tbuckley/cabot-search huggingface dataset:
A phase Ib study targeting PIM1 and CDK4/6 kinases in metastatic renal cell carcinoma (PICKRCC).
Authors: Sheldon L. Holder, Joshua Warrick, Junjia Zhu, Joseph J. Drabick, Monika Joshi
Journal: Journal of Clinical Oncology (2020)

TPS771 Background: Over the last few years there has been a rapid increase in the clinically relevant agents available to treat metastatic renal cell carcinoma (mRCC). We note, however, that the vast majority of new agents available for mRCC do not exploit new clinical targets or pathways. We believe that the identification of new, clinically relevant targets in RCC will propel the field even further forward, expand treatment options, and lead to improved survival for mRCC patients. SGI-1776, a selective PIM1 kinase inhibitor, has previously been shown to induce reduction in tumor size as monotherapy and in combination with sunitinib in mouse pre-clinical studies of RCC. In our tissue microarray studies a subset of ~26% of RCC showed high staining for PIM1 kinase while only 1% of normal adjacent tissue showed similar high staining. Wildtype PIM1 is constitutively active, thus these data suggest that PIM1 activity is increased in a subset of RCC. Abemaciclib is a potent CDK4/6 inhibitor with an IC50 of 2 and 10 nM, respectively. It is also a potent PIM1 inhibitor with an IC50 of 50 nM. We have shown that abemaciclib decreases cell viability and increases apoptosis in RCC cell lines, and does so at greatest effect in combination with sunitinib. We have also shown that abemaciclib induces regression of RCC tumors in a mouse model of RCC, with the most rapid responses observed when abemaciclib is combined with sunitinib. Based on these data we have opened a phase Ib dose escalation study to determine the safety and tolerability of abemaciclib in combination with sunitinib in patients with mRCC. The study includes an expansion cohort at the recommended phase II dose to evaluate for a signal for efficacy. Pattern and intensity of PIM1 staining in tumor tissue will be evaluated as a potential biomarker of response. We are also collecting blood and urine to evaluate additional potential biomarkers of response. Methods: Clinical trial information: NCT03905889 .[Table: see text]
A phase IIa randomized placebo-controlled trial of pomegranate fruit extract/POMx in subjects with clinically localized prostate cancer undergoing active surveillance.
Authors: David Frazier Jarrard, Miko Filon, Wei Huang, KyungMann Kim, Tom Havighurst, Badrinath R. Konety, Daniel Saltzstein, Hasan Mukhtar, Margaret House, Chen S. Suen, Howard L. Parnes, Howard Harry Bailey
Journal: Journal of Clinical Oncology (2020)

285 Background: Due to its high prevalence and often indolent natural history, prostate cancer(PC) active surveillance(AS) is an ideal setting for chemoprevention. Studies assessing pomegranate and its extracts have shown promising anti-proliferative and pro-apoptotic effects in cell lines and animal models and a single-arm clinical trial of pomegranate fruit extract(PFE) reported an increase in PSA doubling time(PSADT) during AS. The primary objective of this trial was to assess the effect of PFE supplementation on plasma levels of Insulin-like Growth Factor-1(IGF-1). Secondary objectives addressed PSA doubling time(PSADT), tumor volume on end-of-study(EOS) biopsy and plasma and prostate tissue biomarkers. Methods: Men with organ-confined favorable-risk PC on AS were randomly assigned to receive PFE 1,000 mg(n=15) or placebo(n=15) once daily for twelve months. Prostate biopsies were performed at study entry and upon completion of the one-year intervention. Tissue biomarkers were assessed by immunohistochemistry(IHC) with automated quantitation. Results: PFE was well-tolerated with no significant toxicities. One patient withdrew before study initiation and 29 completed the one-year intervention. No differences in plasma IGF-1 levels(p=0.5), PSADT, or tissue biomarkers of apoptosis or proliferation were observed. A significant increase in urolithin A(a urinary metabolite of pomegranate) was observed in the PFE arm. IHC analyses of both tumor (Table) and normal-appearing tissue adjacent to tumor showed reductions from baseline in IGF-1, 8-OHdG(DNA damage marker), and androgen receptor expression associated with PFE treatment. A trend towards a reduction in the maximum percent of biopsy core tumor involvement was observed(p=0.06) in PFE. Conclusions: PFE administration for 12-months was not associated with a decrease in plasma IGF-1 levels nor an increase in PSADT. However, exploratory analyses suggest that PFE may contain bioactive compounds capable of altering biomarkers in PC and normal-appearing adjacent tissue providing a rationale for further investigation of PFE in the active surveillance population.
Association of Medicaid Expansion Under the Affordable Care Act With Insurance Status, Cancer Stage, and Timely Treatment Among Patients With Breast, Colon, and Lung Cancer
Authors: Samuel U. Takvorian, Arman Oganisian, Ronac Mamtani, Nandita Mitra, Lawrence N. Shulman, Justin E. Bekelman, Rachel M. Werner
Journal: JAMA Network Open (2020)

