tbuckley/cabot-search huggingface dataset:
Molecular characterization of 350 hepatocellular carcinomas to identify biomarker aberrations with potential novel therapeutic options.
Authors: Celina Ang, John Thomas Miura, T. Clark Gamblin, Sherri Z. Millis, Joanne Xiu, Zoran Gatalica, Sandeep K. Reddy, Nelson S. Yee
Journal: Journal of Clinical Oncology (2015)

4086 Background: Effective treatment strategies for hepatocellular carcinoma (HCC) remain limited. Identification of additional therapies remains paramount as currently available agents have resulted in marginal improvements in overall survival or are not appropriate for this patient population. Methods: 350 HCC sampleswere evaluated on a commercial platform, for both genetic and proteomic aberrations. Tests included Sanger or next generation sequencing (NGS), protein expression by immunohistochemistry (IHC) and gene amplification by in situ hybridization (ISH). Results: TP53 was mutated in 34%, CTNNB1 in 20%, and BRCA2 in 18%; other gene mutation rates were < 5%.TP53-mutated tumors show significantly higher TOP2A (89% vs. 39%, p<0.0001), TS (70% vs. 32%, p=0.0067) and RRM1 expression (40% vs. 12%, p=0.017), implying high rates of proliferation and DNA synthesis. CTNNB1-mutated tumors showed significantly higher SPARC (67% vs. 21%, p=0.0013) and AR expression (53% vs. 22%, p=0.025). Changes in protein expression are shown. Metastatic HCC (N=124) exhibited significantly higher PD-1 (79% vs. 50%, p=0.047) and TS expression (31% vs. 14%, p<0.0008) than non-metastatic (N=226). Analysis of outcomes in a subset of patients treated based on biomarker-therapy associations is ongoing. In 1 patient an EGFR mutation (predictive of response to erlotinib in NSCLC) was identified, and the patient has begun treatment with erlotinib. Conclusions: The molecular profile in HCC suggests potential targeted therapies, such as tyrosine kinase inhibitors, anti-PD1 agents, or PI3 kinase pathway inhibitors. Immuno-modulatory agents may be an option, particularly in metastatic HCC, based on levels of PD-1. Concurrent protein changes in CTNNB1-mutated tumors suggest potential benefit of combination therapies when targeting the WNT pathway. Review of responses to targeted therapies, such as is being tried with erlotinib in the patient with EGFR mutation may provide additional insight into efficacious therapies. % of samples with change, by IHC. High expression levels Low expression levels EGFR TOPO1 PD-1 TOP2A SPARC cMET RRM1 TS PTEN MGMT 83 52 60 38 36 25 82 80 72 31
Outcome of men with relapses after adjuvant BEP for clinical stage I nonseminoma.
Authors: Stefanie Christine Fischer, Torgrim Tandstad, Gabriella Elisabeth Cohn-Cedermark, Constance Thibault, Bruno Vincenzi, Dirk Klingbiel, Costantine Albany, Andrea Necchi, Angelika Terbuch, Anja Lorch, Jorge Aparicio, Axel Heidenreich, Marcus Hentrich, Matthew James Wheater, Carl Wilhelm Langberg, Olof Stahl, Joerg Beyer, Silke Gillessen
Journal: Journal of Clinical Oncology (2019)

