tbuckley/cabot-search huggingface dataset:
Characterization of the inflammatory infiltrate and association with expression of PD-1, PDL1 and PDL2 and survival in triple-negative mammary carcinoma.
Authors: Monique Celeste Tavares, Vladmir Cordeiro Lima, Victor Piana Andrade, Rachel Simoes Riechelmann, Mariana Petaccia
Journal: Journal of Clinical Oncology (2018)

1099 Background: However, recent evidences suggest that lymphocyte infiltration in tumors (LIT), which is presented in breast cancer prior to the treatment, may predict response to the therapy and a better prognosis. Not only the intensity of lymphocyte infiltration, but also the phenotype of that infiltrate, determine the clinical outcome.Objectives:To evaluate the intensity and composition of the LIT in an operated TNBC and its association with the expression of PD-1, PD-L1 and PD-L2. Methods: This is an observational, descriptive and a retrospective cohort study. The studied population consisted of patients diagnosed with invasive TNBC. Results: LIT was evaluated in 165 patients. The mean intensity of the inflammatory infiltrate was 20%.We observed that 47 (28%) had inflammatory infiltrate ≤5%, 86 (52%) between 5 and 50% and 32 (19%) > 50%. The average OS in each group was, respectively, 85 months, 104 months and 148 months (p = 0.002). We established an ideal cutoff point of 5% of LIT for OS analysis, so that average overall survival was 85 months for patients with LIT≤5% and 136 months for those with infiltrate > 5% (p = 0.001) . We included 76 cases in the TMA for IHC analysis. We established an optimal cutoff point of 5% in this group, we observed that the majority 56 (78.87%) had an inflammatory infiltrate > 5%. With a tendency to benefit in specific cancer survival, for patients with inflammatory infiltrate > 5%, but with no statistical significance. We found an average of 4 and 12% expression of tumor-free PD-L1 and no stroma, respectively. The cutoff point for the labeling of PD-L1 in the stroma was 5%, with 17 (22.4%) presenting > 5% and 31 (40.8%) ≤5%; and in tumor was 1%, with 11 (14.5%) > 1% and 51 (67%) ≤1%. There was no association between PD-L1 expression and OS. We found a positive and statistically significant correlation of LIT with labeling PD-L1 in stroma (p = 0.001) and in tumor (p = 0.028). Conclusions: In TNBC, TII above 5% is associated with the increasing of OS. TII is associated with a number of cells labeled positively for PD-L1 both in stroma and in tumor. PD-L1 was not associated with OS. Increased number of FOXP3+ and of PTEN marking cells are associated with better OS.
Breast cancer cell-free DNA (cfDNA) profiles reflect underlying tumor biology: The Circulating Cell-Free Genome Atlas (CCGA) study.
Authors: Minetta C. Liu, Tara Maddala, Alex Aravanis, Earl Hubbell, John F. Beausang, Darya Filippova, Samuel Gross, Arash Jamshidi, Kathryn Kurtzman, Ling Shen, Anton Valouev, Oliver Venn, Nan Zhang, David A. Smith, Fergus Couch, Christina Curtis, Richard Thomas Williams, Eric A. Klein, Anne-Renee Hartman, Jose Baselga
Journal: Journal of Clinical Oncology (2018)

