tbuckley/cabot-search huggingface dataset:
Comparative Genomics Reveals Distinct Immune-oncologic Pathways in African American Men with Prostate Cancer
Authors: Shivanshu Awasthi, Anders Berglund, Julieta Abraham-Miranda, Robert J. Rounbehler, Kevin Kensler, Amparo Serna, Adriana Vidal, Sungyong You, Michael R. Freeman, Elai Davicioni, Yang Liu, R. Jeffrey Karnes, Eric A. Klein, Robert B. Den, Bruce J. Trock, Joshua D. Campbell, David J. Einstein, Raavi Gupta, Steven Balk, Priti Lal, Jong Y. Park, John L. Cleveland, Timothy R. Rebbeck, Stephen J. Freedland, Kosj Yamoah
Journal: Clinical Cancer Research (2020)

The role of immune-oncologic mechanisms of racial disparities in prostate cancer remains understudied. Limited research exists to evaluate the molecular underpinnings of immune differences in African American men (AAM) and European American men (EAM) prostate tumor microenvironment (TME).A total of 1,173 radiation-naïve radical prostatectomy samples with whole transcriptome data from the Decipher GRID registry were used. Transcriptomic expressions of 1,260 immune-specific genes were selected to assess immune-oncologic differences between AAM and EAM prostate tumors. Race-specific differential expression of genes was assessed using a rank test, and intergene correlational matrix and gene set enrichment was used for pathway analysis.AAM prostate tumors have significant enrichment of major immune-oncologic pathways, including proinflammatory cytokines, IFNα, IFNγ, TNFα signaling, ILs, and epithelial-mesenchymal transition. AAM TME has higher total immune content score (ICSHIGH) compared with 0 (37.8% vs. 21.9%, P = 0.003). AAM tumors also have lower DNA damage repair and are genomically radiosensitive as compared with EAM. IFITM3 (IFN-inducible transmembrane protein 3) was one of the major proinflammatory genes overexpressed in AAM that predicted increased risk of biochemical recurrence selectively for AAM in both discovery [HRAAM = 2.30; 95% confidence interval (CI), 1.21-4.34; P = 0.01] and validation (HRAAM = 2.42; 95% CI, 1.52-3.86; P = 0.0001) but not in EAM.Prostate tumors of AAM manifest a unique immune repertoire and have significant enrichment of proinflammatory immune pathways that are associated with poorer outcomes. Observed immune-oncologic differences can aid in a genomically adaptive approach to treating prostate cancer in AAM.
A Cyclin D1–Dependent Transcriptional Program Predicts Clinical Outcome in Mantle Cell Lymphoma
Authors: Santiago Demajo, Robert Albero, Guillem Clot, Giancarlo Castellano, Alba Navarro, Cristina Capdevila, Anna Enjuanes, Ferran Nadeu, Eva Giné, Magda Pinyol, Elaine S. Jaffe, German Ott, Louis M. Staudt, Andreas Rosenwald, David W. Scott, Lisa M. Rimsza, Armando López-Guillermo, Sílvia Beà, Elias Campo, Pedro Jares
Journal: Clinical Cancer Research (2020)

Mantle cell lymphoma (MCL) is characterized by the t(11;14)(q13;q32) translocation leading to cyclin D1 overexpression. Cyclin D1 is a major cell-cycle regulator and also regulates transcription, but the impact of cyclin D1-mediated transcriptional dysregulation on MCL pathogenesis remains poorly understood. The aim of this study was to define a cyclin D1-dependent gene expression program and analyze its prognostic value.
Addressing reproductive health needs of cancer patients: The pilot experience of pioneering oncofertility clinic in Saudi Arabia.
Authors: Hayat Ahmed Alrabiah, Nafisa Abdelhafeiz, Ashwaq Al Olayan, Abdul-Rahman Jazieh
Journal: Journal of Clinical Oncology (2020)