510 Background: Clin. stage I (CSI) non-seminoma (NS) is disease limited to the testis without metastases. One treatment strategy after orchiectomy is adjuvant (adjuv) chemotherapy with BEP after which relapses are rare. Little is known about the outcome of patients (pts) relapsing after such treatment. Methods: Data from 51 pts with CSI NS and relapse after adjuv BEP from 18 centers/11 countries was collected and retrospectively analyzed. Primary endpoints were OS and PFS calculated from start of treatment of relapse. Secondary outcomes were time to, stage at, and treatment of relapse as well as rate of subsequent relapses. Results: 23 pts received one cycle adjuv BEP and 28 pts two. Median time to relapse was 13 months, with the earliest relapse two months after start of adjuv BEP and the latest relapse recorded after 26 years. According to IGCCCG, 84% of pts classified as good prognosis at relapse. With a median follow up of 50 months 5y PFS was 64% (95% CI 52-80%) and 5y OS 79% (95% CI 68-92%). Treatment upon relapse was diverse, the majority of pts received combination- chemotherapy and surgery. 10 pts (20%) had pure mature teratoma at relapse treated with surgery alone. None of these pts experienced a second relapse. If teratoma relapses were excluded, 5y PFS dropped to 58% (44-77%) and 5y OS to 76% (63-92%). Relapses later than three years after adjuv therapy occured in 15/51 pts. (29%) and were associated with a statistically significant higher risk of death from germ-cell cancer (p=0.02). 15/51 pts (29%) experienced a subsequent relapse. Excluding pts with teratoma only, subsequent relapses occured in 15 of the remaining 41 pts (37%). At last follow-up, 41/51 (80%) pts were alive and disease-free, 8/51 (16%) had died from progressive disease and one pt each had died from therapy-related or other causes. Conclusions: Outcome of pts with relapse after adjuv BEP seems to be better compared to pts with relapse after metastatic disease, but worse compared to de novo metastatic pts. There is a substantial rate of late and subsequent relapses. Pts and care-takers need to be informed about this and therapy intensification at first relapse might be considered. However, considering the low rate of relapses, OS in general for CSI NS pts receiving adjuv BEP is excellent.
Generation and persistence of human tissue-resident memory T cells in lung transplantation
Authors: Mark E. Snyder, Michael O. Finlayson, Thomas J. Connors, Pranay Dogra, Takashi Senda, Erin Bush, Dustin Carpenter, Charles Marboe, Luke Benvenuto, Lori Shah, Hilary Robbins, Jaime L. Hook, Megan Sykes, Frank D’Ovidio, Matthew Bacchetta, Joshua R. Sonett, David J. Lederer, Selim Arcasoy, Peter A. Sims, Donna L. Farber
Journal: Science Immunology (2019)

Human tissue-resident memory T cells persist long term in transplanted lungs and develop from infiltrating recipient T cells.
Impact of testosterone replacement therapy after radical prostatectomy on prostate cancer outcomes.
Authors: Reith Sarkar, J Kellogg Parsons, John Paul Einck, Arno James Mundt, A. Karim Kader, Christopher J. Kane, Paul Riviere, Rana R. McKay, James Don Murphy, Brent Shane Rose
Journal: Journal of Clinical Oncology (2019)

