&D). We evaluated the impact of generics on drug volume and expenditures in oncology. Methods: Trends in annual sales volume and expenditures on generic and branded therapeutic oncology prescription drugs were assessed using the IMS MIDAS database of audited biopharmaceutical sales in the US from 2005-14. Volume was measured using standard units (SU), defined as the smallest dose of a product. Sub-analyses were conducted for breast (BC) and colorectal cancer (CRC). The cost savings generated from entry of generic oncology drugs was estimated for the period from 2006-14. Results: Oncology drug volume totaled 745-871 million (M) SU from 2005-14; generics represented 69.1-85.6%. Among brand products with generic entry (N = 21), average sales were $383M in the year prior to and $39M in the year after generic entry (-90%). Generic entry of oncology drugs over the period 2006-14 resulted in total cost-savings of $20.4 billion (B), with an average cost-savings of $970M. For BC, oncology drug volume totaled 486-587M from 2005-14; generics represented 68.0-96.2%. Average sales were $628M in the year prior to and $33M in the year after generic entry (-95%; N = 7). Generic entry resulted in total cost-savings of $10.9B (average $1.6B) in BC. For CRC, oncology drug volume totaled 33-59M from 2005-14; generics represented 9.3-76.8%. Average sales were $863M in the year prior to and $124M in the year after generic entry (-86%; N = 3). Total cost-savings from generic entry in CRC were $7.4B. Conclusions: Generic utilization represents an increasing majority of total oncology volume. Significant cost savings were generated with the entry of steeply discounted generics. The lifecycle of a brand drug, from R&D to patent loss, fuels the generic pipeline and supports the continued development of the next generation of innovative therapies, providing substantial value to patients, the healthcare system and society. Further savings may soon be realized with the generic entry of breakthrough products, such as imatinib and rituximab.