536 Background: New breast cancer screening approaches are needed to detect clinically aggressive subtypes that may not be detected by mammography or are detected late in unscreened populations. CCGA (NCT02889978) is a prospective multi-center observational study for the development of a noninvasive assay for cancer detection. A preplanned substudy of a Women-Only Cohort is reported. Methods: Blood was prospectively collected (N = 1627) from 878 participants (pts) with newly diagnosed untreated cancer (20 tumor types, all stages) and 749 pts with no cancer diagnosis (controls, C) for plasma cfDNA extraction. This substudy included 358 pts with invasive breast cancer (IBC) and 452 C. Three prototype sequencing assays were performed: paired cfDNA and white blood cell (WBC) targeted sequencing (507 genes, 60,000X) for single nucleotide variants/indels, paired cfDNA and WBC whole genome sequencing (WGS, 30X) for copy number variation, and cfDNA whole genome bisulfite sequencing (WGBS, 30X) for methylation; WBC sequencing identified the contribution of clonal hematopoiesis (CH). For each assay, a classification model using 10-fold cross-validation was developed to discriminate IBC from C using a subset of women; sensitivity was estimated at 95% specificity. Results: IBC pts and C had similar age (mean yrs±SD: 58±13 IBC, 59±12 C). 46% of IBC pts were symptomatic (a subset were documented interval cancers), 82% were stage I/II. The subtype breakdown of HR+/HER2+/triple-negative breast cancer (TNBC) was 65%/17%/15%. WGBS returned the highest sensitivity of the 3 assays and is reported here; results were consistent across all assays. Sensitivity (95% CI) was higher for TNBC vs HER2+ vs HR+/HER2- (58% [43-72] vs 40% [28-54] vs 15% [10-20]), and higher for symptomatic vs screen-detected breast cancer (44% [36-52] vs 10% [6-16]). Comparison to tumor WGS and multi-assay classification will be reported. Conclusions: Breast cancers with detectable cfDNA signals at time of diagnosis included clinically aggressive subtypes and symptomatic presentation. Further assay and clinical development in the intended use population is ongoing (NCT03085888). Clinical trial information: NCT02889978.
Nuclear functions of mammalian MicroRNAs in gene regulation, immunity and cancer
Authors: Hongyu Liu, Cheng Lei, Qin He, Zou Pan, Desheng Xiao, Yongguang Tao
Journal: Molecular Cancer (2018)

MicroRNAs (miRNAs) are endogenous non-coding RNAs that contain approximately 22 nucleotides. They serve as key regulators in various biological processes and their dysregulation is implicated in many diseases including cancer and autoimmune disorders. It has been well established that the maturation of miRNAs occurs in the cytoplasm and miRNAs exert post-transcriptional gene silencing (PTGS) via RNA-induced silencing complex (RISC) pathway in the cytoplasm. However, numerous studies reaffirm the existence of mature miRNA in the nucleus, and nucleus-cytoplasm transport mechanism has also been illustrated. Moreover, active regulatory functions of nuclear miRNAs were found including PTGS, transcriptional gene silencing (TGS), and transcriptional gene activation (TGA), in which miRNAs bind nascent RNA transcripts, gene promoter regions or enhancer regions and exert further effects via epigenetic pathways. Based on existing interaction rules, some miRNA binding sites prediction software tools are developed, which are evaluated in this article. In addition, we attempt to explore and review the nuclear functions of miRNA in immunity, tumorigenesis and invasiveness of tumor. As a non-canonical aspect of miRNA action, nuclear miRNAs supplement miRNA regulatory networks and could be applied in miRNA based therapies.
Progress in achieving quantitative classification of psychopathology
Authors: Robert F. Krueger, Roman Kotov, David Watson, Miriam K. Forbes, Nicholas R. Eaton, Camilo J. Ruggero, Leonard J. Simms, Thomas A. Widiger, Thomas M. Achenbach, Bo Bach, R. Michael Bagby, Marina A. Bornovalova, William T. Carpenter, Michael Chmielewski, David C. Cicero, Lee Anna Clark, Christopher Conway, Barbara DeClercq, Colin G. DeYoung, Anna R. Docherty, Laura E. Drislane, Michael B. First, Kelsie T. Forbush, Michael Hallquist, John D. Haltigan, Christopher J. Hopwood, Masha Y. Ivanova, Katherine G. Jonas, Robert D. Latzman, Kristian E. Markon, Joshua D. Miller, Leslie C. Morey, Stephanie N. Mullins‐Sweatt, Johan Ormel, Praveetha Patalay, Christopher J. Patrick, Aaron L. Pincus, Darrel A. Regier, Ulrich Reininghaus, Leslie A. Rescorla, Douglas B. Samuel, Martin Sellbom, Alexander J. Shackman, Andrew Skodol, Tim Slade, Susan C. South, Matthew Sunderland, Jennifer L. Tackett, Noah C. Venables, Irwin D. Waldman, Monika A. Waszczuk, Mark H. Waugh, Aidan G.C. Wright, David H. Zald, Johannes Zimmermann
Journal: World Psychiatry (2018)

