tbuckley/cabot-search huggingface dataset:
Complex biologic heterogeneity of <i>de novo</i> hormone naïve metastatic prostate cancer (HNPCa): Comparison of early progressors and prolonged responders to initial systemic treatment.
Authors: Brian Francis Chapin, Xuemei Wang, Miao Zhang, Paul Gettys Corn, Amado J. Zurita, Mohamed A Elsheshtawi, John W. Davis, Curtis Alvin Pettaway, Mehrad Adibi, Martin Gleave, Matthew R. Cooperberg, Marc C. Smaldone, Sean Eric Mcguire, Shi-Ming Tu, Jennifer Wang, Sumit Kumar Subudhi, Eleni Efstathiou, Christopher Logothetis, Patricia Troncoso, Ana Aparicio
Journal: Journal of Clinical Oncology (2019)

5055 Background: Given the absence of biologically based biomarkers current therapy allocation strategies for men with mHNPCa are based on anatomic distribution and volume of metastases. We sought to determine the strength of the association between clinical predictors (including met volume) and outcomes in men with mHNPCa at extremes of response to initial systemic therapy (ST). Methods: Data from a population screened for a phase II trial of Best ST +/- local therapy in mHNPCa was analyzed (NCT01751438). Pts had to have sustained responses to ST (≥6 mos) in order to be randomized. Early Progressors (EP, castration resistant progression &lt;6 mos from start of ST per PCWG2) were not randomized. Prolonged Responders (PR) were defined as those with progression free survivals (PFS) &gt; median for the 109 randomized pts. Baseline demographics were compared between groups (Fisher’s exact test for categorical and Wilcoxon rank-sum test for continuous variables) and Kaplan Meier estimates of OS determined. Immunohistochemistry and genomic sequencing of untreated tumor biopsies are ongoing. Results: Of 208 screened pts, 27 (13%) were identified as EPs, with a median PFS of 5.9 mos (95%CI: 5.3-6.5). The median PFS for the randomized cohort was 16.8 mos (95%CI: 12.7-37.6). 55 (50%) pts were identified as PRs, with median PFS not reached (NR) at a median follow up of 31 mos (range: 7.5-75). Patients’ demographics are below (Table), grouped by EP and PR cohorts. Median OS was 24.8 mos vs NR in the Eps compared to PRs (p&lt;0.001). Conclusions: The EP group was enriched for high risk features and had a worse outcome. However, 33% of men in the EP group had low volume disease and 22% in the PR group had high volume disease. This suggests that clinical volume is an inadequate predictor of biologic response and highlights the need for biologic sub-typing of de novo mHNPCa. [Table: see text]
Erythrocytic α-Synuclein as a potential biomarker for Parkinson’s disease
Authors: Chen Tian, Genliang Liu, Liyan Gao, David Soltys, Catherine Pan, Tessandra Stewart, Min Shi, Zhiying Xie, Na Liu, Tao Feng, Jing Zhang
Journal: Translational Neurodegeneration (2019)

Erythrocytes are a major source of peripheral α-synuclein (α-Syn). The goal of the current investigation is to evaluate erythrocytic total, oligomeric/aggregated, and phosphorylated α-Syn species as biomarkers of Parkinson's disease (PD). PD and healthy control blood samples were collected along with extensive clinical history to determine whether total, phosphorylated, or aggregated α-Syn derived from erythrocytes (the major source of blood α-Syn) are more promising and consistent biomarkers for PD than are free α-Syn species in serum or plasma. Using newly developed electrochemiluminescence assays, concentrations of erythrocytic total, aggregated and phosphorylated at Ser129 (pS129) α-Syn, separated into membrane and cytosolic components, were measured in 225 PD patients and 133 healthy controls and analyzed with extensive clinical measures. The total and aggregated α-Syn levels were significantly higher in the membrane fraction of PD patients compared to healthy controls, but without alterations in the cytosolic component. The pS129 level was remarkably higher in PD subjects than in controls in the cytosolic fraction, and to a lesser extent, higher in the membrane fraction. Combining age, erythrocytic membrane aggregated α-Syn, and cytosolic pS129 levels, a model generated by using logistic regression analysis was able to discriminate patients with PD from neurologically normal controls, with a sensitivity and a specificity of 72 and 68%, respectively. These results suggest that total, aggregated and phosphorylated α-Syn levels are altered in PD erythrocytes and peripheral erythrocytic α-Syn is a potential PD biomarker that needs further validation.
