tbuckley/cabot-search huggingface dataset:
RAS mutation testing and cetuximab use for colorectal cancer at VA Hospitals.
Authors: Steve Young Lee, Daniel Jacob Becker, Scott DuVall, Julie Ann Lynch
Journal: Journal of Clinical Oncology (2017)

e18244 Background: Extended RAS testing in colorectal cancer predicts response to therapy with EGFR-directed therapies cetuximab and panitumumab. In 2010 VA policy recommended testing of all potentially treatable metastatic colon cancer patients for KRAS mutations. We explored the uptake of RAS testing within the VA system and characterized mutation frequency and cetuximab use. Methods: We extracted records of VA patients with first primary colorectal cancers diagnosed between 2011 and 2015 from the VA Central Cancer Registry (VACCR). We included patients who had RAS testing from 4 commercial laboratories contracted with the VA . We gathered genomic testing results from the commercial vendors. We calculated descriptive statistics of mutation sites and used multivariable logistic regression to evaluate predictors of mutations and cetuximab use. Results: Colon cancer diagnoses decreased in the VA from 4285 cases in 2011 to 3275 cases in 2015 and we observed a concurrent increase in KRAS testing from 4.7% in 2011 (202 cases) to 10.3% in 2015 (336 cases) (p &lt; 0.001). KRAS tested patients were 65.7% white, 26.1% black, 3.1% Hispanic, and 2.8% female. Among 1717 patients tested, 588 had mutations (34.2%), with 441(75%) in codon 2, 117 (19.9%) in codon 13, 23 (3.9%) in codon 61. There were no differences in mutation rates by age, race, ethnicity, or gender categories. A total of 189 patients received cetuximab; 11 of 558 (1.9%) KRAS mutants and 178 of 1095 (16.2%) KRAS wildtype received cetuximab. Across all patients, increasing age in years predicts for cetuximab non-use (OR 0.983, 95% CI 0.97-0.99); gender, race, and ethnicity did not. Conclusions: We found a significant increase in KRAS testing between 2011 and 2015, with mutation patterns reflective of the US population. We found a low rate of inappropriate cetuximab use among patients with KRAS mutations, as well as an also low rate of cetuximab use among KRAS wild type patients among which it may be indicated. Further study is warranted to understand patterns of appropriate and inappropriate use of targeted agents.
Abstract 17334: The Detrimental Effect of Chest Compression Interruptions on Coronary Perfusion Pressure Dynamics
Authors: Norman A Paradis, Karen L Moodie, Christopher L Kaufman, Joshua W Lampe
Journal: Circulation (2015)

Introduction: Guidelines for treatment of cardiac arrest recommend minimizing interruptions in chest compressions based on research indicating that interruptions compromise coronary perfusion pressure (CPP) and blood flow and reducing the likelihood of successful defibrillation. We investigated the dynamics of CPP before, during, and after compression interruptions and how they change over time. Methods: CPR was performed on domestic swine (~30 Kg) using standard physiological monitoring. Blood flow was measured in the abdominal aorta (AAo), the inferior vena cava, the right common carotid and external jugular. Ventricular fibrillation (VF) was electrically induced. Mechanical chest compressions (CC) were started after four minutes of VF. CC were delivered at a rate of 100 compressions per minute (cpm) and at a depth of 2” for a total of 12 min. CPP was calculated as the difference between aortic and right atrial pressure at end-diastole per Utstein guidelines. CPP was determined for 5 compressions prior to the interruption, every 2 seconds during the CC interruption, and for 7 compressions after the interruption. Per protocol, 12 interruptions occurred at randomized time points. Results: Across 12 minutes of CPR, averaged CPP prior to interruption was significantly greater than the averaged CPP after the interruption (22.4±1.0 vs. 15.5±0.73 mmHg). As CPR continued throughout the 12 minutes, CPP during compressions decreased (First 6 min = 24.1±1.4 vs. Last 6 min = 20.1±1.3 mmHg, p=0.05), but the effect of interruptions remained constant resulting in a 20% drop in CPP for every 2 seconds irrespective of the prior CPP. The increase (slope) of CPP after resumption of compressions was significantly reduced over time (First 6 min = 1.47±0.18 vs. Last 6 min = 0.82±0.13 mmHg/compression). Conclusions: Chest compression interruptions have a detrimental effect on coronary perfusion and blood flow. The magnitude of this effect increases over time as a resuscitation effort continues. These data confirm the importance of providing uninterrupted CPR particularly in long duration resuscitations.
Quality of life issues in long-term testicular germ cell tumor survivors.
Authors: Michal Chovanec, Lucia Vasilkova, Lucia Petrikova, Katarina Rejlekova, Jana Obertova, Zuzana Sycova-Mila, Patrik Palacka, Katarina Kalavska, Daniela Svetlovska, Beata Mladosievicova, Jozef Mardiak, Michal Mego
Journal: Journal of Clinical Oncology (2018)