Shortcomings of approaches to classifying psychopathology based on expert consensus have given rise to contemporary efforts to classify psychopathology quantitatively. In this paper, we review progress in achieving a quantitative and empirical classification of psychopathology. A substantial empirical literature indicates that psychopathology is generally more dimensional than categorical. When the discreteness versus continuity of psychopathology is treated as a research question, as opposed to being decided as a matter of tradition, the evidence clearly supports the hypothesis of continuity. In addition, a related body of literature shows how psychopathology dimensions can be arranged in a hierarchy, ranging from very broad "spectrum level" dimensions, to specific and narrow clusters of symptoms. In this way, a quantitative approach solves the "problem of comorbidity" by explicitly modeling patterns of co-occurrence among signs and symptoms within a detailed and variegated hierarchy of dimensional concepts with direct clinical utility. Indeed, extensive evidence pertaining to the dimensional and hierarchical structure of psychopathology has led to the formation of the Hierarchical Taxonomy of Psychopathology (HiTOP) Consortium. This is a group of 70 investigators working together to study empirical classification of psychopathology. In this paper, we describe the aims and current foci of the HiTOP Consortium. These aims pertain to continued research on the empirical organization of psychopathology; the connection between personality and psychopathology; the utility of empirically based psychopathology constructs in both research and the clinic; and the development of novel and comprehensive models and corresponding assessment instruments for psychopathology constructs derived from an empirical approach.
Abstract 18338: Efficacy and Safety of the ICD in ARVC Patients
Authors: Andrea Mazzanti, Kevin Ng, Riccardo Maragna, Alessandro Faragli, Nicola Monteforte, Raffaella Bloise, Carlo Napolitano, Vincenzo Bagnardi, Silvia G Priori
Journal: Circulation (2016)

Introduction: Implantable Cardioverter Defibrillators (ICD) are used to prevent Sudden Cardiac Death (SCD) in patients with Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), but data on their...
Hygienic behavior and allergic sensitization in German adolescents
Authors: G. Bowatte, I. Markevych, M. Standl, S. C. Dharmage, S. Koletzko, I. Lehmann, C.‐P. Bauer, T. Schikowski, A. von Berg, D. Berdel, J. Heinrich
Journal: Allergy (2018)

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STAT3 labels a subpopulation of reactive astrocytes required for brain metastasis
Authors: Neibla Priego, Lucía Zhu, Cátia Monteiro, Manon Mulders, David Wasilewski, Wendy Bindeman, Laura Doglio, Liliana Martínez, Elena Martínez-Saez, Santiago Ramón y Cajal, Diego Megías, Elena Hernández-Encinas, Carmen Blanco-Aparicio, Lola Martínez, Eduardo Zarzuela, Javier Muñoz, Coral Fustero-Torre, Elena Piñeiro-Yáñez, Aurelio Hernández-Laín, Luca Bertero, Valeria Poli, Melchor Sanchez-Martinez, Javier A. Menendez, Riccardo Soffietti, Joaquim Bosch-Barrera, Manuel Valiente
Journal: Nature Medicine (2018)
Nutrition and Inflammation: Are Centenarians Similar to Individuals on Calorie-Restricted Diets?
Authors: Claudio Franceschi, Rita Ostan, Aurelia Santoro
Journal: Annual Review of Nutrition (2018)

