tbuckley/cabot-search huggingface dataset:
Utilization of palliative care in patients with genitourinary malignancies.
Authors: Arya Mariam Roy, Manojna Konda, Akshay Goel, Rashmi Verma
Journal: Journal of Clinical Oncology (2020)

669 Background: Palliative care provides support and improves the quality of life of patients who has terminal illness such as cancer. Studies have shown that integrating palliative care into cancer care soon after the diagnosis of metastatic cancer can improve the quality of life and also prolong survival. The objective of the study was to analyze the acceptance of palliative care and to determine the factors affecting the utilization of palliative care in patients with genitourinary (GU) cancers. Methods: The National Inpatient Sample Database for the year 2016 was queried for the data. Patients who were admitted with a principal diagnosis of Malignant Neoplasm of Prostate (MNP), Renal Cell Carcinoma (RCC), Malignant Neoplasm of Ureter (MNU) were identified using ICD-10 codes and those who had Encounter for Palliative Care (PC) was also identified. Results: A total of 58765 hospitalizations were identified with MNP (n=39853), RCC (n=17786), MNU (n= 1126) during the study period. The total PC utilization for the above patients were 6.4% (n= 3785). Among those, 6.7% (n=1186), 6.3% (n=2531), 6.03% (n=68) from the groups RCC, MNP, MNU respectively received PC. The mean age for the PC utilization was 73 years (MNP= 72 yrs, RCA= 63 yrs, UCC= 73 yrs). Females received more PC when compared to males (6.7% vs 6.4%). Among those who had PC 27.4% (n=1029) died in the hospital. Interestingly, patients who had Medicare and Medicaid had more PC encounters when compared to those with private insurance (OR= 1.21, P= 0.001). Patients admitted on the weekend received more PC when compared to those who admitted during weekdays (OR= 1.12, P= 0.001). Patients admitted to hospitals in the West received more PC than other regions (OR= 1.42, P=0.03). Impact of race, teaching vs non-teaching hospital admissions were not found to be statistically significant in the utilization of PC in the above GU cancers. Conclusions: Medicare and Medicaid patients, weekend admissions, admissions to hospitals in the West received more palliative care. Further studies are needed to reveal the role of socioeconomic status and insurance in the utilization of palliative care in GU malignancies.
A novel orthotopic murine model of neuroendocrine bladder cancer: Insights into the phenotypic plasticity of small cell bladder cancer (SCBC).
Authors: Aysegul Balyimez, Shinjini Ganguly, Petros Grivas, Moshe Chaim Ornstein, Shilpa Gupta, Jorge A. Garcia, Byron H Lee, Rahul D. Tendulkar, Kevin L. Stephans, Jay P. Ciezki, Jesse McKenney, Eric A. Klein, Omar Y. Mian
Journal: Journal of Clinical Oncology (2020)