100 Background: Currently there is little data to guide the use of post-radical prostatectomy (RP) testosterone replacement therapy in prostate cancer. We sought to evaluate the impact of post-RP testosterone replacement on prostate cancer outcomes in a large national cohort. Methods: We conducted a population-based cohort study using the Veterans Affairs Informatics and Computing Infrastructure. We identified node-negative and non-metastatic prostate cancer patients diagnosed between 2001-2015 treated with RP. We excluded patients for missing covariate and follow-up data. We then coded receipt of testosterone replacement after RP as a time-dependent covariate. Other covariates included: age, Charlson Comorbidity index, diagnosis year, body mass index, race, PSA, clinical T/N/M stage, Gleason score, and receipt of hormone therapy. Biochemical recurrence was defined as a post-RP PSA≥0.2. We evaluated prostate cancer-specific survival, overall survival, and biochemical recurrence free survival using multivariable Cox regression. Results: Our cohort included 28,651 patients, of whom 469 (1.6%) received testosterone replacement after RP. Median follow up was 7.4 years. There were no differences in clinical T stage, median post-RP PSA (testosterone: 0 non-testosterone: 0; p = 0.18), or hormone therapy use between treatment groups. Testosterone patients were more likely to be of younger age, have higher comorbidity, non-black, have a lower median pre-treatment PSA (5.0 vs 5.8; p &lt; 0.001), and have higher BMI. The median time from RP to TRT was 3.0 years. After controlling for potential confounders, we found no difference in prostate cancer specific mortality (HR 0.73; 95% CI 0.32-1.62; p = 0.43), overall survival (HR 1.11; 95% CI 0.86-1.44; p = 0.43), non-cancer mortality (HR 1.17; 95% CI 0.89-1.55; p = 0.26) biochemical recurrence free survival (HR 1.07; 95% CI 0.84-1.36; p = 0.59) between testosterone users and non-users. Conclusions: Our results suggest that testosterone replacement is safe in prostate cancer patients who have undergone RP, though prospective data is necessary to confirm this finding.
Genome‐wide Association Studies of Specific Antinuclear Autoantibody Subphenotypes in Primary Biliary Cholangitis
Authors: Chan Wang, Xiaodong Zheng, Peng Jiang, Ruqi Tang, Yuhua Gong, Yaping Dai, Lan Wang, Ping Xu, Wenjuan Sun, Lu Wang, Chongxu Han, Yuzhang Jiang, Yiran Wei, Kui Zhang, Jian Wu, Youlin Shao, Yueqiu Gao, Jianjiang Yu, Zhigang Hu, Zhidong Zang, Yi Zhao, Xudong Wu, Na Dai, Lei Liu, Jinshan Nie, Bo Jiang, Maosong Lin, Li Li, You Li, Sufang Chen, Lixin Shu, Fang Qiu, Qiuyuan Wu, Mingming Zhang, Ru Chen, Rohil Jawed, Yu Zhang, Xingjuan Shi, Zhen Zhu, Hao Pei, Lihua Huang, Weifeng Zhao, Ye Tian, Xiang Zhu, Hong Qiu, M. Eric Gershwin, Weichang Chen, Michael F. Seldin, Xiangdong Liu, Liangdan Sun, Xiong Ma
Journal: Hepatology (2019)

Anti‐nuclear antibodies to speckled 100 kDa (sp100) and glycoprotein 210 (gp210) are specific serologic markers of primary biliary cholangitis (PBC) of uncertain/controversial clinical or prognostic significance. To study the genetic determinants associated with sp100 and gp210 autoantibody subphenotypes, we performed a genome‐wide association analysis of 930 PBC cases based on their autoantibody status, followed by a replication study in 1,252 PBC cases. We confirmed single‐nucleotide polymorphisms rs492899 ( P = 3.27 × 10 −22 ; odds ratio [OR], 2.90; 95% confidence interval [CI], 2.34‐3.66) and rs1794280 ( P = 5.78 × 10 −28 ; OR, 3.89; 95% CI, 3.05‐4.96) in the human major histocompatibility complex (MHC) region associated with the sp100 autoantibody. However, no genetic variant was identified as being associated with the gp210 autoantibody. To further define specific classical human leukocyte antigen (HLA) alleles or amino acids associated with the sp100 autoantibody, we imputed 922 PBC cases (211 anti‐sp100‐positive versus 711 negative cases) using a Han Chinese MHC reference database. Conditional analysis identified that HLA‐DRβ1‐Asn77/Arg74, DRβ1‐Ser37, and DPβ1‐Lys65 were major determinants for sp100 production. For the classical HLA alleles, the strongest association was with DRB1*03:01 ( P = 1.51 × 10 −9 ; OR, 2.97; 95% CI, 2.06‐4.29). Regression analysis with classical HLA alleles identified DRB1*03:01 , DRB1*15:01 , DRB1*01 , and DPB1*03:01 alleles can explain most of the HLA association with sp100 autoantibody. Conclusion : This study indicated significant genetic predisposition to the sp100 autoantibody, but not the gp210 autoantibody, subphenotype in PBC patients. Additional studies will be necessary to determine if these findings have clinical significance to PBC pathogenesis and/or therapeutics.
Abstract P137: Impaired Microvascular and Endothelial Function Among African-Americans With Coronary Artery Disease
Authors: An Young, Samaah Sullivan, Kasra Moazzami, Bruno Lima, Amit Shah, Tene Lewis, Lisa Elon, lian li, Arshed Quyyumi, Viola Vaccarino
Journal: Circulation (2019)