<h3>Importance</h3> The effect of the Patient Protection and Affordable Care Act's Medicaid expansion on cancer care delivery and outcomes is unknown. Patients with cancer are a high-risk group for whom treatment delays are particularly detrimental. <h3>Objective</h3> To examine the association between Medicaid expansion and changes in insurance status, stage at diagnosis, and timely treatment among patients with incident breast, colon, and non–small cell lung cancer. <h3>Design, Setting, and Participants</h3> This quasi-experimental, difference-in-differences (DID) cross-sectional study included nonelderly adults (aged 40-64 years) with a new diagnosis of invasive breast, colon, or non–small cell lung cancer from January 1, 2011, to December 31, 2016, in the National Cancer Database, a hospital-based registry capturing more than 70% of incident cancer diagnoses in the United States. Data were analyzed from March 8 to August 15, 2019. <h3>Exposures</h3> Residence in a state that expanded Medicaid on January 1, 2014. <h3>Main Outcomes and Measures</h3> The primary outcomes were insurance status, cancer stage, and timely treatment within 30 and 90 days of diagnosis. <h3>Results</h3> A total of 925 543 patients (78.6% women; mean [SD] age, 55.0 [6.5] years; 14.2% black; and 5.7% Hispanic) had a new diagnosis of invasive breast (58.9%), colon (14.6%), or non–small cell lung (26.5%) cancer; 48.3% resided in Medicaid expansion states and 51.7% resided in nonexpansion states. Compared with nonexpansion states, the percentage of uninsured patients decreased more in expansion states (adjusted DID, −0.7 [95% CI, −1.2 to −0.3] percentage points), and the percentage of early-stage cancer diagnoses rose more in expansion states (adjusted DID, 0.8 [95% CI, 0.3 to 1.2] percentage points). Among the 848 329 patients who underwent cancer-directed therapy within 365 days of diagnosis, the percentage treated within 30 days declined from 52.7% before to 48.0% after expansion in expansion states (difference, −4.7 [95% CI, −5.1 to −4.5] percentage points). In nonexpansion states, this percentage declined from 56.9% to 51.5% (difference, −5.4 [95% CI, −5.6 to −5.1] percentage points), yielding no statistically significant DID in timely treatment associated with Medicaid expansion (adjusted DID, 0.6 [95% CI, −0.2 to 1.4] percentage points). <h3>Conclusions and Relevance</h3> This study found that, among patients with incident breast, colon, and lung cancer, Medicaid expansion was associated with a decreased rate of uninsured patients and increased rate of early-stage cancer diagnosis; no evidence of improvement or decrement in the rate of timely treatment was found. Further research is warranted to understand Medicaid expansion's effect on the treatment patterns and health outcomes of patients with cancer.
Lipids and ketones dominate metabolism at the expense of glucose control in pulmonary arterial hypertension: a hyperglycaemic clamp and metabolomics study
Authors: Jacob T. Mey, Adithya Hari, Christopher L. Axelrod, Ciarán E. Fealy, Melissa L. Erickson, John P. Kirwan, Raed A. Dweik, Gustavo A. Heresi
Journal: European Respiratory Journal (2020)