e22107 Background: Curative treatment for testicular germ cell tumors (GCTs) may lead to adverse health sequelae. This study aimed to evaluate a long-term quality of life (QOL) in GCT survivors. Methods: GCT survivors (N = 155) from the National Cancer Institute of Slovakia prospectively completed European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-TC26 and Mini-Mental State Examination (MMSE) questionnaires at the median 10 years of follow up (range 5-32) as a primary exploratory aim. Seventeen survivors (11%) had orchiectomy alone (controls), while 138 (89%) survivors received treatment beyond orchiectomy. The study group consisted of survivors receiving a cisplatin-based chemotherapy, radiotherapy to the retroperitoneal lymph nodes or both. Results: Compared with the controls (QLQ-C30), survivors cured with chemotherapy reported problems in physical functioning (P = 0.03), while survivors cured with radiotherapy were concerned with their role functioning (P = 0.04). Chemotherapy or radiotherapy treated survivors suffered from pain (both P < 0.05) and dyspnoea (both P < 0.05). All study subgroups reported financial difficulties resulting from the treatment compared to the controls (all P < 0.05). In QLQ-TC26, survivors treated with radiotherapy or radiotherapy plus chemotherapy reported issues in sexual functioning (both P < 0.05) and family problems (P = 0.02 for radiotherapy plus chemotherapy) compared to the controls. All study subgroups had difficulties in performing their jobs compared to the controls (all P < 0.05). MMSE did not show deep cognitive impairment and survivors reported a good global health status despite several QOL difficulties. Conclusions: Our prospective study showed self-reported QOL issues in long-term GCT survivors. Job and financial problems were pronounced among all study subgroups. Future interventional studies for cancer survivors are suggested.
Metastasis risk prediction in non-translocation soft tissue sarcoma with a novel gene expression profile assay.
Authors: Sujana Movva, Weiwei Shan, Margaret von Mehren, Jeffrey M. Farma, Natalie Lassen, Clare Johnson, Derek Maetzold, Robert W. Cook
Journal: Journal of Clinical Oncology (2016)