Background: African-Americans have disproportionately higher burden of mortality from coronary artery disease (CAD) compared to Caucasians even after adjusting for socioeconomic and cardiovascular risk factors. Racial differences in arterial stiffness have been described, but data on microcirculatory and endothelial vascular function are more limited and it is unknown whether they differ by race in CAD patients. Methods: We studied 313 patients with a recent history of myocardial infarction (MI). Microvascular function was assessed by digital pulse amplitude tonometry (EndoPAT) to determine reactive hyperemia index (RHI), and endothelial function as brachial artery flow mediated dilation (FMD) using ultrasound. Arterial stiffness was assessed using applanation tonometry (Sphygmocor) to determine pulse-wave velocity (PWV) and central augmentation index (C-AIx). Data on sociodemographics, cardiovascular risk factors, medication use, and CAD severity were collected. Multivariate linear regression models were used to assess the relationship between race and various vascular function measures with adjustment for risk factors. Measures of arterial stiffness were included as control factors in the adjusted model for FMD and RHI. Results: The mean age of this post-MI sample was 51 years (± 6.7 SD); 50% were African-Americans and 49% were female. Compared to Caucasians, African-Americans had worse microvascular function as indicated by lower mean (± SD) RHI (1.7±0.5 vs 2.0±0.6, p&lt;0.0001) and worse endothelial function [FMD mean (3.4±2.4 vs 4.7±3.1, p=0.0002)]. African-Americans also had greater arterial stiffness, including a higher mean C-AIx (26.5±9.0 vs 23.0±9.3, p=0.0019) and PWV (7.7±2.0 vs 7.1±1.8, p&lt;0.0267). After adjustment for cardiovascular risk factors, medications, CAD severity, and arterial stiffness (C-AIx and PWV), black race remained significantly associated with lower RHI (β=-0.30, p&lt;0.001) and FMD (β=-1.06, p=0.004). Conclusion: African-Americans with CAD have impaired microvascular and endothelial vasodilatory function compared to Caucasians, independent of CAD risk factors and arterial stiffness. Racial differences in microcirculatory and endothelial function may contribute to worse outcomes among African-Americans with CAD.
Efficacy of plerixafor with GCSF for mobilization of PBSC: A single center experience.
Authors: Adwaita Anant Gore, Vipul Sheth, Amit Ghanekar, Reetu Jain, Tapan K Saikia
Journal: Journal of Clinical Oncology (2015)