37 Background: Fertility and reproductive health issues are commonly encountered in cancer patients and survivors and unfortunately, they are not systematically addressed in many cancer care centers. We are reporting the initial experience in our dedicated Oncofertility Clinic that was established to address all reproductive and fertility issues for all oncology patients at our cancer center. Methods: We launched the first dedicated oncofertility clinic in the region on April 2018, staffed by a consultant of obstetrics and gynecology with the help of a team from in vitro fertilization (IVF) unit and a medical oncologist. It is held on a weekly basis and receives referral from medical oncology, hematology, stem cell transplant and radiation oncology. Eligible patients are males and premenopausal females going for chemotherapy or radiation therapy aiming for fertility preservation or cancer survivors who completed treatment and complaining of infertility problems. The clinic provides fertility preservation through the following procedures: Oocytes freezing (OF), in-vitro fertilization (IVF), sperm freezing, and ovarian transposition. Oncofertility care also includes management of sexual and hormonal dysfunction, and contraception methods. We are capturing the demographic, clinical data of all patients who were served in the clinic and the number of interventions and procedures that they underwent. Results: Between April 2018 and April of 2020, the clinic served 100 patients 60% were female, Median age was 35 years (16 -39). Diagnoses were distributed between breast cancer (36%), lymphoma (10%), and sickle cell anemia patients undergoing hematopoietic stem cell transplant (10%). The table depicts the types and number of procedures performed on these patients. Conclusions: Our pilot experience revealed the critical need of such clinic to help patients in fertility preservation, management of symptoms of gonadal toxicity. Future plans include implementation of systematic screening approach cancer populations who will benefit from the services and monitor the long- term impact of the clinic on the served patients. [Table: see text]
THU0170 Immunoglobulin g fc-receptor (fcgr) iiia polymorphisms and disease expression in rheumatoid arthritis
Authors: JG Brun, TM Madland, CA Vedeler
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Fc receptors for IgG (FcγR) modulate immune responses. Fcγ receptors are expressed on various leukocytes and contain allelic polymorphisms with different capacity for IgG binding and phagocytosis. The FcγR polymorphisms have been implicated as genetic factors that may influence the susceptibility to autoimmune disease. FcγRIII has two isoforms (A and B) and is encoded by genes on chromosome 1. For FcγRIIIA, the presence of the valine (V) allele confers a higher receptor affinity for IgG1, IgG3 and IgG4 than does the presence of the phenylalanine (F) allele. <h3>Objectives</h3> We investigated the distribution of the FcγRIIIA alleles in rheumatoid arthritis (RA), and whether they were related to disease expression and severity. <h3>Methods</h3> Ninety-six controls and 114 patients fulfilling ACR criteria for RA were genotyped for FcγRIIIA polymorphisms using PCR. Physician’s global assessment of RA type estimated RA disease expression. In addition, usual measures of disease activity were recorded. <h3>Results</h3> Crosstabulation of the FcγRIIIA genotypes V/V and V/F combined vs the F/F genotype showed that more patients with aggressive RA than expected had the V/V and V/F genotypes (P &lt; 0.05). The FcγRIIIA V/F genotype and the V allele was slightly more frequent among RA patients than among controls. This finding however, was not statistically significant. We found no significant associations with the clinical and laboratory variables of disease activity. <h3>Conclusion</h3> The results of previous studies regarding FcγRIIIA in RA are not consistent. The present findings of a more severe disease among patients homo- and heterozygous for the valine (V) allele, and the suggested tendency of more than expected V/V and V/F genotypes among RA patients as compared to controls, lend support to the notion of FcγRIIIA as a possible disease susceptibility and disease-modifying gene in RA.
Covid-19: FDA defies Trump to publish rigorous vaccine development guidelines
Authors: Owen Dyer
Journal: BMJ (2020)

President Trump’s claim that a covid-19 vaccine could be available before the US election on 3 November has become untenable following the publication of Food and Drug Administration (FDA) guidelines on vaccine development. The guidelines urge companies not to submit applications for emergency use authorisation until they have followed subjects in phase III trials for an average of two months after their last vaccine dose is given.

The guidelines appear to have been given against the president’s wishes, the first time in the pandemic that a federal public health agency has explicitly opposed Donald Trump.

“New FDA Rules make it more difficult for them to speed up vaccines for approval before …
Utilization of anti-HER2 regimens among HER2-positive metastatic breast cancer patients.
Authors: Sandhya Mehta, Jinlin Song, Melissa Pavilack, Jipan Xie, Xiaoyu Nie, Mohini Vembusubramanian, Jackie Kwong
Journal: Journal of Clinical Oncology (2020)