571 Background: SCBC is an aggressive subtype of bladder cancer with high metastatic potential and few effective treatment options. We developed an orthotopic mouse model of SCBC to understand the development of this rare bladder cancer variant and identify epigenetic drivers of neuroendocrine differentiation. Methods: Lentiviral particles carrying Cre recombinase were produced using Lenti-sgNeo#2/Cre. The bladders of Rb1 fl/fl Trp53 fl/fl Myc LSL/LSL (RPM) mice was transduced with Cre recombinase expressing lentivirus via transurethral catheterization. Mice were monitored by micro-ultrasound (mUS) and detected tumors were verified by histology. SCBC morphology was confirmed by H&amp;E staining and synaptophysin IHC. Whole transcriptome (RNAseq) analysis was performed to correlate transcriptomic profile of neuroendocrine mouse tumors to a cohort of human SCBC tumors. Results: Transurethral catheterization successfully transduced the bladder urothelium without evidence of exposure of ectopic (non-urothelial) tissues. RPM mice developed SCBC visible on mUS with a latency of 8-10 weeks. As expected in neuroendocrine tumors, mice developed liver and lung metastases. High grade neuroendocrine morphology and NE markers were confirmed on H&amp;E and IHC, respectively, by a GU pathologist. Western blot analysis confirmed cMyc expression and suppression of TP53 and RB1. Synaptophysin expression was confirmed by IHC. Transcriptomic profiling of both mouse and human SCBC demonstrated concordant gene expression. Gene expression profiling of urothelial and non-urothelial neuroendocrine tumors suggested a phenotypic convergence. Conclusions: We developed a novel genetically engineered murine model of SCBC. Ongoing work seeks to identify epigenetic markers playing role in the development of this aggressive variant of bladder cancer. We are assessing the activity of immune checkpoint inhibitors in this immunocompetent background.
Mild depletion of vitamin B2, B6 and B12 superimposed on mild folate depletion: Effects on DNA methylation, uracil incorporation and gene expression in the mouse colon
Authors: Zhenhua Liu, Sang-Woon Choi, Jimmy W. Crott, Mary K. Keyes, Hyeran Jang, Joel B. Mason
Journal: Cancer Research (2006)

3896  Epidemiological and experimental studies suggest that diminished folate status increases the risk of colorectal carcinogenesis, and that this effect may be mediated through the induction of abnormalities in DNA methylation and nucleotide synthesis. Folate’s biochemical functions within one-carbon metabolism are dependent on adequate availability of several other B-vitamins, including vitamin B2, B6 and B12. This study therefore investigated if mild depletion of vitamins B2, B6 and B12 superimposed upon the effects of mild folate depletion would impact on select molecular events in the colonic mucosa relevant to carcinogenesis: genomic DNA methylation, uracil misincorporation and gene expression. Four-month old C57BL/6J mice (n=108) were divided into 6 groups and pair-fed one of six diets for 10 wks: vitamin replete, mild folate (0 mg/kg) depletion alone, or mild folate depletion combined with mild inadequacies of vitamin B2 (0.5 mg/kg), vitamin B6 (0.5 mg/kg), and/or vitamin B12 (0 mg/kg). Genomic DNA methylation, uracil misincorporation and gene expression were measured in colonic DNA by LC/MS, GC/MS and real-time PCR, respectively. Assays of vitamin status in the blood showed that very mild, but significant, inadequacies of vitamins B2, B6 and B12 were successfully induced in the corresponding groups (p ≤ 0.05). Although genomic DNA methylation in the folate-deplete group (1.55+0.13) was not significantly reduced when compared to the folate-sufficient group (1.60±0.28), DNA hypomethylation (0.90±0.18) did occur with mild folate depletion combined with mild inadequacies of B2, B6, and B12 (P ≤ 0.05). Similarly, minor reductions in the expression of the APC and p53 genes produced by mild folate depletion alone were significantly magnified by the combined depletion of all the abovementioned B-vitamins, resulting in a 5-fold and 16-fold reduction in expression, respectively (P ≤ 0.01). Uracil incorporation was not significantly altered by vitamin depletion (P ≥ 0.05). These findings indicate that a mild depletion of folate that is of insufficient magnitude by itself to produce adverse molecular consequences in the colon may produce such effects when present in conjunction with mild inadequacies of other one-carbon nutrients, producing large decreases in the expression of relevant tumor suppressor genes even in the absence of any genetic predisposition to colon carcinogenesis. This underscores the potential impact that ‘subclinical’ B-vitamin depletions may have when they act in concert with one another.
Dupilumab Improves Sinus Opacification in All Sinuses in Patients With Severe Chronic Rhinosinusitis With Nasal Polyps (CRSwNP): Results From the SINUS-24 Phase 3 Study
Authors: Joseph Han, Gary Gross, Leda Mannent, Nikhil Amin, Seong Cho, Claus Bachert
Journal: Journal of Allergy and Clinical Immunology (2020)
A phase Ib/II trial of perioperative intratumoral MVA-BN-brachyury (MVA) plus systemic PROSTVAC and atezolizumab (Atezo) for intermediate-risk and high-risk localized prostate cancer (AtezoVax).
Authors: Benjamin Louis Maughan, Alejandro Sanchez, Brock B. O'Neil, William Thomas Lowrance, Christopher B. Dechet, Daniel Joseph Albertson, Deepika Sirohi, Sumati Gupta, Umang Swami, Neeraj Agarwal
Journal: Journal of Clinical Oncology (2020)