e18011 Background: The combination of plerixafor & GCSF is approved for mobilization of hematopoietic stem cells for autologous transplantation in patients with lymphoma & myeloma whose cells who mobilize poorly. The primary study objective was to assess the efficacy of plerixafor & G-‐CSF as an upfront mobilization regimen, as measured by the number of CD34+ cells collected in each apheresis session (2 days). Methods: In this single centre retrospective analysis, patients received GCSF (10 mcg/kg/day) subcutaneously for 4 days; on the evening of day 4 and day 5 they were given Plerixafor (0.24 mg/kg) subcutaneously. Patients underwent apheresis on day 5 and day 6 after a morning dose of GCSF. Results: Total of 14 patients were included. All patients of lymphoma had received > 3 lines of chemotherapy. 2 patients had received prior radiation. 2 patients of Myeloma were heavily pretreated with multiple lines including Lenalidomide (1 was Relapse post autologous transplant). Remaining 4 patients received upfront Plerixafor in view of comorbidities. All of them received atleast 2 doses of Plerixafor. The median age was 40 years. 8(57%) were males. 6 (43%) patients had Myeloma and 8 patients (57%) had lymphoma. Among the 14 patients who underwent apheresis, 13 (92%) yielded the minimum required cell collection of ≥ 2×106 CD34+ cells/kg in 2 days of apheresis session. 7 (87%) patients within the NHL group & 6 (100%) patients within the Myeloma group yielded the minimum target cell collection. 6( 40%) of all patients achieved the optimum target cell collection (i.e. ≥ 5x106 CD34+ cells/kg for Lymphoma or ≥ 6×106 CD34+ cells/kg for MM) in 2 days of apheresis session. The median total number of CD34+ cells collected over 2 days was 4.2x106CD34+ cells/kg (range, 2.0 to 30.2 x106cells/kg). Following HDCT & PBSC rescue, 12 (85%) achieved neutrophil engraftment and 8 (57%) achieved platelet engraftment within 14 days. The median time to neutrophil & platelet engraftment were 11 days (range8–15) & 12days (range10‐29) respectively. Conclusions: This is the largest single center data in India demonstrating the efficacy of Peripheral blood stem cell mobilization with upfront Plerixafor and G--‐CSF in Lymphoma and Myeloma therapy.
Rate of <i>TP53</i> mutations in HPV-positive (HPV<sup>+</sup>) recurrent/metastatic head and neck cancer (RMHNC) patients.
Authors: Dzung Thach, Moin Ahmad, Adrienne L Penta, Gisela N Sulkowski, Bhaskar Kallakury, Joeffrey J Chahine, John E. Niederhuber, Ramaswamy K Iyer, John F. Deeken
Journal: Journal of Clinical Oncology (2015)

e17094 Background: While the vast majority of patients with locally advanced HPV+ HNC are cured by combined modality treatment, more than 1 in 4 pts will suffer recurrence. Understanding the genomic basis for recurrence risk could be critical to personalizing initial treatment. Methods: Resected recurrent tumors from HPV+ RMHNC pts were analyzed for the presence of tumor somatic mutations using the Cancer Hotspot Panel v2 on the Ion Torrent PGM. The data was bioinformatically analyzed using Torrent Suite, Variant Caller, Ion Reporter v4.2, and R scripts. Synonymous mutation results were excluded from further analysis. Results: Tumors from 9 consecutive pts were analyzed. Demographics were as follows: all were male, average age was 63 yrs, median time to recurrence was 18 mos (range 6 – 32); 4 were non-smokers and 5 had a smoking history of 10 pack-years or more. All were treated with primary chemoradiation for newly diagnosed disease. Sites for first recurrence were: local (2), lung (5) and liver (2). Mutated genes and frequencies were: TP53 (9), KDR/VEGFR-2 (8), FBXW7 (3), and SMARCB1 (2). TP53 alterations included missense (5) or stop/loss (4) mutations. Conclusions: An unexpected high rate of TP53 mutations were found in this cohort of HPV+ pts with RMHNC. The TCGA project found only 3% of HPV+ HNC tumors had nonsynonymous mutations in TP53. Such pts may be at high-risk for recurrence, and treatment escalation -- rather than de-escalation -- should be considered.
Next Phase in Effective Cost Control in Health Care
Authors: Aaron Glickman, Sarah S. P. DiMagno, Ezekiel J. Emanuel
Journal: JAMA (2019)

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Abstract P021: Cardiac Biomarkers, Electrolytes, and Anemia with Arrhythmias over Two Weeks in Chronic Kidney Disease: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Esther Kim, Ron C Hoogeveen, Elizabeth Selvin, Christie M Ballantyne, Elsayed Z Soliman, Josef Coresh, Kunihiro Matsushita, Lin Y Chen
Journal: Circulation (2019)