11055 Background: Accurate prognostication for non-translocation soft tissue sarcoma (NT-STS) with a complex karyotype remains a clinical obstacle. We previously reported the development of a gene expression profiling assay, the STS-profile, for metastasis risk prediction in NT-STS. In a cohort of 77 primary NT-STS patients, STS-profile-stratified Class 1 (low risk) and Class 2 (high risk) tumors had 5-year metastasis-free survival (MFS) of 79% and 12%, respectively (p<0.0001); results that outperform current staging factors. This study evaluated the impact of tumor heterogeneity on the STS-profile, and assessed its accuracy in two independent cohorts of NT-STS from the external sample set used to discover CINSARC, a 67-probe metastasis risk predictor for NT-STS. Methods: For the heterogeneity study, 14 primary STS cases with multiple FFPE tissue blocks were collected according to an Institutional Review Board approved protocol. RNA was extracted from tissue sections and RT-PCR for the genes in the profile was performed. Class prediction was determined by Partial Least Squares (PLS) predictive modeling for the heterogeneity and independent performance studies. Results: Twelve of 14 (86%) cases exhibited concordant class predictions in the heterogeneity study. Multivariate Cox regression analysis showed that the STS-profile was a more significant predictor of MFS than CINSARC in both cohorts (Cohort 1 STS-profile HR=4.56, p<0.0001 vs CINSARC HR 3.44, p=0.0005; Cohort 2 STS-profile HR=3.31, p=0.0006 vs CINSARC HR=1.89, p=0.20). The STS-profile also generated higher positive predictive values (PPV) when compared to CINSARC in both cohorts (Table 1). Conclusions: Our results suggest minimal impact of molecular heterogeneity on the accuracy of the STS-profile in predicting metastasis risk. Assessed in two independent cohorts of NT-STS within the CINSARC dataset, the STS-profile assay was able to distinguish two groups with significantly different metastatic risk. Cohort 1, n=138 Cohort 2, n=109 N 5-yr MFS (# events) PPV N 5-yr MFS (# events) PPV Class 1 78 75% (17) 78% 73 76% (14) 75% Class 2 60 19% (47) 36 30% (27) CINSARC low risk 55 81% (10) 65% 28 80% (5) 44% CINSARC high risk 83 31% (54) 81 48% (36)
Natural pattern-recognition-receptor agonists in prophylactic vaccines for in situ vaccination of lymphoma.
Authors: Mark Aleynick, Paul Peng, Linda Hammerich, Antoine Tanne, Judith Agudo, Brian D. Brown, Nina Bhardwaj, Joshua Brody
Journal: Journal of Clinical Oncology (2016)

e14516 Background: In patients with advanced-stage lymphoma, in situ vaccination has yielded partial and complete remissions in phase I/II clinical trials. Though responses have been observed with various Toll-like Receptor (TLR) and RIG-like Receptor (RLR) agonists, the optimal immune stimulant (or combination thereof) is not known. Therefore, potent clinical-grade dendritic cell (DC) activators are needed. We hypothesize that ‘natural’ TLR agonists (TLRa) and other Pathogen Associated Molecular Patterns in prophylactic vaccines (e.g. typhim vi, MMR, influenza) could simultaneously target multiple Pattern Recognition Receptors (PRR) and strongly activate Flt3L-primed DC, perhaps better than synthetic TLRa. These vaccines could be repurposed as DC activators for in situ vaccination, with immediate translation into the clinic. Methods: Flt3L-primed DC were cultured with a panel of vaccines and DC phenotype was evaluated by flow cytometry. Co-culture assays with JEDI (CD8), OT-1 (CD8), and DO11.10 (CD4) T cells were used to evaluate Flt3L-DC processing and presentation of antigen. Using the A20 murine lymphoma model, vaccines were evaluated for in situ vaccination efficacy in vivo. Results: Several vaccines showed potent DC activation and several showed significant increases in T cell activation, antigen-specific proliferation, and tumor killing. Interestingly, there was only partial overlap between vaccines demonstrating optimal DC activation and strong T cell responses. Potent vaccines were used in vivo for monotherapy and combination therapy in a Flt3L-primed in situ vaccination. Vaccine combination (more than monotherapy) induced tumor regression in a majority of animals, suggesting synergistic immune activation, partly through demonstrable TLR4 and TRIF-dependent immune cell activation. Conclusions: Prophylactic vaccines contain natural PRR agonists and potently activate DC, resulting in increased antigen-specific (and tumor-specific) T cell activation. Combinatorial vaccine therapy displayed additive or synergistic activity in vitro and in vivo. Vaccines are effective clinical grade DC activators and may be repurposed for use in the in situ vaccination maneuver.
P01.006 Gamma knife radiosurgery for diffuse low-grade gliomas: An Egyptian experience.
Authors: R Emad, A N M El Shehaby, W A Reda, K Abdel Karim, A Nabeel, S R Tawadros
Journal: Neuro-Oncology (2018)