TPS382 Background: Many patients with intermediate or high-risk localized prostate cancer relapse after prostatectomy, identifying an unmet need. Cancer vaccines increase the infiltrating lymphocyte concentration in localized and metastatic prostate cancer (PMID 25255802, 29858218). We hypothesize that treatment with a combination of two vaccines plus PD-L1 inhibition will be safe and significantly stimulate immune infiltration within the tumor microenvironment. MVA is a modified vaccinia virus that is replication-deficient, inducing the generation of tumor antigen-specific killer T-cells. PROSTVAC is a poxviral based cancer vaccine using a vaccinia virus prime and fowlpox based boost along with co-stimulatory molecules B7.1, leukocyte function-associated antigen-3, and intercellular adhesion molecule-1. Methods: This study is a single-arm,, phase I/II investigator initiated trial (NCT04020094). Primary objectives: 1) Safety, 2) Quantitative change in infiltrating CD8+ lymphocytes between the biopsy and prostatectomy as measured by immunofluorescence. Secondary endpoints: 1) 6- and 12-month undetectable PSA rate; 2) PSA-PFS compared to institutional historic control. Inclusion criteria: unfavorable intermediate to very high-risk prostate adenocarcinoma (per NCCN). Exclusion criteria: non-adenocarcinoma histology and metastatic disease (including regional nodal metastasis). A total of 22 patients will be enrolled starting with a 6 patient safety lead in. Prostate MRI will be obtained prior to treatment. Treatment schema: 2 neoadjuvant cycles (Atezo + MVA + PROSTVAC), followed by prostatectomy then 6 additional adjuvant cycles (Atezo + PROSTVAC). Neoadjuvant cycle 1: atezolizumab (1200mg IV Q3wks), PROSTVAC-V (Prime, 2x10 8 Inf.U subcutaneous), MVA (2 x 10 8 Inf.U/0.5 ml, intra-tumoral injection, volume determined by MRI). Neoadjuvant cycle 2: atezolizumab, PROSTVAC-F (Boost, 1x10 9 Inf.U, subcutaneous), MVA. Adjuvant: atezolizumab and PROSTVAC-F. Clinical trial information: NCT04020094.
Abstract 16481: A Novel Role of Apolipoprotein E Glycosylation in Atherogenic L5 Low-Density Lipoprotein
Authors: Liang-Yin Ke, Hua-Chen Chan, Chih-Chieh Chen, Chu-Huang Chen
Journal: Circulation (2019)

Introduction: Electronegative L5 LDL exhibits atherogenic properties in vitro and in vivo, and its levels are elevated in patients with increased cardiovascular risk. Apolipoprotein E (APOE) conten...
Baseline lymphocyte to monocyte ratio (LMR) and systemic inflammation index (SII) as prognostic factors in metastatic renal cell carcinoma (mRCC) patients treated with nivolumab: Preliminary results of the Meet-URO 15 (I-BIO-REC) study.
Authors: Sara Elena Rebuzzi, Sebastiano Buti, Andrea Sbrana, Giuseppe Procopio, Ugo De Giorgi, Maria Giuseppa Vitale, Francesco Massari, Daniele Santini, Alessia Cavo, Giuseppe Luigi Banna, Mariella Soraru', Alessio Cortellini, Marco Messina, Valentino Martelli, Veronica Mollica, Marco Stellato, Helga Lipari, Fabio Catalano, Alessio Signori, Giuseppe Fornarini
Journal: Journal of Clinical Oncology (2020)