282 Background: HER2-positive (+) metastatic breast cancer (mBC) has a poor prognosis and many patients require multiple lines of HER2 targeted regimens. This study aims to examine the treatment sequencing of anti-HER2 regimens for HER2+ mBC among Medicare beneficiaries. Methods: A retrospective study was conducted using linked 1999-2016 Surveillance, Epidemiology, and End Results (SEER) cancer registries and Medicare claims. Adults patients who had mBC diagnosis, HER2+ status documented in SEER or claims of ≥1 anti-HER2 drug, continuous enrollment in Medicare from the date of mBC diagnosis until end of study period/death, and 2 anti-HER2 regimens with or without chemotherapy (Ch) or hormonal therapy (HT) were included. Discontinuation of anti-HER2 regimen was defined as the absence of claims for all anti-HER2 drugs for &gt;60 days, or initiation of a different anti-HER2 drug. Re-initiation of the same regimen after &gt;60 days was considered as a new regimen. The first two anti-HER2 regimens and subsequent therapies were summarized. Results: 804 patients with 2 anti-HER2 regimens were included. Trastuzumab (T) based regimen (defined as: T±Ch/HT; without other anti-HER2 drugs) was the most common 1st regimen (82%), followed by T+ pertuzumab (P) (14%) and lapatinib (L) (3%). For the 2nd regimen, T (52%) was most common, followed by T+P (18%), L (11%), trastuzumab emtansine (T-DM1) (11%) and T+L (7%). After a 2nd regimen, 578 (72%) initiated a subsequent therapy, with over half switching to non-targeted therapies [52%; HT alone (35%), Ch±HT (17%)] followed by T (17%), T-DM1 (12%) and T+P (7%). Among those with subsequent therapy, 2 T-based regimens followed by HT alone (21%) was the most common sequence. After the 1st regimen, 52% patients reused the same anti-HER2 drugs in the 2nd regimen, 21% added another anti-HER2 drug and 27% switched to a different anti-HER2 regimen. After the 2nd regimen, 14% reused anti-HER2 drugs and 6% added another anti-HER2 drug, 25% switched to a different anti-HER2 regimen; 15% reused anti-HER2 drugs from the 1st regimen. Conclusions: Trastuzumab based regimen was the mainstay of anti-HER2 drug regimens during the study timeframe. Despite availability of multiple anti-HER2 drugs, reuse of prior anti-HER2 drugs and switching to non-targeted therapies alone were common after using 2 anti-HER2 regimens. These findings underscore the unmet needs in later lines of therapy. Recently approved anti-HER2 agents may provide additional treatment options for pre-treated HER2+ metastatic breast cancer patients.
Resource utilization rates among English versus limited English proficient patients (pts) by patient-report of low health literacy (LHL).
Authors: Nadine Jackson McCleary, Ellana Haakenstad, Jessi Rowell, Jessica Cleveland, Sunyi Zhang, Sherry Lee, Michael J. Hassett, Deborah Schrag
Journal: Journal of Clinical Oncology (2020)

107 Background: About 30 million people in the US report Limited-English Proficiency (LEP). LEP cancer pts are less likely to understand their medical condition(s) and are at increased risk of LHL, emergency department (ED) visits or hospitalizations. We examined the relationship between LEP, LHL, and ED visits/hospitalization in oncology. Methods: Dana-Farber Cancer Institute’s New Pt Intake Questionnaire (NPIQ) documents clinical and social determinants of health, including LHL. Pts reported LHL if they responded “a little bit”, “somewhat” or “not at all” to 1 of 2 questions: 1) “How confident are you in filling out medical forms?” and 2) “How confident are you in understanding medical statistics?”. Pts reported LEP if they noted a primary language other than English at registration. ED visits/hospitalizations were determined from Partners Healthcare System records. Statistically significant relationships between LEP, LHL and ED visits/hospitalizations and pt demographics (age, sex, race/ethnicity, zip code) and clinical (disease center, treatment intent) characteristics were determined with χ 2 tests. Results: From 5/30/15 – 4/30/20, 21570 of 98200 eligible pts responded to NPIQ (response rate 22.0%). LHL differed by age (p-value &lt; 0.001), gender (p-value &lt; 0.001) and race/ethnicity (p-value = 0.007). Among LEP pts reporting LHL, financial distress (p-value = 0.004), emotional distress (PROMIS score; p-value = 0.014), and prior cancer (p-value = 0.006) were more prevalent; however, there was no significant statistical increase in ED visits (p-value = 0.237) or hospitalizations (p-value = 0.965) compared to LEP not reporting LHL. Conclusions: The results indicate that sociodemographic and other pt characteristics contribute to ED and hospital utilization in LEP cancer pts. Future studies will employ prospective data to examine the covariates’ predictive ability for resource utilization with LHL among LEP pts. [Table: see text]
Metabolic syndrome, metabolic comorbid conditions and risk of early-onset colorectal cancer
Authors: Hanyu Chen, Xiaobin Zheng, Xiaoyu Zong, Zitong Li, Na Li, Jinhee Hur, Cassandra DL Fritz, William Chapman Jr, Katelin B Nickel, Andrew Tipping, Graham A Colditz, Edward L Giovannucci, Margaret A Olsen, Ryan C Fields, Yin Cao
Journal: Gut (2020)

