tbuckley/cabot-search huggingface dataset:
Hypertension and impaired renal function as biomarkers of efficacy of bevacizumab (bev) in ovarian cancer: A retrospective study.
Authors: Audie Bercelle Bavouidibio, Reza-Thierry Elaidi, Haïl Aboudagga, Mara Brizard, Pierre Combe, Yann Orven, Marie Courbebaisse, Brigitte Sabatier, Gilles Chironi, Eric Pujade Lauraine, Fabrice Lecuru, Stephane Oudard, Jacques Medioni
Journal: Journal of Clinical Oncology (2015)

e16566 Background: Bev can be responsible for hypertension (HBP) in 25% of patients (pts). The aim of the study was to determine the relation between HBP and impaired renal function induced by bev and efficacy in pts with ovarian cancer. Methods: We conducted a retrospective, exhaustive study of pts treated with bev in monotherapy or in association with chemotherapy at the European Pompidou Hospital (Paris, France) between Aug 2007 and Apr 2014. Blood pressure (BP) and Creatinine Clearance (Cockroft-Gault equation) (CrCl) were measured every 21 days. Efficacy was determined using RECIST Criteria and progression free survival (PFS). Toxicity was measured by CTC v4.0 and by analysis of difference in absolute value of the maximum toxicity of CrCl. Results: Eighty pts were included (median age of 63 years [27-90], ECOG score 0 or 1 in86%). PFS was 15.6 months [12.2-17.8]. HBP (all grades) was observed in 81% of pts and grade 3 in 13%. Renal impairment (all grades) was observed in 63% of pts and grade 3 in 5% (see Table). There was neither relationship between PFS and toxicity grade, nor between PFS and the cycle of highest toxicity. Absolute value of the maximum toxicity was not different between responders and non-responders pts. In contrast, analyses over time showed a significant difference between responders and non-responders in terms of SBP (p = 0.02) and DBP (p <0.001) increases. The same results were obtained for CrCl (p = 0.0061). Conclusions: Repeated measures along time of BP and CrCl are potential biomarkers of response of bev in ovarian cancer. These results need to be confirmed in a controlled prospective series. Hypertension Creatinine Clearance grade 0-1 2 ≥ 3 0-1 2 ≥ 3 n % n % n % n % n % n % Cycle 1 65 81 14 18 1 1 44 55 34 43 2 3 Cycle 2 66 83 11 14 3 4 35 44 40 50 3 4 Cycle 3 57 71 15 19 6 8 31 39 41 51 0 0 Cycle 4 57 71 18 23 3 4 32 40 44 55 2 3
Fibroblast growth factor receptor status and response to immune checkpoint inhibition in metastatic urothelial cancer.
Authors: Tracy L Rose, Michele C Hayward, Ashley H Salazar, Patrick Eulitt, Katrina McGinty, Anthony Drier, Sara Elizabeth Wobker, Young E. Whang, Blaine Y Brower, Mary Dunn, Daniel James Crona, Yoichiro Shibata, Joshua M Uronis, Gregory Mayhew, Matthew I. Milowsky, William Y. Kim
Journal: Journal of Clinical Oncology (2019)

458 Background: Fibroblast growth factor receptor (FGFR) inhibitors are a promising new targeted therapy for patients with metastatic urothelial cancer (UC) and FGFR alterations. FGFR-altered tumors are more likely to be of the luminal molecular subtype, which is less immune infiltrated and may be less likely to respond to immune checkpoint inhibitors (ICP). Methods: Metastatic UC patients at the University of North Carolina who underwent targeted exon sequencing (any CLIA-certified platform) and were treated with ICP since 2014 were identified. Patients with any FGFR alteration were compared to patients without alterations (including mutations, fusions, and amplifications in FGFR1-4). Overall response rates (ORR) to ICP were assessed by a radiologist (K.M.) per RECIST 1.1 and compared between FGFR-altered and unaltered tumors using Fisher’s exact tests. Patients who died prior to radiologic assessment were considered non-responders. Results: 66 patients (median age 70, 65% male, 76% white, 21% black) were identified. Most patients (74%) had received prior platinum-based chemotherapy, and 13% had received 2 or more prior lines of therapy. At the time of initiation of ICP, 32% of patients had a hemoglobin &lt; 10, 33% had liver metastases, and 72% had a performance status &gt; 0. Fifteen (22%) patients had FGFR alterations. The ORR for all patients was 15%, with ORR of 13% in FGFR-altered patients compared with 16% in unaltered patients (p = 1.0). No patients (0/9, 0%) with known pathogenic mutations in FGFR3 responded to ICP compared to 10/57 (18%) of patients without these alterations (p = 0.33). 46% of FGFR-altered patients who stopped ICP due to progression received subsequent therapy. Conclusions: Response rates to ICP are low and there was no difference in ORR between FGFR-altered and unaltered patients. While no patient with pathogenic FGFR3 mutations responded to ICP in our cohort, this difference did not reach statistical significance. Given low response rates overall, some FGFR-altered patients may benefit from treatment with FGFR inhibitors prior to ICP. Analysis of larger cohorts of patients as well as patients from clinical trials and more in-depth molecular profiling may add further clarity.
Reducing Collateral Damage From Mandates for Time to Antibiotics in Pediatric Sepsis—<i>Primum Non Nocere</i>
Authors: Luregn J. Schlapbach, Scott L. Weiss, Joshua Wolf
Journal: JAMA Pediatrics (2019)