Diffuse low-grade gliomas constitute about 15% of all gliomas. The management of these tumors is challenging and has optimally involved maximal resection followed by radiotherapy, with or without chemotherapy, specially in high-risk population. High-risk patients refer to those <40 years of age with incomplete resection/biopsy or those ≥ 40 years of age with any degree of resection. Limited reports are available on the role of gamma knife radiosurgery in the treatment of diffuse low-grade gliomas. The aim of this study was to assess the efficacy and safety of gamma knife radiosurgery in the treatment of high-risk diffuse low-grade gliomas. Between March 2009 and November 2015, 30 patients with high-risk low-grade diffuse gliomas underwent gamma knife radiosurgery. A total of 44 treatment sessions were performed, including 14 volume-staged treatments. There were 19 males and 11 females. The mean age at the time of treatment was 30 years (6–57 years). Seven patients underwent previous surgery/biopsy. The remaining 23 patients were diagnosed by MRS/MRI. Twenty patients presented with epilepsy. The mean tumor volume was 9.5 cc (0.9–22.4 cc). The mean prescription dose was 12 Gy (10–16 Gy). The mean follow up duration was 37 months (8–80 months). Tumor control was achievable in 25 patients (83%) and progression occurred in 5 patients (17%). Symptomatic edema occurred in 9 patients (30%). Seizure-control was reported in 13/20 (65%) patients and non-control in 7/20 (35%) patients. Two patients died. The 5-year progression-free survival rate and overall survival rate were 75% and 92%, respectively. Gamma knife radiosurgery provides an effective and safe treatment option for high-risk diffuse low-grade gliomas. Randomized clinical trials are required to further determine the role of gamma knife radiosurgery in these tumors’ treatment paradigm.
TCT-436 Aldehydes: potential drivers of valve leaflet thrombosis post transcatheter aortic valve replacement?
Authors: Mark Hensey, Stephanie Sellers, Janarthanan Sathananthan, Dale Murdoch, Abdullah Alenezi, Aurelie Fabre, Bruce Murphy, Jonathon Leipsic, Martin Quinn, John Webb
Journal: Journal of the American College of Cardiology (2018)
Uptake of the Biologic Filgrastim and Its Biosimilar Product Among the Medicare Population
Authors: Steven Kozlowski, Noy Birger, Stephaeno Brereton, Stephen J. McKean, Michael Wernecke, Leah Christl, Jeffrey A. Kelman
Journal: JAMA (2018)

Uptake of the Biologic Filgrastim and Its Biosimilar Product Among the Medicare Population Biologic pharmaceuticals are complex, high-cost therapeutics used to treat severe and chronic conditions. 1 Biosimilar biological products can increase access to therapy and lower health care costs.The development and approval of biosimilar biologics in the United States was made possible by the Biologics Price Competition and Innovation Act passed in 2010.As of June 1, 2018, 10 biosimilars had been approved by the US Food and Drug Administration (FDA). 2 This study evaluated uptake of the first approved biosimilar biologic, filgrastim-sndz (Zarxio), relative to its originator filgrastim product (Neupogen).These products share multiple indications for neutropenia and malignancy.Tbo-filgrastim (Granix), a stand-alone alternative biologic with a single indication, was also evaluated. Methods| All filgrastim administrations of any dose between January 1, 2014, and December 31, 2016, in Medicare Part B claims were identified using Healthcare Common Procedure Coding System billing codes.Beneficiaries were enrolled in Medicare fee for service from at least 6 months Figure.Trends in All Filgrastim Administrations
Abstract 14709: Right Sternal Lead Placement Increases Eligibility for Subcutaneous Defibrillator Implantation in Adults With Congenital Heart Disease
Authors: Hideo Okamura, Christopher J McLeod, Mohammad U Bashir, Tracy L Webster, Crystal R Bonnichsen, Martha Grogan, Sabrina D Phillips, Carole A Warnes, Naser M Ammash, Heidi M Connolly, Paul A Friedman
Journal: Circulation (2015)