Individuals capable of reaching the extreme limit of human life such as centenarians are characterized by an exceptionally healthy phenotype—that is, a low number of diseases, low blood pressure, optimal metabolic and endocrine parameters, and increased diversity in the gut microbiota—and they are epigenetically younger than their chronological age. We present data suggesting that such a remarkable phenotype is largely similar to that found in adults following a calorie-restricted diet. Interviews with centenarians and historical data on the nutritional and lifestyle habits of Italians during the twentieth century suggest that as children and into adulthood, centenarians lived in an environment that was nonobesogenic, but at the same time the environment did not produce malnutrition. Centenarians appear to be creatures of habit, and we argue that their habit of eating meals at the same time each day favored the maintenance of circadian rhythms, including their sleep cycle. Finally, we argue that centenarians’ chronic inflammatory status, which we dubbed inflammaging, is peculiar, likely adaptive, and less detrimental than in younger people.
Anti-tumor activity of PM1183 (lurbinectedin) in combination with capecitabine in metastatic breast cancer patients: Results from a phase I trial.
Authors: Ahmad Awada, Philippe Georges Aftimos, Emiliano Calvo, Valentina Boni, Victor Moreno, Bernard Doger, Xarles Erik Luepke, Katrin Zaragoza, Mariano Siguero, Carmen Maria Kahatt, Arturo Soto-Matos, Tamara Sauri, Josep Tabernero
Journal: Journal of Clinical Oncology (2018)

1072 Background: PM1183 (lurbinectedin, Zepsyre) is a new anticancer drug that blocks transcription, induces DNA double-strand breaks, and modulates the tumor microenvironment. Single-agent PM1183 has antitumor activity in various solid tumors, including metastatic breast cancer (MBC), and pre-clinical synergism/additivity with fluoropyrimidines. A phase I trial determined the recommended dose (RD) for the oral fluoropyrimidine capecitabine (XEL) as 1650mg/m2 BID Day (D) 1 to D14 plus PM1183 2.2 mg/m2 D1, every 3 weeks. Here we present results of the MBC patients (pts) treated in this trial. Methods: MBC pts with adequate organ function and < 3 prior chemotherapy lines for advanced disease were treated with PM1183+XEL until disease progression, or unacceptable toxicity. Stable asymptomatic brain metastases were allowed. Results: A total of 28 female MBC pts were treated between April 2013 and September 2016; 15 at RD. At cut-off, 5 pts (3 at RD) were still on treatment. Baseline characteristics and efficacy data are shown in Table 1. At RD, hematological toxicities consisted of neutropenia [40% grade (G) 3; 7% G4] and anemia (13% G3). No febrile neutropenia was observed. Non-hematological toxicities were generally mild to moderate, including nausea, fatigue, palmar-plantar erythrodysesthesia syndrome, diarrhea, and decreased appetite. All AEs were reversible and manageable with dose reductions, omissions and/or delays. Main dose-limiting toxicities (DLTs) at maximum tolerated dose were hematological. Conclusions: The PM1183+XEL combination showed encouraging clinical activity in MB. Further development is warranted in this indication. Clinical trial information: NCT02210364.Baseline characteristics and efficacy of PM1183+XEL. All dose levels (n= 28) RD (n= 15) Median Age (range; years) 51 (29-71) 46 (29-71) ECOG 0/1 (%) 64/36 73/27 Visceral disease (%) 96 100 HR+/triple negative (%) 71/29 60/40 Efficacy of PM1183+XEL ORR (95% CI; %) 57 (39-79) 47 (21-73) ORR of HR+ (95% CI; %) 60* (36-81) 56** (21-86) Clinical benefit rate (%) 68 67 Duration of response (95% CI; mo) 6.8 (3.9-10.2) 6.8 (1.3–not reached) Progression free survival (95% CI; mo) 7.3 (3.9-10.2) 5.5 (1.1-10.2) *12/20 pts; **5/9 pts.
Tumor infiltrating lymphocytes to predict DFS from intense dose-dense (idd) EPC regimen: Results from the German Adjuvant Intergroup Node-positive study (GAIN-1).
Authors: Aurelia Noske, Karsten Weber, Volker Moebus, Sabine Schmatloch, Wilko Weichert, Claus-Henning Kohne, Christine Solbach, Barbara Ingold Heppner, Katja Steiger, Volkmar Mueller, Peter A. Fasching, Thomas Karn, Marion van Mackelenbergh, Frederik Marme, Wolfgang D Schmitt, Christian Schem, Elmar Stickeler, Carsten Denkert, Sibylle Loibl
Journal: Journal of Clinical Oncology (2018)