Tumor volumetric correlation with plasma cell free DNA (cfDNA) mutation detection in metastatic lung cancers.
Authors: Justin Haseltine, Michael Offin, Mackenzie L. Myers, Alex Makhnin, Ariana Adamski, Henry Li, Mark Li, Tristan Shaffer, Samantha Henderson, Ronglai Shen, Marc Ladanyi, Maria E. Arcila, David Randolph Jones, Valerie W. Rusch, Charles M. Rudin, James M. Isbell, Bob T. Li, Andreas Rimner
Journal: Journal of Clinical Oncology (2019)

e14610 Background: In patients with metastatic lung cancers, analysis of cfDNA is increasingly used to detect oncogenes, frequently allowing matched targeted therapy. Mutation detection in cfDNA may be influenced by several factors, such as disease burden. We hypothesized that volumetrics, as routinely analyzed during radiation simulation, correlates with mutation detection in cfDNA. Methods: Patients underwent cfDNA analysis between 10/2016 and 1/2018. Those with metastatic NSCLC, adequate imaging for volumetric analysis (PET/CT and MRI brain), and who were treatment naïve at plasma draw were included. Plasma underwent a 21-gene next generation sequencing assay (Resolution Bioscience). A single observer segmented tumor volumes. Volume of disease was correlated with mutation detection in cfDNA for all 21 genes including the 8 NCCN oncogenes (EGFR, ALK, ROS1, BRAF, KRAS, HER2, RET, MET) with univariate Mann-Whitney. Results: Of the 210 pts with plasma, 52 met inclusion criteria. There were 22 males (42%), median age 67yo (IQR 59-74), 24 former smokers (median pack-years: 25), 44 adenocarcinomas (85%), 21 matched to targeted therapy based on cfDNA results (40%), and median cfDNA extracted concentration was 1.56 ng/mL (IQR 1.1 – 2.6 ng/mL). Involved sites included lymph nodes (n = 43), bone (n = 25), brain (n = 15), liver (n = 13), and adrenals (n = 12). Median total tumor volume was 67.0 mL (IQR 36.6-184.6 mL). When evaluating all 21 genes, cfDNA was mutation positive in 40 pts and negative in 12 pts. Median tumor volume was 77.6 mL and 40.4 mL for positive and negative, respectively (p = 0.12). For the 8 NCCN oncogenes, cfDNA was positive in 18 pts and negative in 34 pts. Median tumor volume was 105.3 mL and 67.0 mL for positive and negative, respectively (p = 0.40). Conclusions: Volumetric analysis showed there was a non-significant trend toward larger tumor volume among pts with positive cfDNA mutation detection. As the use of cfDNA continues to expand into earlier disease stage settings, volumetrics at diagnosis may become an increasingly important tool to help predict cfDNA mutation detection to guide targeted therapy. Further studies of volumetrics and cfDNA analysis are warranted.
Association of disease prognostic model (PM) with baseline quality of life (QOL) in metastatic castration resistant prostate cancer (mCRPC).