Individuals with idiopathic pulmonary arterial hypertension (PAH) display reduced oral glucose tolerance. This may involve defects in pancreatic function or insulin sensitivity but this hypothesis has not been tested; moreover, fasting nutrient metabolism remains poorly described in PAH. Thus, we aimed to characterise fasting nutrient metabolism and investigated the metabolic response to hyperglycaemia in PAH. 12 participants (six PAH, six controls) were administered a hyperglycaemic clamp, while 52 (21 PAH, 31 controls) underwent plasma metabolomic analysis. Glucose, insulin, C-peptide, free fatty acids and acylcarnitines were assessed from the clamp. Plasma metabolomics was conducted on fasting plasma samples. The clamp verified a reduced insulin response to hyperglycaemia in PAH (−53% versus control), but with similar pancreatic insulin secretion. Skeletal muscle insulin sensitivity was unexpectedly greater in PAH. Hepatic insulin extraction was elevated in PAH (+11% versus control). Plasma metabolomics identified 862 metabolites: 213 elevated, 145 reduced in PAH (p&lt;0.05). In both clamp and metabolomic cohorts, lipid oxidation and ketones were elevated in PAH. Insulin sensitivity, fatty acids, acylcarnitines and ketones correlated with PAH severity, while hepatic extraction and fatty acid:ketone ratio correlated with longer six-min walk distance. Poor glucose control in PAH could not be explained by pancreatic β-cell function or skeletal muscle insulin sensitivity. Instead, elevated hepatic insulin extraction emerged as an underlying factor. In agreement, nutrient metabolism in PAH favours lipid and ketone metabolism at the expense of glucose control. Future research should investigate the therapeutic potential of reinforcing lipid and ketone metabolism on clinical outcomes in PAH.
Outcomes of adult urogenital sarcomas: Analysis of surveillance, epidemiology, and end results (SEER) database 2004 to 2015.
Authors: Snigdha Nutalapati, Quan Chen, Bin Huang, Reema Anil Patel, Mehmet Asim Bilen, Zin Myint
Journal: Journal of Clinical Oncology (2020)

423 Background: Urogenital sarcomas are rare type of soft tissue sarcomas and represent only 1-2% of all genitourinary cancers. Given the paucity of literature, we aimed to study the clinical characteristics and factors impact outcomes of adult urological sarcomas. Methods: Adult males aged ≥ 20 years with sarcomas primarily originating from urogenital sites were identified from national SEER database between 2004-2015. Descriptive analysis was performed for all cases. Survival analysis, including Kaplan Meier estimates and Cox regression were performed. Results: A total of 1177 genitourinary sarcomas were identified. Urinary bladder (20.56%) was the most common primary site followed by spermatic cord (20.31%) and kidney (17.33%). The most common histological subtype was liposarcoma (32.9%) followed by leiomyosarcoma (32.0%). 10-year survival rate was highest for liposarcoma 58.3% (95% CI 50.3-65.5) followed by leiomyosarcoma 40.2% (95% CI 32.0-48.2), rhabdomyosarcoma 37.3% (95% CI 22.6-52.1), synovial sarcoma 22.7% (95% CI 5.6-46.6), carcinosarcoma 8.9% (95% CI 4.3-15.4) and 0% for angiosarcoma. Median follow up was 23 months and overall median survival was 54 months. There was a significant overall survival difference by age, race, primary sites, histological subtypes, grade, stage, insurance status, geographic, socioeconomic status and treatment in both univariate and multivariate analysis. On multivariate analysis, factors associated with unfavorable prognosis include age &gt; 75 years (HR 3.9, 95% CI 2.9-5.2), distant metastasis (HR 2.0, 95% CI 1.5-2.7), ureteral sarcomas (HR 6.2, 95% CI 2.3-17.1) and having Medicaid insurance (HR 1.7, 95% CI 1.2-2.3).Surgery alone (HR 0.5, 95% CI 0.4-0.7) or in combination with chemotherapy (HR 0.4, 95% CI 0.3-0.6) or radiation (HR 0.4, 95% CI 0.3-0.6) had favorable prognosis compared to non-surgical approach. Conclusions: Urinary bladder is the most common primary sites of all urological sarcomas. Our study showed age &gt; 75, poorly differentiated histology, angiosarcoma subtype, ureteral primary site, distant metastasis, poor socioeconomic status, Appalachian area and radiation alone were associated with less favorable outcomes.
Regression tree analysis to identify the best candidates for neoadjuvant chemotherapy (NAC) in patients with clinically lymph node-positive penile squamous cell carcinoma (PSCC).
Authors: Marco Bandini, Yao Zhu, Dingwei Ye, Antonio Augusto Ornellas, Nick Watkin, Michael Ager, Oliver W. Hakenberg, Axel Heidenreich, Daniele Raggi, Mario Catanzaro, Friederike Haidl, Filippo Pederzoli, Alberto Briganti, Francesco Montorsi, Juan Chipollini, Mounsif Azizi, Maarten Albersen, Oscar Brouwer, Philippe E. Spiess, Andrea Necchi
Journal: Journal of Clinical Oncology (2020)