Introduction: The subcutaneous implantable cardioverter defibrillator (S-ICD) is an attractive option for patients with congenital heart disease (CHD) in whom a transvenous system is contraindicated. However, more than 10% of adult patients with CHD fail S-ICD screening due to a large T- to R-wave ratio. We hypothesized right-sternal electrodes may permit S-ICD placement in patients who fail left-sternal screen. Methods: We prospectively screened 40 patients with CHD for S-ICD using the standard proprietary approach. We also screened with right sternal electrodes (with left can electrode position). Results: The mean age of the cohort was 46+/-15 years; 24 males were enrolled. CHD anomalies consisted of tetralogy of Fallot (n=11), Ebstein’s anomaly (n=7), atrial septal defect (n=6), dextro-looped transposition of the great artery (n=5) and other (n=11). Left side screening ECG failed in 9 patients (23%), five of whom passed with right sternal electrodes, increasing the pass rate from 77% to 90%. Figure shows the screening ECG and chest x-ray of a patient who failed in all three vectors on the left side but passed in the alternative vector on the right side and underwent right sided implantation. Conclusions: The addition of right sternal electrodes during screening increases S-ICD eligibility and may avoid thoracotomy for high risk patients with CHD.
TCT-744 Axillary Intraaortic Balloon Pumps Reduces Time to Ambulation after Ventricular Assist Device or Transplant for Advanced Heart Failure
Authors: Vinod Chainani, Baldeep Dhaliwal, Russell Riehl, Aditya Bansal, Sapna Desai, John Reilly
Journal: Journal of the American College of Cardiology (2018)
Vitamin D and aromatase inhibitor-induced arthralgia: Analysis of Canadian cancer trial group MA.27 data.
Authors: Polly Ann Niravath, Bingshu E. Chen, Judy Anne Chapman, Sandeep K Agarwal, Robert L Welschhans, Tim Bongartz, Krishna R. Kalari, Lois E. Shepherd, John Bartlett, Kathleen I. Pritchard, Karen A. Gelmon, Susan G. Hilsenbeck, Mothaffar F. Rimawi, C. Kent Osborne, Paul E. Goss, James N. Ingle
Journal: Journal of Clinical Oncology (2016)

10020 Background: Approximately half of the women who take aromatase inhibitor (AI) therapy will develop joint pain, termed aromatase inhibitor-induced arthralgia (AIA). AIA becomes so painful that up to 20% of women will discontinue AI’s because of it. However, there is no standard treatment for this common, though poorly understood, problem. Methods: Using plasma samples from the MA.27 study, we identified 72 cases (with AIA) and 144 matched controls. We compared change in vitamin D level between baseline and 6 months in 204 cases and controls. We also correlated inflammatory cytokines with development of AIA. We measured 9 inflammatory cytokines which are implicated in low estrogen states, arthritis, and/or vitamin D deprivation -- Il-1, IL-6, TNF-α, IFNg, IL-10, IL-12p70, IL-17, IL-23, and CCL-20. Finally, we aimed to develop a multivariate model to predict for AIA using baseline factors such as vitamin D level, previously identified musculoskeletal SNP’s, age, BMI, and vitamin D receptor polymorphism. Results: After correcting for seasonal and geographic variation, the month 6 Vitamin D plasma levels increased by 4.52 ng/mL (p = 0.049), suggesting intake of vitamin D. However, there was no difference in the change in vitamin D levels between cases and controls. Elevated inflammatory cytokines were not correlated with the development of AIA. However, those with the Vitamin D receptor (VDR) FOK-I polymorphism were more likely to have a lower IL-1β level after 6 months of use as compared to those with wildtype VDR. In the multivariate model, the clinical factors listed above did not reliably predict development of AIA in this subset of patients. Conclusions: In this retrospective study, there is no correlation between vitamin D levels and the development of AIA. However, vitamin D receptor polymorphisms may explain some of the variation in individual responses to Vitamin D replacement. Patients with the Fok-I VDR polymorphism were more likely to have a significant reduction in IL-1β level. Case Control N 68 136 Mean Δ Vit D 3.7 5.1 p =0.393 Standard Deviation 9.3 11.4 Minimum Δ Vit D -11.5 -29.7 Maximum Δ Vit D 28.9 62.57
Systemic oxidative stress in congenital central hypoventilation syndrome
Authors: Donatella Degl'Innocenti, Matteo Becatti, Marta Peruzzi, Claudia Fiorillo, Matteo Ramazzotti, Niccolò Nassi, Cinzia Arzilli, Raffaele Piumelli
Journal: European Respiratory Journal (2018)