527 Background: Immunogenic infiltrate in breast cancer (BC) may influence the prognosis and response to systemic therapies. The association and prognostic role of tumor infiltrating lymphocytes (TILs), PD-1 and PD-L1 expression were investigated in high-risk, node positive breast carcinomas. Methods: The prospective adjuvant phase III GAIN trial compared two dose-dense regimens, iddEPC (epirubicin (E), paclitaxel (P), cyclophosphamide (C)) vs. EC-PX (capecitabine (X)) and Ibandronate vs. observation in patients with node-positive primary breast cancer. A total of 1318 FFPE tumor samples were available for analysis of TILs by HE morphology, and PD-1, and PD-L1 by immunohistochemistry. The association of immune parameters and their prognostic and potential predictive role were analyzed by Cox regression models. The median FU was 74.3 months (range: 0.1-113.7). Results: Increased TILs, PD-1 and PD-L1 positive TILs were significantly associated with higher grade, higher Ki67, ER/PR negative and triple negative BC (each p < 0.0001). TILs and PD-L1 positive TILs were slightly more frequent in HER2 positive BC (p = 0.005). Spearman analysis revealed positive, moderate to low correlations between TILs, PD1 and PD-L1. At multivariate Cox regression analysis with clinical covariables, TILs had a significant positive impact on DFS in the iddEPC-arm (HR = 0.57 [0.39-0.84], p = 0.0043) but not in the EC-PX-arm (HR = 1.26 [0.86-1.87], p = 0.2384, interaction p = 0.0336). Especially, HR+/HER2- BC with TILs and treated with iddEPC had a better DFS compared to no TILs (HR = 0.59 [0.38-0.93], p = 0.0227). PD-1 positive TILs in TNBC were associated with a significant better DFS (HR = 0.50 [0.25-0.99], p = 0.0457). PD-L1 expression had no impact on patient outcome. Conclusions: TILs and expression of immune checkpoints are common in high-grade, highly proliferative, triple negative and in part in HER2 positive BC. Tumor infiltrating lymphocytes predict the benefit from intense dose-dense EPC whereas the prevalence and prognostic impact of PD-1 /PD-L1 seem to play an inferior role in this node-positive breast cancer cohort with adjuvant chemotherapy.
Abstract B17: Utility of MRI and PET/CT to differentiate benign versus malignant peripheral nerve sheath tumors (MPNST)
Authors: Ronnie Sebro, Paul Niziolek
Journal: Clinical Cancer Research (2018)

Abstract Aim: To assess the utility of MRI and PET/CT to differentiate benign versus malignant peripheral nerve sheath tumors (MPNST). Methods: We retrospectively identified 68 patients with histologically confirmed nerve sheath tumors. All of these patients had pretreatment magnetic resonance imaging (MRI) studies and 17 patients had pretreatment 18-fluorodeoxyglucose positron emission tomography (PET/CT). Age, history of neurofibromatosis, maximum size of the tumor, MR features, and maximum standardized uptake values (SUV) from PET/CT were obtained. We used Wilcoxon-Rank sum or Fisher's exact tests to compare benign versus malignant nerve sheath tumors. Results: There was no significant difference in the mean age of the patients with benign versus MPNST (P=0.85). Patients with NF1 had higher odds of MPNSTs (OR=26.7, P=2.6 x10-7). There was no difference in the mean size of the benign versus MPNSTs (P=0.44). Homogeneous enhancement of a lesion after intravenous contrast (OR=0.08, P=0.008) and the target sign (OR=0.0, P=0.041), were both associated with decreased odds of MPNST. Bone destruction seen on MRI (P=5.7x10-4) and an enlarged nerve (OR = 3.89, P=0.048) were associated with increased odds of MPNST. MPNSTs had significantly higher mean maximum SUV than benign nerve sheath tumors (P=0.0272). The previously published threshold maximum SUV of 3.5 had 100% sensitivity and 50% specificity to exclude MPNST as 50% (4/8) of the benign nerve sheath tumors had a maximum SUV &amp;gt;3.5. Conclusion: MRI and PET/CT are useful for differentiating benign from MPNST, but neither is specific. A maximum SUV of 3.5 is highly sensitive for identifying MPNST; however, tissue sampling is often necessary to confirm the diagnosis since using this threshold results in a large proportion of false positives. Citation Format: Ronnie Sebro, Paul Niziolek. Utility of MRI and PET/CT to differentiate benign versus malignant peripheral nerve sheath tumors (MPNST) [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr B17.
Safety and efficacy of pembrolizumab (pembro) plus capecitabine (cape) in metastatic triple negative breast cancer (mTNBC).
Authors: David B. Page, Isaac K Kim, Katherine Sanchez, Nicole Moxon, Staci L. Mellinger, Alison Katherine Conlin, Anupama Kurup Acheson, Kelly Shea Perlewitz, Stacy K. Lewis, Kathleen A. Kemmer, Zahi Ibrahim Mitri, Reva K Basho, Emily Riffle, Jenny Ahn, Joanna Pucilowska, Maritza Martel, Walter John Urba, Heather L. McArthur
Journal: Journal of Clinical Oncology (2018)