Authors: Anna Prizment, Susan Halabi, Sean McSweeney, Amy Eisenberg, Arpit Rao, Shilpa Gupta, Alicia K. Morgans, Charles J. Ryan
Journal: Journal of Clinical Oncology (2019)

e16579 Background: PM’s in mCRPC accurately predict survival, but little is known about their association with QOL. We hypothesize that pre-treatment QOL is inversely correlated with PM derived scores. Our study explored associations between baseline Halabi PM derived risk score (including metastatic site, opioid use, ECOG performance status (ECOG PS), Alk phos, albumin, hemoglobin, LDH, and PSA) and multiple QOL domains at treatment initiation with docetaxel and prednisone (DP). Methods: The DP arm of MAINSAIL, a multicenter, randomized Phase 3 study of DP +/- lenalidomide in mCRPC, was analyzed via ProjectDataSphere. Halabi PM score was computed as continuous with higher score reflecting worse survival and classified as low- ( &lt; 140 points), intermediate- (140-194.96) or high-risk groups ( &gt; 194.96 points). QOL tests included FACT-P (higher score = better QOL), BPI-SF Severity score (BPI-SFSS; higher score = higher pain severity); and BPI-SF Interference score (BPI-SFIS, higher score = worse pain). General linear regression model was used to calculate beta estimates and 95% confidence intervals. Results: The sample included 526 mCPRC pts (median 68 years, White: 91.9%, Black: 5.3%, median PSA 75.95 ng/ml). Median [range] for FACT-P, BPI-SFSS and BPI-SFIS were 111 [0-152], 1.8 [0-9.3], and 1.4 [0-10], respectively. PM score was correlated with BPI-SFIS and BPI-SFSS and inversely correlated with FACT-P with correlation of 0.36, 0.31 and -0.33, respectively (all p &lt; 0.0001). For each unit increase in the PM score, BPI-SFIS increased by 2.1 points), BPI-SFSS increased by 1.5 points, and FACT-P decreased by 16.4 points. Using the three-risk groups, pts in the intermediate and high-risk groups had worse FACT-P QOL and higher BPI-SFIS and BPI-SFSS than pts in the low-risk group. In multivariate analysis, factors negatively impacting FACT-P QOL, BPI-SFSS and BPI-SFIS were higher ECOG PS, visceral metastases and opioid use. Declining hemoglobin levels were associated with increased BPI-SFSS and BPS-SFIS. Conclusions: Higher PM scores are associated with a lower baseline QOL overall, higher pain and higher pain interference. These results should be validated prospectively.
Immunohistochemical evaluation of Cyclin D1 and β-Catenin expression in subtypes of triple-negative breast cancer.
Authors: Tatiana N. Gudtskova, Larisa N. Vashchenko, Nikolay S. Karnaukhov, Mramza V. Kvarchiya, Ekaterina S. Bosenko, Natalya S. Saforyan, Roza G. Luganskaya
Journal: Journal of Clinical Oncology (2019)

e12553 Background: The purpose of the study was to reveal characteristics of Cyclin D1 and β-Catenin expression in subtypes of triple negative breast cancer (TNBC). Methods: The study included 60 patients diagnosed with verified TNBC (T1N1M0/T2N0M0, ER-/PR-/Her2-). Immunohistochemical staining with CK5/6, EGFR, Cyclin D1, β-Catenin antibodies was performed. Basal-like (BL) subtype was identified when &gt; 25% cells were CK5/6+ and/or EGFR+ (any staining). The expression of β-Catenin was assessed by its location: the membrane, cytoplasm, nucleus. Cells with negative staining on the membrane and cytoplasmic staining were counted and calculated as a percentage of the total number of tumor cells. Nuclear expression of β-Catenin was considered positive with at least 1 positively stained cell in the field of view at x200 magnification. Parametric statistical methods were used. Significance of the difference between the two means was assessed by the Student's t-test. Results: A number of TNBC samples showed Cyclin D1 overexpression. The loss of β-Catenin on the cell membrane and its abnormal accumulation in the cytoplasm was significantly more frequent in TNBC with Cyclin D1 overexpression. These processes were more pronounced in BL cancers. Loss of membrane expression in BL cancers: 29.6±6.1 and 58±7.4%; accumulation in the cytoplasm: 33.4±5.4 and 63.3±7.2%, with low and high Cyclin D1 respectively. Loss of membrane expression in non-BL cancers: 17.6±3.8 and 33.3±4.3%; accumulation in the cytoplasm: 27.3±6.3 and 49.5±8.2%, with low and high Cyclin D1 respectively. Only BL TNBC demonstrated β-catenin translocation to the nucleus (up to 20 stained cells in the field of view): in 33.3% tumors with Cyclin D1 overexpression and in 12% of tumors with its low expression. Conclusions: Levels of expression of β-catenin and Cyclin D1 in TNBC may have predictive value, and the choice of these biomarkers as targets will improve the treatment with new-generation medications.