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Abstract P282: Sub-Optimal Sleep Duration is Independently Associated With Morbid Obesity in the United States
Authors: Ehimen Aneni, Javier Valero-Elizondo, Chukwuemeka U Osondu, Eric J Brandt, Khurram Nasir
Journal: Circulation (2019)

Introduction: Extremes of sleep duration and morbid obesity are independent risk factors for cardiovascular disease (CVD). There are only a few studies that have examined the relationship between the two and even less have studied their association in a national cohort. Methods: We utilized the National Health Interview Survey (2013-2017) for this study. We assessed the cross-sectional association between habitual self-reported sleep duration (in hours) and obesity groups. We also conducted subgroup analysis to show the trends in sleep duration among subgroups with morbid obesity (BMI ≥35kg/m 2 ) Results: After exclusion of 1,897 persons who reported sleeping more than 12 hours in a day, there were 154,872 participants in the study representing a population of 227.9 million US adults annually. The prevalence of moderate (BMI 35 -39.9kg/m 2 ) and severe obesity (BMI ≥ 40kg/m 2 ) was 7.1% and 8.1% respectively. The prevalence of morbid obesity was highest among blacks, females and persons aged 40 - 64 years (21.5%, 17.5% and 17.3% respectively). There was a U-shaped distribution in the prevalence of moderate and severe obesity with increase in sleep duration. The lowest prevalence was seen among persons who slept 7-&lt;9hours. Females, blacks and persons aged 40 - 64years had a higher prevalence of severe obesity at every subgroup of sleep duration. Across sleep duration, Asians and Hispanics demonstrated a clear U-shaped trend for severe, but not moderate obesity. In multivariate analysis controlling for demographics, CVD risk factors and comorbidities, sleeping less than 7 hours was independently associated with moderate and severe obesity, while sleeping 9 or more hours was associated with severe obesity. The above findings are depicted in attached figure. Conclusion: Compared to 7-&lt;9 hours of sleep, shorter and longer (sub-optimal) sleep duration, was independently associated with morbid obesity. The relationship between sleep and morbid obesity differs by race and requires further exploration.
Abstract P343: Patients With Cardiovascular Disease Are Not Meeting American Heart Association Secondary Prevention Recommendations
Authors: Paul M Ndunda, Mohinder Vindhyal, Tabitha Muutu
Journal: Circulation (2019)