751 Background: Biomarkers to select mRCC patients most likely to benefit to immune-checkpoint inhibitors are still needed. The ongoing retrospective multicentre Meet-URO 15 (I-BIO-REC) study evaluates the prognostic role of peripheral blood cells in mRCC patients treated with nivolumab. Methods:The primary endpoint of the study was median overall survival (mOS) according to baseline neutrophil to lymphocyte ratio (NLR), but here preliminary analyses on baseline LMR and SII (secondary endpoints) are reported. LMR was defined as the ratio of lymphocyte to monocyte (cutoff = 3) and SII as platelet x neutrophil/lymphocyte (cutoff = 1375). Results: From May 2016 to January 2019 189 patients started nivolumab as 2nd (62%), 3rd (25%) and &gt; 3rd (13%) line. Median age was 69 years, 67% were male and 87% had clear cell histology. Baseline IMDC group was favorable in 26%, intermediate in 63% and poor in 11%. Lymph-nodes, visceral and bone metastases were present in 55%, 92% and 37%. mOS and progression-free survival (PFS) were 30.5 months and 9.5 months. Overall response rate (ORR) and disease control rate (DCR) were 28% and 57%. LMR was available in 150 patients: LMR ≥ 3 (44%) correlated with statistically significant longer OS [NR vs 26.8 months, HR 0.50 (0.29-0.88); p = 0.016] but not PFS (10.3 vs 9.9 months, HR 0.87 (0.58-1.31); p = 0.5) with similar ORR (34% vs 33%) and DCR (60% vs 63%) compared to LMR &lt; 3. SII was available in 162 patients. SII &lt; 1375 (82%) correlated with statistically significant longer PFS [11.5 vs 3.4 months; HR 2.16 (1.36-3.43), p = 0.001] and OS [NR vs 9.5 months; HR 3.87 (2.21-6.78), p &lt; 0.001] with higher ORR (35% vs 20%) and DCR (65% vs 40%) compared to SII ≥ 1375. Univariate and multivariate analyses adjusted for IMDC group, line of therapy and metastatic sites, confirmed the statistically significant correlation between SII with PFS and OS, but not for LMR. Conclusions: Preliminary analyses of our study showed a prognostic role of baseline SII, while it is uncertain for LMR in mRCC patients treated with nivolumab.
Integrative genomic profiling of RCC treated with second-line nivolumab.
Authors: Pankaj Vats, Saravana Dhanasekaran, Rohit Malik, Yupin Zhang, Xuhong Cao, Fengyun Su, Rui Wang, Alicia Ali, Stephanie Erickson, Megan Dahl, Charles Voliva, Rohit Mehra, Arul Chinnaiyan, Ajjai Shivaram Alva
Journal: Journal of Clinical Oncology (2020)