Meta-analysis utilizing public data suggests role of innate immunity in the pathogenesis of hurthle cell carcinoma (HCC).
Authors: David Allen, Ross Wanner, Sean McDermott, Jihad Aljabban, Saad Syed, Charles Elmaraghy, Dexter Hadley
Journal: Journal of Clinical Oncology (2019)

e13048 Background: Hurthle Cell Carcinoma (HCC), a variant of follicular thyroid carcinoma, is a rare form of thyroid cancer. Though it accounts for 3-10% of thyroid cancer cases, very little is known about its pathogenesis. While HCC holds good survival rates, it is still vital to understand the pathogenesis of HCC in order to further optimize treatment protocols. Methods: We tagged 46 HCC samples and 90 healthy thyroid samples as a control. Gene signatures were analyzed in Ingenuity Pathway Analysis, using statistical significance p &lt; 0.05 and absolute log ratio &gt; 0.5 between disease and controls. Methods: Search Tag Analyze Resource was employed to conduct meta-analysis using the National Center for Biotechnologys Gene Expression Omnibus to define HCC pathogenesis. Results: Hepatic fibrosis, hepatic stellate cell activation and retinoic acid receptor (RAR) activation were the top canonical activators associated with HCC. Of the molecules involved, Defensin Beta 1 (DEFB1), Lipocalin-2 (LCN2), Aldehyde Dehydrogenase 1 Family Member A3 (ALDH1A3), and CDC28 Protein Kinase Regulatory Subunit 2 (CKS2) had the highest associations with HCC. The most down-regulated molecules were Hemoglobin Subunit Beta (HBB), Hemoglobin Subunit Alpha 1 and 2 (HBA1/HBA2), Cellular Retinoic Acid Binding Protein 1 (CRABP1), and BH3-Interacting Domain-Containing Protein 3 (HRK). Conclusions: These results suggest that there are a variety of factors at play regarding the development of HCC. Defensins are peptides made by neutrophils, however DEFB1 is specifically known for its ability to resist bacterial growth on epithelial surfaces, playing a major role in innate immunity. LCN2 is also known for resisting growth on surfaces and does so by sequestering iron-containing siderophores, thus effectively stopping growth of microorganisms. Additionally, ALDH1A3 and CRABP1 are associated with RAR activation. While the exact pathogenesis of HCC is not well known yet, we demonstrate that the two most up-regulated factors in HCC are strongly involved in innate immunity. This suggests that the dysfunction of innate immunity may play a vital role in the neoplastic pathogenesis of HCC.
Generation of monocyte-derived tumor-associated macrophages using tumor-conditioned media provides a novel method to study tumor-associated macrophages in vitro
Authors: Brooke Benner, Luke Scarberry, Lorena P. Suarez-Kelly, Megan C. Duggan, Amanda R. Campbell, Emily Smith, Gabriella Lapurga, Kallie Jiang, Jonathan P. Butchar, Susheela Tridandapani, John Harrison Howard, Robert A. Baiocchi, Thomas A. Mace, William E. Carson
Journal: Journal for ImmunoTherapy of Cancer (2019)

Tumor-associated macrophages (TAM) are expanded and exhibit tumor-promoting properties within the tumor microenvironment. Current methods to study TAM have not been replicated across cancer types and often do not include exogenous growth factors from the tumor, a key factor in TAM differentiation in vivo.In this study, an in vitro method to generate monocyte- derived TAM using tumor- conditioned media (TCM) and a cytokine cocktail containing IL-4, IL-10, and M-CSF was utilized to study the phenotype, morphology, and function of TAM across multiple cancer types. TCM was generated from two breast cancer cell lines and an Epstein-Barr virus-positive lymphoma cell line. The properties of in vitro generated TAM were compared to in vitro generated M1 and M2- like macrophages and TAM isolated from patients with cancer.TAM generated in this fashion displayed an increase in CD163/CD206 co-expression compared to M2- like macrophages (87 and 36%, respectively). TAM generated in vitro exhibited increased transcript levels of the functional markers IL-6, IL-10, CCL2, c-Myc, iNOS, and arginase compared to in vitro generated M2-like macrophages. Functionally, in vitro generated TAM inhibited the proliferation of T cells (47% decrease from M1-like macrophages) and the production of IFN-γ by natural killer cells was inhibited (44%) when co-cultured with TAM. Furthermore, in vitro generated TAM secreted soluble factors that promote the growth and survival of tumor cells.Limited access to patient TAM highlights the need for methods to generate TAM in vitro. Our data confirm that monocyte-derived TAM can be generated reliably using TCM plus the cytokine cocktail of IL-4, IL-10, and M-CSF. Given the ability of TAM to inhibit immune cell function, continued study of methods to deplete or deactivate TAM in the setting of cancer are warranted.