Introduction: In the United States, cardiovascular disease (CVD) is the leading cause of mortality. More than 92 million Americans have one or more types of CVD and 800,000 die from it annually. More than 47% of myocardial infarction survivors and 30% of stroke survivors get recurrent events, and therefore there is need for data on secondary preventive care, if the AHA’s 2020 impact goal is to be achieved. We assessed the hypothesis that patients with CVD were not meeting AHA secondary preventive guidelines, and there was gender and racial disparities in care. Methods: This study is an analysis of the 2017 Behavioral Risk Factor Surveillance System a chronic disease survey conducted by the CDC. The sample included 51,626 subjects with a history of stroke and coronary artery disease. The secondary preventive measures analyzed included: exercise, diet, smoking cessation, alcohol intake, body mass index, use of blood pressure medications in hypertensive patients and the use of aspirin. Gender and racial disparities were analyzed using multiple logistic regression analysis and age, race, education and income were adjusted for in the outcomes. Results: The median age of the study cohort was 69 years (variance=140). White, black and Hispanic patients represented 79.3%, 8.6% and 6.7% respectively. Females comprised 48.5%. Comorbidities included: hypertension (72.8%), dyslipidemia (63.5%), diabetes mellitus (31.5%) and chronic kidney disease (11.5%). Among CVD patients, 57.1% reported ever smoking and 17.4% of them still smoked. Only 39.2% met AHA aerobic exercise guidelines and 12.1% met both the aerobic and muscle strengthening exercise guidelines. Thirty nine percent of CVD patients undertook more than 150 minutes of aerobic exercise and 12% did 1-149 minutes per week. Obesity/overweight was present in 73.8%. Only 67.8% of patients with CVD were using aspirin, 20% were not on any cholesterol medication (not specified whether statin) while among hypertensive patients, 90.1% were on antihypertensive medications. There were major racial and gender disparities in smoking status [women vs men adjusted OR (aOR) 1.23 (1.21 - 1.25), Hispanic vs white aOR 1.71 (1.66 - 1.76)], aspirin [women vs men aOR 0.66 (0.62 - 0.71), Hispanic vs white aOR 0.56(0.47 - 0.58)]. Women were more likely to be on BP medications [women vs men aOR 1.25 (1.22 - 1.29)]. Conclusion: Patients with stroke do not meet AHA lifestyle and aspirin recommendations. There are major gender and racial disparities in the use of CVD secondary preventive measures.
Ductal and acinar carcinomas of the prostate: A comparative comprehensive genomic profiling study.
Authors: Nick Liu, Leszek Kotula, Timothy Byler, Joseph Jacob, Brian Michael Alexander, Laurie M. Gay, Oleg Shapiro, Sherri Z. Millis, Julia Andrea Elvin, Jon Chung, Jo-Anne Vergilio, Shakti Ramkissoon, Eric Allan Severson, Jonathan Keith Killian, Siraj Mahamed Ali, Alexa Betzig Schrock, Vincent A. Miller, Andrea Necchi, Gustavo de La Roza, Jeffrey S. Ross
Journal: Journal of Clinical Oncology (2019)

271 Background: Prostatic ductal carcinoma (PDC) is an uncommon centrally located prostate with a characteristic tubulopapillary histology. PDC shares some biomarker features with the more common prostatic acinar carcinoma (PAC) including PSA expression. Methods: In this comparative comprehensive genomic profiling (CGP) study, FFPE samples from 61 clinically advanced PDC and 4,132 PAC were profiled for all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Results: The age, frequency of genomic alterations (GA) per tumor and TP53 GA of PDA and PAC were similar (Table). TMPRSS2:ERG fusions and AR GA were more often identified in PAC than PDC whereas PTEN GA were more common in PDC than PAC. Targetable GA were identified at similar frequencies in both groups focused on BRCA2 (PARP inhibitors), BRAF (BRAF/MEK inhibitors) and PIK3CA (MTOR inhibitors). ATM GA (PARP inhibitors) were more common in PAC than PDC. CDK12 GA potentially associated with immunotherapy (IO) benefit were similar in PDA and PAC as were the frequencies of MSI-High status, median TMB and high TMB levels. Conclusions: The pathologic features of PDC and PAC have been classically maintained as representative of 2 different tumor types with potentially contrasting histogenesis. In the current CGP-based study, PDA and PAC did not display significant differences in genomic signatures. CGP may reveal biomarkers that could direct patients to targeted (PARP, MTOR and BRAF/MEK inhibitors) or immunotherapies ( CDK12 GA, MSI-High or high TMB status) in both PDA and PAC. [Table: see text]
The effect of a structured exercise intervention on CTCs and platelet cloaking in patients with metastatic prostate cancer.
Authors: Lauren Brady, Brian Hayes, Grainne Sheill, Anne-Marie Baird, Emer M. Guinan, Bryan Stanfill, Tatjana Vlajnic, Orla Casey, John Patrick Greene, Emma Allott, Juliette M. Hussey, Fidelma Cahill, Mieke Van Hemelrijck, Nicola Peat, Sarah Maria Rudman, Lorelei Mucci, Orla Sheils, O'Leary John, Ray McDermott, Stephen P. Finn
Journal: Journal of Clinical Oncology (2019)