2 Background: PSCC patients (pts) with palpable inguinal lymph node (ILN) disease have a poor overall survival (OS). For them, use of neoadjuvant chemotherapy (NAC) is recommended in guidelines, but limited data are available to inform pt selection. We aim to identify predictors of poor OS in clinically ILN-positive (ILN+) pts to define the optimal candidates for NAC. Methods: Within an international, multicenter database of 924 PSCC pts, we identified 334 ILN+ pts with available data. ILN involvement was defined either with the presence of palpable ILN disease or based on preoperative CT-scan. FDG-PET/CT-scan was performed based on clinical judgment of the treating physician. Univariable and multivariable analyses (MVA) assessed predictors of overall mortality (OM). A regression-tree method for censored data was used to generate a risk stratification tool for prediction of 24m OM after diagnosis of ILN+ PSCC. Kaplan-Meier method was used to define the OS benefit related to the use of NAC according to the regression-tree stratified sub-groups. Results: Median age at diagnosis was 58yrs, and 105 (31.4%) had ECOG≥1. Of all, 120 (35.9%), 152 (45.5%), and 62 (18.6%) harbored cN1, cN2, and cN3 disease. Additionally, 152 (45.5%) and 117 (35%) had monolateral vs bilateral clinical ILN involvement. FDG-PET/CT was adopted in 42 (12.2%) pts, and 16 (4.8%) had pelvic LN uptake. Median OS was 107m, with 24m OS = 66%. At MVA, cN2 (HR: 2.28, p=0.006), cN3 (HR: 2.15, p=0.02), PET/CT scan-detected pelvic and ILN involvement (HR: 2.57, p=0.007) were independently associated with higher OM, whether bilateral clinical ILN+ was only univariably significant (HR: 1.56, p=0.02). At regression-tree analysis (AUC 70%), pts with cN3 and cN2 with PET/CT-detected pelvic and ILN involvement had the higher risk of 24m OM (&gt;54%). NAC was associated with improved 24m OS rates (54 vs. 33%) only in this pt subgroup (p=0.002). Conclusions: NAC improves OS in pts with cN3 or cN2 and pelvic FDG-PET/CT scan-detected disease. Our regression-tree may serve to screen ILN+ pts, to identify the optimal NAC candidates before radical treatments.
Contemporary racial disparities in PSA screening in a large, integrated health care system.
Authors: James T. Kearns, Oluwaseun Adeyemi, William E. Anderson, Timothy C. Hetherington, Yhenneko J. Taylor, Jason Zhu, Earle Frederick Burgess, Kris E. Gaston
Journal: Journal of Clinical Oncology (2020)

308 Background: The USPSTF prostate cancer screening guidelines have changed significantly in the past decade, from a recommendation of do not screen in 2012 to a 2018 recommendation that focuses on shared decision making. Additionally, most guidelines further acknowledge that African American men should be screened more intensively than Caucasian men due to increased incidence of prostate cancer and increased prostate cancer mortality. Our objective was to characterize racial disparities in PSA screening in a large healthcare system with a diverse patient population to understand contemporary trends. Methods: This retrospective cohort study used data from the Atrium Health Enterprise Data Warehouse, which includes clinical records from over 900 care locations across North Carolina, South Carolina, and Georgia. Participants included all men ≥ 40 years seen in the ambulatory or outpatient setting during 2014-2018. PSA testing was determined through laboratory data. Clinical and demographic data were collected. Between-group comparisons were conducted using generalized estimating equations models to account for within-subject correlation. Statistical significance was defined as p &lt; 0.05. Results: There were 582,846 individual men seen from 2014-2018, including 416,843 Caucasians (71.5%) and 85,773 African Americans (14.7%). Screening rates declined among all groups from 2014-2018 (see table). African American men were screened at a similar or lower rate than Caucasian men in each year (from 18.6% vs 19.0% in 2014 to 11.9% vs 12.2% in 2018, respectively). Conclusions: PSA screening declined significantly between 2014 and 2018. African American men screened at a similar or lower rate than Caucasian men each year. Given the consensus that African American men should be more intensively screened for prostate cancer, significant racial disparities remain in prostate cancer screening. Further study is warranted to understand patient, provider, and system factors that contribute to disparities in prostate cancer care and outcomes.[Table: see text]
PIVOT-09: A phase III randomized open-label study of bempegaldesleukin (NKTR-214) plus nivolumab versus sunitinib or cabozantinib (investigator's choice) in patients with previously untreated advanced renal cell carcinoma (RCC).
Authors: Nizar M. Tannir, Neeraj Agarwal, Sumanta K. Pal, Daniel C. Cho, Maria Formiga, Jun Guo, Daniel J. George, Mary Ann Tagliaferri, Stina Mui Singel, Bridget A. O'Keeffe, Alison L. Hannah, Minna Balbas, Konstantin Penkov
Journal: Journal of Clinical Oncology (2020)