Case 43-1984
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, P. M. Mauch, N. L. Harris
Journal: New England Journal of Medicine (1984)

Presentation of CaseA 35-year-old woman was admitted to the hospital because of tracheal stenosis.She was well until five years earlier, when she began to experience pruritus. Three years later cough and cervical lymphadenopathy developed. She was seen at another hospital, where examination of a lymph-nodebiopsy specimen showed Hodgkin's disease, nodularsclerosis type. Fever developed, and she was transferred to a cancer center, where examination revealed diffuse excoriations and bilateral cervical and axillary lymphadenopathy. X-ray films of the chest (Fig. 1) showed a mediastinal mass that occupied at least half of the transverse thoracic diameter; most of the mass lay . . .
Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: Findings from the multinational, randomized, phase III NALA trial.
Authors: Cristina Saura, Mafalda Oliveira, Yin-Hsun Feng, Ming-Shen Dai, Sara A. Hurvitz, Sung-Bae Kim, Beverly Moy, Suzette Delaloge, William John Gradishar, Norikazu Masuda, Marketa Palacova, Maureen E. Trudeau, Johanna Mattson, Yoon Sim Yap, Richard Bryce, Bin Yao, Judith D. Bebchuk, Kiana Keyvanjah, Adam Brufsky
Journal: Journal of Clinical Oncology (2019)

1002 Background: NALA (ClinicalTrials.gov NCT01808573) is a multinational, randomized, open-label, phase III trial of neratinib (an irreversible pan-HER tyrosine kinase inhibitor [TKI]) + capecitabine (N+C) vs lapatinib (a reversible dual TKI) + capecitabine (L+C) in patients with stage IV HER2+ metastatic breast cancer (MBC) who had received ≥2 prior HER2-directed regimens for MBC. Methods: Patients were randomized 1:1 to N (240 mg qd po) + C (750 mg/m 2 bid po) or L (1250 mg qd po) + C (1000 mg/m 2 bid po). Co-primary endpoints were centrally assessed progression-free survival (PFS) and overall survival (OS). Secondary endpoints were investigator-assessed PFS; objective response rate (ORR); duration of response (DoR); clinical benefit rate (CBR); time to intervention for symptomatic metastatic central nervous system (CNS) disease; safety; and patient-reported health outcomes. Results: 621 patients were randomized (307 to N+C; 314 to L+C). The risk of disease progression or death was reduced by 24% with N+C vs L+C (HR = 0.76; 95% CI 0.63–0.93; p = 0.006); 6- and 12-month PFS rates were 47.2% vs 37.8% and 28.8% vs 14.8% for N+C vs L+C, respectively. OS rates at 6 and 12 months were 90.2% vs 87.5% and 72.5% vs 66.7% for N+C vs L+C, respectively (HR = 0.88; 95% CI 0.72–1.07; p = 0.2086). ORR in patients with measurable disease at screening was improved with N+C vs L+C (32.8% vs 26.7%; p = 0.1201), as was CBR (44.5% vs 35.6%; p = 0.0328) and DoR (HR = 0.50; 95% CI 0.33–0.74; p = 0.0004). Time to intervention for symptomatic CNS disease (overall cumulative incidence 22.8% vs 29.2%; p = 0.043) was delayed with N+C vs L+C. Treatment-emergent adverse events (TEAEs) were similar between arms, but there was a higher rate of grade 3 diarrhea with N+C vs L+C (24.4% vs 12.5%). TEAEs leading to neratinib/lapatinib discontinuation were lower with neratinib (10.9%) than with lapatinib (14.5%). Conclusions: N+C significantly improved PFS with a trend towards improved OS vs L+C. N+C also resulted in a delayed time to intervention for symptomatic CNS disease. Tolerability was similar between the two arms, with no new safety signals observed. Clinical trial information: NCT01808573.