243 Background: Physical activity has been described as an effective adjunct for improving quality of life in patients with metastatic prostate cancer (PrCa). Circulating tumor cells (CTCs) are a morphologically distinct set of cancer cells, involved in disease progression. Platelet cloaking, the surrounding and subsequent attachment of platelets to CTCs, has been proposed as effective in aiding extravasation, thus enhancing metastatic spread. The ExPeCT (Exercise, Prostate Cancer and Circulating Tumor Cells) trial aimed to examine the impact of a structured exercise intervention on the mechanisms of metastasis, including CTC cloaking, in patients with metastatic PrCa. Methods: ExPeCT was a multi-center, randomized trial for patients with metastatic PrCa (n=61). Participants were randomized to either control or exercise arms. Participants in the exercise arm (n=29) completed six months of prescribed aerobic exercise. Whole blood was collected for all participants at baseline (T0), three months (T3) and six months (T6), and analyzed for the presence of CTCs, CTC clusters and platelet cloaking. Results: No significant difference in CTC number between the exercise and control arms was observed (p=0.2630), however significant alterations in CTC number were observed within group over time (p&lt;0.001). Platelet cloaking was modelled as a binary response (presence/absence). A trend towards higher levels of platelet cloaking in the control group was observed (p=0.1005). Further, all findings were compared to a range of clinical variables. CTC clusters were positively correlated with PSA levels (p=0.0393) and a positive correlation between CTC number and white blood cell count (p&lt;0.001) was determined. Conclusions: No significant relationship between CTCs and physical activity was observed, however the exercise program was well tolerated by ExPeCT participants. This study has, for the first time, shown platelet cloaking of CTCs in metastatic PrCa, in addition to a significant positive correlation between CTCs and white blood cells. These findings provide critical insight into immune crosstalk and the metastatic cascade in metastatic PrCa. Clinical trial information: NCT02453139.
Radium-223 treatment patterns in a large real-world population.
Authors: Hanson Hanqing Zhao, Lauren Howard, Amanda de Hoedt, Martha K Terris, Christopher L. Amling, Christopher J. Kane, Matthew R. Cooperberg, William J. Aronson, Thomas Polascik, Stephen J. Freedland
Journal: Journal of Clinical Oncology (2019)

190 Background: For men with symptomatic metastatic castration resistant prostate cancer (mCRPC), radium-223 was shown to improve overall survival in the phase III, double blind ALSYMPCA trial. Despite the observed benefits, the application and practice patterns of Radium-223 outside of clinical trials are largely unknown. Here we aim to better characterize the use of radium-223 in a large and heterogeneous real-world population. We identify treatment patterns associated with radium-223 and link these patterns with time to skeletal related event (SRE) and mortality. Methods: We reviewed charts of all men with diagnosed with mCRPC in the entire Veterans Affairs (VA) system alive as of January 1, 2013 who received radiun-223. We generated Kaplan Meier curves for survival and time to SRE based on treatment patterns. We examined the association between common treatment patterns and mortality and time to SRE with Cox models. Results: We identified 318 men with bone mCRPC who received radium-223. Median age at radium start was 69 ys and median follow up was 25.3 months. Median survival was 11 months. 277 patients died during the study period (87%). 50% (158/318) completed ≤4 injections. There was a significant difference mortality among four consolidated treatment patterns (p=0.005) and but no difference SRE (p=0.10). On univariable and multivariable analysis, men who received AR target + docetaxel + radium-223 had increased mortality vs. men who received AR target + radium-223 (p=0.010 and 0.005, respectively). Multivariable analysis showed that non-black race, bone pain, SRE prior to radium, and higher PSA were all linked with worse mortality. Conclusions: We described the largest known cohort of men in the real world who received radium-223. We identified common treatment patterns with differing risk for overall mortality. Further prospective studies are needed to better understand whether differences in survival are attributed to worsening disease status requiring more aggressive therapy, lead-time bias, or true differences in treatment efficacy.
Cost-effectiveness of a two-gene urine biomarker assay in MRI strategies for the initial detection of prostate cancer.
Authors: Tim Govers, Matthew J. Resnick, Geert Trooskens, Wim Van Criekinge, Jack A. Schalken
Journal: Journal of Clinical Oncology (2019)