720 Background: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer comprising up to 80% of RCC. Anti-vascular endothelial growth factor receptor (VEGFR) is a common therapy. Immune checkpoint inhibitor therapy with anti-PD1 antibody Nivolumab is a standard second line option in mccRCC. Overall response rate with Nivolumab however is only 25%. Since there is a critical need to develop and refine predictive biomarkers for anti-PD1 checkpoint inhibitor immunotherapy, we undertook a genomics based approach to gain further insights. Methods: Archival pre-treatment tissues from 37 metastatic mccRCC patients who had received anti-VEGFR first and then Nivolumab were collected and profiled by integrated next generation sequencing (NGS) including whole exome sequencing and RNA sequencing. Integrative NGS analysis was used to discover somatic mutations, indels, copy-number alterations and gene expression changes among the samples in this cohort. In-addition, we characterized the T-Cell clone type by adaptive immunoSEQ TCR sequencing on the matched tumor/benign adjacent tissue samples. Clinical outcome data was correlated with high throughput sequencing results to delineate the characteristics of responders and non-responders. Results: Integrative NGS profiling and analysis of ccRCC tumors revealed 1) the characteristic copy number alteration including frequent loss at 3p, 8p21.3 and 9p21.3 as well as gain at 5q, and 12p12.1. 2) a low mutational burden 3) tumors with PBRM1 mutation were relatively enriched in the “No Clinical Benefit Category”. 4) CD8 immunohistochemistry showed significant enrichment of CD8+ cells ( pval-0.05) in the clinical benefit group compared to patients with no-clinical benefit. The clinical benefit group tended to have higher number of TCR clones. Conclusions: Integrative genomic sequencing analysis of ccRCC tumors in Nivolumab treated patients revealed CD8 expression as a putative biomarker. Greater T-cell clonotypes &amp; clonal expansion correlated with clinical benefit. PBRM1 mutant status did not select for clinical benefit. A model combining CD8 expression with T-cell characteristics was developed.
ORMDL3 but not neighboring 17q21 gene LRRC3C is expressed in human lungs and lung cells of asthmatics
Authors: Gyu Young Hur, Alexa Pham, Marina Miller, Ning Weng, Jingwen Hu, Richard C. Kurten, David H. Broide
Journal: Allergy (2020)

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The real-world efficacy of abiraterone acetate (ABA) and docetaxel (DOC) in the treatment of African-American (AA) patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC).
Authors: Katherine E.R. Smith, Jacqueline T Brown, Yuan Liu, Jennifer Ann LaFollette, Melvin R. Moore, Mehmet Asim Bilen
Journal: Journal of Clinical Oncology (2020)

52 Background: The landscape of mCSPC treatment changed with the addition of ABA and DOC. The prevalence of AA pts in the trials that led to these approvals was &lt; 10%. We characterized the clinical outcomes (CO) of a cohort of AA pts treated with these agents. Methods: We retrospectively reviewed 51 AA pts with mCSPC treated with ABA or DOC at Grady Memorial Hospital from 2015-2018. The CO included median overall survival (mOS), progression-free survival (mPFS) and PSA response (PSAr) as defined by a ≥ 50% drop in PSA over the 1 st 12 weeks of treatment. Cox proportional hazard model and Kaplan-Meier method were used for association with OS and PFS and logistic regression model for PSAr. Results: Median age was 63 years, 64% were grade group 5 and 67% had an ECOG status of 0-1. 82% had high volume disease per CHAARTED; 51% did per LATITUDE. 21 pts received ABA; 30 received DOC. The groups (ABA vs DOC) were balanced except for high volume disease per LATITUDE (28.6 vs. 66.7%) and lymph node metastases (66.7 vs. 96.7%). The DOC cohort received a mean of 5.2 cycles. Median follow-up was 10.3 months (mos). The overall mOS was 37.8 mos, mPFS was 10.3 mos, and PSAr was 89.6%. CO trended toward favoring ABA over DOC but did not differ significantly with a 12-month OS of 100% vs. 81.7% and PFS of 53.7% vs. 35.4%, respectively. Albumin and hemoglobin at baseline were associated with CO (Table). Conclusions: We present the first real world efficacy of ABA and DOC in a cohort of AA pts with mCSPC and found similar outcomes between the two groups. These findings warrant a larger study for validation.[Table: see text]
Abstract 18227: Acellular Extracellular Matrix Scaffold Reprograms Cardiac Fibroblasts and Stimulates Adaptive Cardiac Remodeling and Repair
Authors: Daniyil A Svystonyuk, Jeannine D Turnbull, Guoqi Teng, Darrell D Belke, David G Guzzardi, Daniel S Park, Sean Kang, Paul W Fedak
Journal: Circulation (2017)