Factors that lead to metabolic dysregulation are associated with increased risk of early-onset colorectal cancer (CRC diagnosed under age 50). However, the association between metabolic syndrome (MetS) and early-onset CRC remains unexamined.We conducted a nested case-control study among participants aged 18-64 in the IBM MarketScan Commercial Database (2006-2015). Incident CRC was identified using pathologist-coded International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, and controls were frequency matched. MetS was defined as presence of ≥3 conditions among obesity, hypertension, hyperlipidaemia and hyperglycaemia/type 2 diabetes, based on ICD-9-CM and use of medications. Multivariable logistic regressions were used to estimate ORs and 95% CIs.MetS was associated with increased risk of early-onset CRC (n=4673; multivariable adjusted OR 1.25; 95% CI 1.09 to 1.43), similar to CRC diagnosed at age 50-64 (n=14 928; OR 1.21; 95% CI 1.15 to 1.27). Compared with individuals without a metabolic comorbid condition, those with 1, 2 or ≥3 conditions had a 9% (1.09; 95% CI 1.00 to 1.17), 12% (1.12; 95% CI 1.01 to 1.24) and 31% (1.31; 95% CI 1.13 to 1.51) higher risk of early-onset CRC (ptrend <0.001). No associations were observed for one or two metabolic comorbid conditions and CRC diagnosed at age 50-64. These positive associations were driven by proximal (OR per condition 1.14; 95% CI 1.06 to 1.23) and distal colon cancer (OR 1.09; 95% CI 1.00 to 1.18), but not rectal cancer (OR 1.03; 95% CI 0.97 to 1.09).Metabolic dysregulation was associated with increased risk of early-onset CRC, driven by proximal and distal colon cancer, thus at least in part contribute to the rising incidence of early-onset CRC.
Minimum important difference of the EQ-5D-5L and EQ-VAS in fibrotic interstitial lung disease
Authors: Amy Po Yu Tsai, Seo Am Hur, Alyson Wong, Mohsen Safavi, Deborah Assayag, Kerri A Johannson, Julie Morisset, Charlene Fell, Jolene H Fisher, Hélène Manganas, Shane Shapera, Gerard Cox, Andrea S Gershon, Nathan Hambly, Nasreen Khalil, Teresa To, Pearce George Wilcox, Andrew Halayko, Martin RJ Kolb, Christopher J Ryerson
Journal: Thorax (2020)

Rationale The European Quality of Life 5-Dimensions 5-Levels questionnaire (EQ-5D-5L) is a multidimensional patient-reported questionnaire that supports calculation of quality-adjusted life-years. Our objectives were to demonstrate feasibility of use and to calculate the minimum important difference (MID) of the EQ-5D-5L and its associated visual analogue scale (EQ-VAS) in patients with fibrotic interstitial lung disease (ILD). Methods Patients who completed the EQ-5D-5L were identified from the prospective multicentre CAnadian REgistry for Pulmonary Fibrosis. Validity, internal consistency and responsiveness of the EQ-5D-5L were assessed, followed by calculation of the MID for the EQ-5D-5L and EQ-VAS. Anchor-based methods used an unadjusted linear regression against pulmonary function tests (PFTs) and dyspnoea and other quality of life questionnaires. Distribution-based method used one-half SD and SE measurement (SEM) calculations. Results 1816 patients were analysed, including 472 (26%) with idiopathic pulmonary fibrosis. EQ-5D-5L scores were strongly correlated with the dyspnoea and other quality of life questionnaires and weakly associated with PFTs. The estimated MID for EQ-5D-5L ranged from 0.0050 to 0.054 and from 0.078 to 0.095 for the anchor-based and distribution-based methods, respectively. The MID for EQ-VAS ranged from 0.5 to 5.0 and from 8.0 to 9.7 for the anchor-based and distribution-based methods. Findings were similar across ILD subtypes, sex and age. Conclusion We used a large and diverse cohort of patients with a variety of fibrotic ILD subtypes to suggest validity and MID of both the EQ-5D-5L and EQ-VAS. These findings will assist in designing future clinical trials and supporting cost-effectiveness analyses of potential treatments for patients with fibrotic ILD.
Genome-Wide Analysis Identifies an Essential Human TBX3 Pacemaker Enhancer
Authors: Vincent W.W. van Eif, Stephanie I. Protze, Fernanda M. Bosada, Xuefei Yuan, Tanvi Sinha, Karel van Duijvenboden, Auriane C. Ernault, Rajiv A. Mohan, Vincent Wakker, Corrie de Gier-de Vries, Ingeborg B. Hooijkaas, Michael D. Wilson, Arie O. Verkerk, Jeroen Bakkers, Bastiaan J. Boukens, Brian L. Black, Ian C. Scott, Vincent M. Christoffels
Journal: Circulation Research (2020)