TPS763 Background: Bempegaldesleukin (BEMPEG; NKTR-214) is a first-in-class interleukin-2 (IL-2) receptor pathway agonist that activates and expands effector T cells and natural killer cells in the tumor microenvironment and increases tumor PD-L1 expression, making BEMPEG a promising agent for combination with immune checkpoint inhibitors. In a phase 1/2 study, BEMPEG plus nivolumab (NIVO) demonstrated an encouraging objective response rate (ORR) in first-line advanced RCC (46%) and a manageable safety profile. BEMPEG plus NIVO offers a potential novel immunooncology treatment option for patients with advanced RCC. Methods: A global, multicenter, randomized, open-label phase 3 study is evaluating the efficacy and safety of BEMPEG plus NIVO vs investigator’s choice of tyrosine kinase inhibitor (TKI; sunitinib [SUNI] or cabozantinib [CABO]) in patients with previously untreated advanced or metastatic RCC with a clear-cell component. Patients must not have had prior systemic therapy (including neoadjuvant, adjuvant or vaccine therapy) for RCC. Key exclusion criteria include active brain metastasis and autoimmune disease requiring systemic immunosuppressive agents. Approximately 600 patients will be randomized 1:1 to receive 0.006 mg/kg BEMPEG plus 360 mg NIVO intravenously every 3 weeks or TKI (50 mg SUNI [4 weeks on, 2 weeks off schedule] or 60 mg CABO; orally each day). Patients will be stratified by International Metastatic RCC Database Consortium (IMDC) prognostic score (0 [favorable risk] vs 1-2 [intermediate risk] vs 3-6 [poor risk]) and TKI choice (SUNI vs CABO). Primary objectives are ORR by blinded independent central review (BICR) and overall survival in the IMDC intermediate/poor risk population and the intention-to-treat (ITT) population. Secondary objectives are progression-free survival by BICR in the IMDC intermediate/poor risk population and the ITT population, safety, PD-L1 expression as a predictive biomarker, and quality of life. Enrollment is ongoing. Clinical trial information: NCT03729245.
Association between ethnicity and under-5 mortality: analysis of data from demographic surveys from 36 low-income and middle-income countries
Authors: Cesar G Victora, Aluisio J D Barros, Cauane Blumenberg, Janaina Calu Costa, Luis Paulo Vidaletti, Fernando C Wehrmeister, Bruno Masquelier, Lucia Hug, Danzhen You
Journal: The Lancet Global Health (2020)

The UN Sustainable Development Goals (SDGs) call for stratification of social indicators by ethnic groups; however, no recent multicountry analyses on ethnicity and child survival have been done in low-income and middle-income countries (LMICs).We used data from Demographic and Health Surveys and Multiple Indicator Cluster Surveys collected between 2010 and 2016, from LMICs that provided birth histories and information on ethnicity or a proxy variable. We calculated neonatal (age 0-27 days), post-neonatal (age 28-364 days), child (age 1-4 years), and under-5 mortality rates (U5MRs) for each ethnic group within each country. We assessed differences in mortality between ethnic groups using a likelihood ratio test, Theil's index, and between-group variance. We used multivariable analyses of U5MR by ethnicity to adjust for household wealth, maternal education, and urban-rural residence.We included data from 36 LMICs, which included 2 812 381 livebirths among 415 ethnic groups. In 25 countries, significant differences in U5MR by ethnic group were identified (all p<0·05 likelihood ratio test). In these countries, the median mortality ratio between the ethnic groups with the highest and lowest U5MRs was 3·3 (IQR 2·1-5·2; range 1·5-8·5), whereas among the remaining 11 countries, the median U5MR ratio was 1·9 (IQR 1·7-2·5; range 1·4-10·0). Ethnic gaps were wider for child mortality than for neonatal or post-neonatal mortality. In nearly all countries, adjustment for wealth, education, and place of residence did not affect ethnic gaps in mortality, with the exception of Guatemala, India, Laos, and Nigeria. The largest ethnic group did not have the lowest U5MR in any of the countries studied.Significant ethnic disparities in child survival were identified in more than two-thirds of the countries studied. Regular analyses of ethnic disparities are essential for monitoring trends, targeting, and assessing the impact of health interventions. Such analyses will contribute to the effort towards leaving no one behind, which is at the centre of the SDGs.Bill & Melinda Gates Foundation, UNICEF, Wellcome Trust, Associação Brasileira de Saúde Coletiva.