Background: Targeting cardiac fibroblasts may attenuate structural remodeling and progressive loss of cardiac function post-MI. Extracellular matrix (ECM) biomaterials can promote cardiac repair by...
Effects of Germline VHL Deficiency on Growth, Metabolism, and Mitochondria
Authors: Silverio Perrotta, Domenico Roberti, Debora Bencivenga, Paola Corsetto, Katie A. O’Brien, Martina Caiazza, Emanuela Stampone, Leanne Allison, Roland A. Fleck, Saverio Scianguetta, Immacolata Tartaglione, Peter A. Robbins, Maddalena Casale, James A. West, Clara Franzini-Armstrong, Julian L. Griffin, Angela M. Rizzo, Antonio A. Sinisi, Andrew J. Murray, Adriana Borriello, Federico Formenti, Fulvio Della Ragione
Journal: New England Journal of Medicine (2020)

Mutations in VHL, which encodes von Hippel-Lindau tumor suppressor (VHL), are associated with divergent diseases. We describe a patient with marked erythrocytosis and prominent mitochondrial alterations associated with a severe germline VHL deficiency due to homozygosity for a novel synonymous mutation (c.222C→A, p.V74V). The condition is characterized by early systemic onset and differs from Chuvash polycythemia (c.598C→T) in that it is associated with a strongly reduced growth rate, persistent hypoglycemia, and limited exercise capacity. We report changes in gene expression that reprogram carbohydrate and lipid metabolism, impair muscle mitochondrial respiratory function, and uncouple oxygen consumption from ATP production. Moreover, we identified unusual intermitochondrial connecting ducts. Our findings add unexpected information on the importance of the VHL-hypoxia-inducible factor (HIF) axis to human phenotypes. (Funded by Associazione Italiana Ricerca sul Cancro and others.).
Impact of baseline serum IL-8 on metastatic hormone-sensitive (mHSPC) prostate cancer outcomes in the phase III CHAARTED trial (E3805).
Authors: Lauren Christine Harshman, Xin Victoria Wang, Hidemi S. Yamamoto, Anis Hamid, Charles G. Drake, Michael Anthony Carducci, Robert S. DiPaola, Raina N. Fichorova, Christopher Sweeney
Journal: Journal of Clinical Oncology (2020)

171 Background: IL-8 (CXCL-8) is a cytokine produced by leukocytes and tumor cells, which promotes inflammation, angiogenesis, anti-apoptosis, and metastasis. Our published training set identified serum IL-8 levels drawn within 28 days of androgen deprivation therapy (ADT) initiation as prognostic for shorter overall survival (OS). We sought to validate this finding using samples from CHAARTED patients treated with ADT +/- docetaxel for mHSPC. Methods: We assayed serum samples drawn ≤28 days from ADT initiation from 233 patients using the same Mesoscale multiplex ELISA assay as the training set. Multivariable Cox proportional hazards models adjusted for ECOG performance status, disease volume, and prior local therapy (radiation/prostatectomy vs. none) with IL-8 as continuous and binary variables. The training median 9.3 pg/mL was the a priori binary cutpoint. Fixed-effects meta-analysis of the training and validation sets was performed. Results: Higher IL-8 levels were prognostic for shorter OS and time to CRPC for ADT alone and ADT + docetaxel (Table) and were independent of disease volume or docetaxel use. Meta-analysis of binary IL-8 levels &gt;9.3pg/mL from patients treated with ADT alone (training + validation cohorts) was prognostic for poorer OS (HR 1.8, 95% CI: 1.2-2.7, p= 0.007) and shorter time to CRPC (HR: 1.4, 95%CI: 0.99-1.9, p=0.057). The validation cohort’s baseline median IL-8 level was similar at 10 pg/mL. Conclusions: Higher IL-8 is prognostic for shorter time to CRPC and OS independent of docetaxel use, disease volume and presentation with metachronous or de novo metastatic disease. These findings support targeting IL-8 as a strategy to improve mHSPC outcomes.[Table: see text]