Background: Chronic kidney disease (CKD) increases the risk of arrhythmias and sudden cardiac death; however, it is unclear whether this association is due to cardiac overload, cardiac injury, electrolyte abnormalities, anemia, or all of the above. We therefore investigated the relationships between several biomarkers representing these conditions with various arrhythmias among CKD. Methods: In 2016-17 (visit 5), 2187 older participants (71-94 years) in the ARIC Study underwent 2-week continuous heart rhythm monitoring (Zio XT Patch). We conducted a cross-sectional study of 1276 participants with CKD. We used modified Poisson regression to examine the associations of natriuretic peptide (NT-proBNP) representing cardiac overload, high-sensitivity cardiac troponin-T (hs-cTnT) reflecting cardiac injury, potassium and magnesium (electrolyte abnormalities), and hemoglobin (anemia) with arrhythmias detected during the 2-week period: atrial fibrillation (AF), non-sustained ventricular tachycardia (NSVT), long pause (&gt;3 sec), Mobitz II or complete atrioventricular block (AVB), and ventricular ectopy (VE). Results: There were 9% with AF, 33% with NSVT, 4% with long pause, 2% with AVB, and 29% with VE. NT-proBNP was associated with all arrhythmias except AVB ( Table 1 ). Higher hs-cTnT was associated with AF, NSVT, and VE. Lower potassium below 4.2 mmol/L was associated with AF while lower magnesium below &lt;2 mg/dL was associated with VE. Hemoglobin showed no associations with arrhythmias. Conclusions: Of the plausible mechanisms contributing to arrhythmias in CKD, biomarkers of cardiac overload and injury were associated with most arrhythmias tested. Lower potassium and lower magnesium demonstrated a significant relationship with AF and VE, respectively. Our results suggest cardiac alterations as key conditions behind high arrhythmic burden in CKD, with somewhat limited contributions of electrolytes and anemia.
Concordance of systematic and fusion biopsy with surgical pathology.
Authors: Alice Yu, Tammer Yamany, Nawar Hanna, Eduoard Nicaise, Amirkasra Mojtahed, Mukesh Harisinghani, Chin-Lee Wu, Douglas M. Dahl, Matthew Wszolek, Michael L. Blute, Adam S. Feldman
Journal: Journal of Clinical Oncology (2019)

93 Background: Multiparametric MRI is increasingly used in prostate cancer detection. Previous studies have shown that detection rate of clinically significant cancer is higher in MRI targeted biopsy than systematic biopsy. However, the concordance between the Gleason score on fusion biopsy and radical prostatectomy is less well known. The objective of this study is to look for predictors of histopathologic concordance between biopsy (fusion and systematic) and radical prostatectomy. Methods: We used an institutional database of men who underwent mpMRI-ultrasound fusion targeted and systematic biopsy followed by radical prostatectomy. Gleason score on targeted, systematic and combination (targeted + systematic) biopsy were compared with Gleason score on radical prostatectomy, and concordance was recorded. The McNemar test was used to compare concordance and upgrade rates. Predictors of concordance and upgrade such as age, prostate volume, PSA, PSA density, Gleason score on biopsy, number of targets reported on mpMRI, and PI-RADS score were evaluated with Fisher’s exact test and logistic regression. Results: Surgical pathology was concordant with 47.4% of systematic biopsies, 52.0% of targeted biopsies and 58.4% of combination biopsies. There was no significant difference in concordance rates between systematic and targeted biopsy (P = 0.37). However, combination biopsy was superior to both systematic (RR 1.23, 95% CI 1.08-1.40, P = 0.03) and targeted biopsy (RR 1.12, 95% CI 1.02 – 1.24, P = 0.03) in predicting concordance with surgical pathology. Risk of upgrade to a higher Gleason score on surgical pathology was significantly lower with combination biopsy compared to systematic (RR 0.57, 95% CI 0.46-0.69, P &lt; 0.001) or targeted biopsy alone (RR 0.72, 95% CI 0.61-0.84, P = 0.001). Upgrade rates were 43.9% for systematic biopsy, 34.7% for targeted, and 24.9% for combination. Lastly, we found no significant predictors of concordance or upgrade. Conclusions: Combination biopsy is associated with the highest concordance rate between biopsy and radical prostatectomy when compared with systematic or targeted biopsy alone. Performing targeted biopsy alone will underestimate tumour aggressiveness on surgical pathology.