1033 Background: In mTNBC, anti-PD-1/L1 monotherapy was associated with objective response rates (ORR) of 23-26% in the first-line setting, but ORR of 5-6% in later lines. We hypothesize that concurrent pembro plus standard-of-care chemotherapy is safe, and may increase clinical benefit by allowing for earlier treatment with anti-PD-1, when tumor burden and iatrogenic immunosuppression are minimized. This is the first study to explore the combination cape with PD-1/L1 blockade in breast cancer. Methods: In a pilot/phase II study, we evaluate the tolerability and preliminary efficacy of concurrent pembro (200mg IV q21 day) plus investigator-selected 1st/2nd line paclitaxel (80mg/m2 IV weekly) or oral cape (2,000mg BID, weekly 1 on/1 off). The primary endpoint of the pilot phase is tolerability, defined as the proportion of subjects receiving > 6 weeks concurrent therapy without dose discontinuation. Toxicities are reported per CTCAE v4.0. The secondary endpoint is 12-week ORR by RECIST1.1, with potential phase II expansion according to a Simon 2-stage design (if ≥4/14 ORR). Exploratory objectives include intratumoral/peripheral immunologic assessments by T-cell receptor sequencing, multispectral immunofluorescence, and real-time multi-parametric flow cytometry. Here, we report the results of the pilot phase of the cape cohort (NCT02734290). Results: As of 1/1/2018, 100% (9/9) of safety-evaluable subjects tolerated concurrent cape+pembro for at least 6 weeks. Toxicities were generally consistent with monotherapy experience (diarrhea: grade I-II 56%; hand-foot: grade I-II 67%), and improved with dose-reduction. Partial responses have been observed in three subjects, two having metaplastic pathology. A fourth subject experienced durable stable disease, with ongoing response at 48 weeks. Conclusions: This study met the primary endpoint of safety for cape plus pembro in mTNBC and the combination will be explored for efficacy in the next stage of this study. These data may also inform the evaluation of concurrent anti-PD-1/L1 plus cape in the adjuvant setting. Clinical trial information: NCT02734290.
Pfizer pays $24m to settle kickback claims over patient assistance charity
Authors: Owen Dyer
Journal: BMJ (2018)

Pfizer will pay the US government $23.85m (£18m; €20.7m) to resolve allegations that it broke federal law by helping Medicare patients to pay their deductible on expensive Pfizer drugs so that the government would pay the rest.

Medicare prescription drug plans pay most of the drug costs for beneficiaries of the programme aged over 65, but patients are liable for a deductible or co-payment on each prescription, which cannot exceed $405 a year.

Some Medicare patients who would be discouraged from taking a drug by the co-payment can be tempted to change their mind if a benefactor pays it, thus forcing the government to bear the rest of the drug’s cost. Several drug companies have been acting as such benefactors, the US government believes, funding the co-payments on their priciest drugs through patient charities founded for that purpose—breaching the anti-kickback statute of the False Claims Act. …