<b>This study is the first to demonstrate an increase in ROS in CCHS patients. This implies that therapeutic strategies based on antioxidants should be taken in consideration and the mechanisms provoking the increase of ROS should be clarified.</b>http://ow.ly/5Rhp30lJ7Yi
Statins for primary prevention of cardiovascular events and mortality in old and very old adults with and without type 2 diabetes: retrospective cohort study
Authors: Rafel Ramos, Marc Comas-Cufí, Ruth Martí-Lluch, Elisabeth Balló, Anna Ponjoan, Lia Alves-Cabratosa, Jordi Blanch, Jaume Marrugat, Roberto Elosua, María Grau, Marc Elosua-Bayes, Luis García-Ortiz, Maria Garcia-Gil
Journal: BMJ (2018)

To assess whether statin treatment is associated with a reduction in atherosclerotic cardiovascular disease (CVD) and mortality in old and very old adults with and without diabetes.Retrospective cohort study.Database of the Catalan primary care system (SIDIAP), Spain, 2006-15.46 864 people aged 75 years or more without clinically recognised atherosclerotic CVD. Participants were stratified by presence of type 2 diabetes mellitus and as statin non-users or new users.Incidences of atherosclerotic CVD and all cause mortality compared using Cox proportional hazards modelling, adjusted by the propensity score of statin treatment. The relation of age with the effect of statins was assessed using both a categorical approach, stratifying the analysis by old (75-84 years) and very old (≥85 years) age groups, and a continuous analysis, using an additive Cox proportional hazard model.The cohort included 46 864 participants (mean age 77 years; 63% women; median follow-up 5.6 years). In participants without diabetes, the hazard ratios for statin use in 75-84 year olds were 0.94 (95% confidence interval 0.86 to 1.04) for atherosclerotic CVD and 0.98 (0.91 to 1.05) for all cause mortality, and in those aged 85 and older were 0.93 (0.82 to 1.06) and 0.97 (0.90 to 1.05), respectively. In participants with diabetes, the hazard ratio of statin use in 75-84 year olds was 0.76 (0.65 to 0.89) for atherosclerotic CVD and 0.84 (0.75 to 0.94) for all cause mortality, and in those aged 85 and older were 0.82 (0.53 to 1.26) and 1.05 (0.86 to 1.28), respectively. Similarly, effect analysis of age in a continuous scale, using splines, corroborated the lack of beneficial statins effect for atherosclerotic CVD and all cause mortality in participants without diabetes older than 74 years. In participants with diabetes, statins showed a protective effect against atherosclerotic CVD and all cause mortality; this effect was substantially reduced beyond the age of 85 years and disappeared in nonagenarians.In participants older than 74 years without type 2 diabetes, statin treatment was not associated with a reduction in atherosclerotic CVD or in all cause mortality, even when the incidence of atherosclerotic CVD was statistically significantly higher than the risk thresholds proposed for statin use. In the presence of diabetes, statin use was statistically significantly associated with reductions in the incidence of atherosclerotic CVD and in all cause mortality. This effect decreased after age 85 years and disappeared in nonagenarians.