The development and function of the pacemaker cardiomyocytes of the sinoatrial node (SAN), the leading pacemaker of the heart, are tightly controlled by a conserved network of transcription factors, including TBX3 (T-box transcription factor 3), ISL1 (ISL LIM homeobox 1), and SHOX2 (short stature homeobox 2). Yet, the regulatory DNA elements (REs) controlling target gene expression in the SAN pacemaker cells have remained undefined.Identification of the regulatory landscape of human SAN-like pacemaker cells and functional assessment of SAN-specific REs potentially involved in pacemaker cell gene regulation.We performed Assay for Transposase-Accessible Chromatin using sequencing on human pluripotent stem cell-derived SAN-like pacemaker cells and ventricle-like cells and identified thousands of putative REs specific for either human cell type. We validated pacemaker cell-specific elements in the SHOX2 and TBX3 loci. CRISPR-mediated homozygous deletion of the mouse ortholog of a noncoding region with candidate pacemaker-specific REs in the SHOX2 locus resulted in selective loss of Shox2 expression from the developing SAN and embryonic lethality. Putative pacemaker-specific REs were identified up to 1 Mbp upstream of TBX3 in a region close to MED13L harboring variants associated with heart rate recovery after exercise. The orthologous region was deleted in mice, which resulted in selective loss of expression of Tbx3 from the SAN and (cardiac) ganglia and in neonatal lethality. Expression of Tbx3 was maintained in other tissues including the atrioventricular conduction system, lungs, and liver. Heterozygous adult mice showed increased SAN recovery times after pacing. The human REs harboring the associated variants robustly drove expression in the SAN of transgenic mouse embryos.We provided a genome-wide collection of candidate human pacemaker-specific REs, including the loci of SHOX2, TBX3, and ISL1, and identified a link between human genetic variants influencing heart rate recovery after exercise and a variant RE with highly conserved function, driving SAN expression of TBX3.
Creation of a telehealth task force to improve successful use of telehealth to maintain patient access during the COVID-19 pandemic.
Authors: Avnish K Bhatia, Lauren Waldman, Melissa Hunt, Amy Leader, Janene Palidora, Megan Sabonjian, Preethi Selvan, Ayaka Shimada, Brooke Worster, Gregory D. Garber
Journal: Journal of Clinical Oncology (2020)

264 Background: In response to the COVID-19 National Emergency, the Sidney Kimmel Cancer Center (SKCC) medical oncology practice desired to greatly expand telehealth (TH) utilization to decrease patient risk while maintaining access to care. TH utilization requires resources (smart phones, internet) and there are disparities in digital media access in our patient population. A digital literacy survey performed at the SKCC in 2018 noted that 30% of patients used Android phones and &gt; 60% of patients accessed the internet from a PC. Methods: In response to increased TH demand and need for support, the SKCC launched an oncology-dedicated Telehealth Task Force (TTF) to address barriers to TH access. The TTF team consisted of nine full-time individuals with digital and healthcare literacy to assist in telehealth and patient portal troubleshooting. Critical functions of TTF’s targeted patient solutions include; set-up and delivery of smartphones, creating email accounts, performing test visits, creating EHR patient portal accounts, real- time assistance during TH visits with implementation of this intervention beginning on April 3, 2020 with monitoring of patient interactions/touchpoints. Results: The SKCC medical oncology TTF noted increased interactions with patients immediately with a marked increase in the composite of medical oncology appointments completed by TH (51.0% in April 2020 compared to a prior level of 15.7% in March 2020). Additionally, there was a statistically significant increase in the proportion of patients have an active patient portal EHR account during this same period (14.6%; 95% CI, 12.3% to 16.9%; p &lt; 0.0001). Oncology infusion treatment appointments remained relatively consistent over time. Conclusions: The SKCC medical oncology practice experienced an exponential rise in TH utilization during an uncertain public health crisis. Disparity in digital literacy and resources essential for successful TH use were quickly appreciated as potential barriers to access. The creation of a dedicated Telehealth Task Force was critical in maintain access to care for oncology patients given their vulnerability to infection. Further investigation of TH supports to improve TH use are warranted. [Table: see text]