91 Background: MRI is increasingly used in men with a suspicion for prostate cancer (PCa) to target abnormal areas next to systematic biopsy. Although, MRI increases the detection of clinically significant PCa compared to systematic biopsy alone, overdiagnosis and overtreatment of insignificant disease still exists. The 2-gene mRNA PCR urine test combined with traditional risk factors SelectMDx (MDxhealth Irvine Ca) predicts clinically significant PCa, and can be used to reduce overdiagnosis and overtreatment. We assessed the cost-effectiveness of SelectMDx in a population of U.S. men who in the current situation undergo initial MRI and biopsies. Methods: We developed a decision-analytic model to simulate the downstream outcomes in the current MRI strategy, i.e. systematic biopsy plus targeted biopsy in case of a positive MRI. SelectMDx was assessed in two different diagnostic pathways: 1) before MRI to select patients for MRI and biopsy, 2) after a negative MRI to select patients for systematic biopsy. Outcomes were quality-adjusted life years (QALYs) and costs. Model parameters were informed by literature. Two scenarios regarding the mortality of missed PCa were used, using SPCG trial data and using data from the PIVOT trial. Results: Using SelectMDx before MRI (1) resulted in a health gain of 0.003 and 0.030 QALY per patient compared to the current MRI strategy, using the SPCG and PIVOT data, respectively. Cost savings were $1590 per patient and about $496 million for the yearly population of men at risk in the U.S. (n = 311,879). SelectMDx after negative MRI (2) resulted in a health gain of 0.008 and 0,011 QALY per patient using the SPCG and PIVOT data.. Cost savings were $436 per patient and about $136 million for the yearly population. Conclusions: The use of SelectMDx to guide prostate biopsy decision-making can improve health outcomes and lower costs. Cost savings were highest when SelectMDx was used before MRI to select patients for MRI and biopsy. With respect to health gain, the use of SelectMDx after negative MRI was most beneficial when assuming higher mortality for missed PCa (SPCG). When the mortality was assumed to be lower (PIVOT) SelectMDx should be used before MRI to result in the highest health gain.
The nonsurgical management of upper tract urothelial carcinoma: A role for active surveillance?
Authors: Jamil Syed, Kevin Nguyen, Juan Javier-Desloges, Michael Leapman, Jay D. Raman, Brian M. Shuch
Journal: Journal of Clinical Oncology (2019)

485 Background: Approximately 7% of patients with localized upper tract urothelial cancer (UTUC) are treated without definitive therapy. Understanding outcomes and alternative therapy would aid in counseling older patients with co-morbidities. Methods: We utilized the National Cancer Database to identify patients with localized UTUC managed non-surgically between 2004 and 2013. Patient demographics, co-morbidity, tumor grade, and chemotherapy and radiation utilization were recorded. Survival analyses were performed with the Kaplan-Meier method and a cox proportional hazard regression model. Results: We identified 3,157 (10.9%) patients with localized UTUC who did not receive definitive surgery. Median age was 79 years, 55% were males, 79% had government health insurance, and 68% had a CDS of 0. Tumor grade was low (grade 1 or 2) in 632 (36.4%) and high (grade 3 or 4) in 1104 (63.6%). Median overall survival (OS) for the cohort was 2.2 years, significantly shorter for patients with greater co-morbidities. Chemotherapy or radiation was performed in 294 (9.3%) and 197 (6.3%) patients respectively. There were no OS differences for individuals receiving chemotherapy. Of patients who received radiation therapy, the median OS was 1.4 vs 2.0 years, (p&lt;0.001) favoring no radiation. Those with high grade tumors had worse survival (1.9 vs 3.8 years (p&lt;0.001). Significant predictors of shorter OS included older age, male gender, higher CDS, and government insurance. Conclusions: In this population-based cohort, 10.9% of patients with localized UTUC were managed non-surgically. Radiation and chemotherapy were not routinely utilized, and did not demonstrate improved survival. Median OS was significantly shorter for those with higher grade disease, increasing co-morbidity profile, male gender, and those with government insurance status.
Taking an engineer's view: Implications of network analysis for computational psychiatry
Authors: A. David Redish, Rebecca Kazinka, Alexander B. Herman
Journal: Behavioral and Brain Sciences (2019)

An engineer's viewpoint on psychiatry asks: What are the failure modes that underlie psychiatric dysfunction? And: How can we modify the system? Psychiatry has made great strides in understanding and treating disorders using biology; however, failure modes and modification access points can also exist extrinsically in environmental interactions. The network analysis suggested by Borsboom et al. in the target article provides a new viewpoint that should be incorporated into current theoretical constructs, not placed in opposition to them.