Haemophagocytic lymphohistiocytosis in patients treated with immune checkpoint inhibitors: analysis of WHO global database of individual case safety reports
Authors: Roberta Noseda, Raffaela Bertoli, Laura Müller, Alessandro Ceschi
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Immune checkpoint inhibitor (ICI) use in clinical practice has unravelled a spectrum of immune-related adverse events (irAEs) due to immune system hyper-activation. ICI-related haemophagocytic lymphohistiocytosis (HLH) has been recently outlined in single case reports, raising a concern about the need of increasing our knowledge on this rare yet life threatening ICI haematological toxicity. <h3>Methods</h3> To determine ICI-related HLH clinical, haematological, and coagulation features, its timing and outcome, concurrent irAEs and concomitant infections, we performed a retrospective observational cross-sectional study and queried VigiBase, the WHO global database of suspected adverse drug reactions (ADRs), on September 30th, 2018. We retrieved the individual case safety reports reporting HLH in association with ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab or durvalumab, gathered in the database starting from the ICIs' approval dates by the US Food and Drug Administration. The main outcome measures were co-suspected drugs, concurrent irAEs, HLH clinical, haematological and coagulation features, concomitant infections, HLH median time to onset and outcome. <h3>Results</h3> Among 49′883 ICI-related ADRs collated in VigiBase as of September 30th, 2018, HLH was reported in 38 cases of which 34 (90%) mentioned ICIs as the solely suspected drugs. ICI-related HLH showed clinical, haematological and coagulation features similar to those of HLH with different etiology. Concurrent irAEs occurred in 5 (13%) patients and 6 (16%) reported concomitant viral infections. 31 (82%) cases defined ICI-related HLH outcome, which resolved in 19 (61%) cases. HLH developed a median of 6.7 weeks after initiation of ICI treatment (IQR 2.9–15.4, <i>n</i>&nbsp;= 18, 47%). <h3>Conclusions</h3> By evaluating the largest cohort of ICI-related HLH cases, we observed that ICI-related HLH arises with a delayed timing with respect to initiation of ICI treatment, and usually presents without other irAEs and concomitant infections. Keeping in mind these findings, clinicians should consider ICIs' involvement in the onset of HLH whenever they diagnose a disease of this group of syndromes in cancer patients treated with ICIs.
A Pharmacodynamic Evaluation of Switching From Ticagrelor to Prasugrel in Patients With Stable Coronary Artery Disease: Results of the SWAP-2 Study
Authors: Dominick J. Anaiolillo, Nicholas Curzen, Paul A. Gurbel, Paul Vaitkus, Fred Lipkin, Wei Li, Joseph A. Jakubowski, Marjorie Zettler, Mark B. Effron, Dietmar Trenk
Journal: Circulation (2013)
Abstract 14962: United States Health Care Utilization and Comorbidities Among Adults With Congenital Heart Disease
Authors: Anushree Agarwal, Ian S Harris, Zian H Tseng, Robert Thombley, Vaikom S Mahadevan, Raymond A Dudley
Journal: Circulation (2017)

Introduction: The number of adults with congenital heart disease (CHD) is rapidly growing worldwide yet their health care needs as a population, especially in the United States, has not yet been de...