tbuckley/cabot-search huggingface dataset:
Emerging therapeutic agents for genitourinary cancers
Authors: Kevin Zarrabi, Azzam Paroya, Shenhong Wu
Journal: Journal of Hematology & Oncology (2019)

The treatment of genitourinary malignancies has dramatically evolved over recent years. Renal cell carcinoma, urothelial carcinoma of the bladder, and prostate adenocarcinoma are the most commonly encountered genitourinary malignancies and represent a heterogeneous population of cancers, in both histology and approach to treatment. However, all three cancers have undergone paradigm shifts in their respective therapeutic landscapes due to a greater understanding of their underlying molecular mechanisms and oncogenic drivers. The advance that has gained the most recent traction has been the advent of immunotherapies, particularly immune checkpoint inhibitors. Immunotherapy has increased overall survival and even provided durable responses in the metastatic setting in some patients. The early success of immune checkpoint inhibitors has led to further drug development with the emergence of novel agents which modulate the immune system within the tumor microenvironment. Notwithstanding immunotherapy, investigators are also developing novel agents tailored to a variety of targets including small-molecule tyrosine kinase inhibitors, mTOR inhibitors, and novel fusion proteins to name a few. Erdafitinib has become the first targeted therapy approved for metastatic bladder cancer. Moreover, the combination therapy of immune checkpoint inhibitors with targeted agents such as pembrolizumab or avelumab with axitinib has demonstrated both safety and efficacy and just received FDA approval for their use. We are in an era of rapid progression in drug development with multiple exciting trials and ongoing pre-clinical studies. We highlight many of the promising new emerging therapies that will likely continue to improve outcomes in patients with genitourinary malignancies.
P14.42 Diagnostic challenges of infratentorial hemangioblastomas: improvement of current radiological classification scheme
Authors: I Jung, E Kim, J Moon, S Kang, J Chang
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Hemangioblastomas (HBMs) are known to exhibit very typical radiological features and thus classified by well-established radiological classification scheme. However, after we have experienced unusual cases in which current radiological classification system was not enough to categorize them, we reviewed our series of infratentorial HBMs in order not only to evaluate the relevance of current classification scheme, but also to possibly improve it. Also, we added descriptions on several cases with unusual radiological magnetic resonance imaging (MRI) findings in which differential diagnosis was challenging. MATERIAL AND METHODS We retrospectively reviewed preoperative MRI of 118 patients with pathologically diagnosed infratentorial HBMs at our institution between 2002 and 2015. Total 128 tumors were included to this study and classified into four categories based on the presence and nature of cystic components: extratumoral cystic (Type Ce, classical cystic with a mural nodule), intratumoral cystic (Type Ci), mixed cystic (Type Cm), and solid (Type S). The association with von Hippel-Lindau (VHL) disease was also investigated. RESULTS In 118 patients (65 male and 53 female), 79 (66.9%) had solitary HBMs and 39 (33.1%) were diagnosed with VHL disease. Type Ce with typical radiological findings was the most prevalent type of HBM (63.3%), followed by Type S (21.1%). HBMs with intratumoral cysts were uncommon (Type Ci, 11.7%) and mixed extratumoral and intratumoral cysts (Type Cm) accounted for only 3.9%. No intergroup differences were observed in the proportions of each subtype between the solitary and VHL disease-associated HBMs. CONCLUSION Radiological features of HBMs are usually typical thus preoperative presumption is not difficult in majority of cases. Improved radiological classification scheme is more practical because it does not only help surgeons determine whether the cystic wall should be removed or not, but also covers cases with atypical radiological presentations. For solid and extraparenchymal HBMs, differential diagnosis is more difficult as well as very critical as surgical removal is often very challenging.
Single-cell transcriptional analyses of spasmolytic polypeptide-expressing metaplasia arising from acute drug injury and chronic inflammation in the stomach
Authors: Kevin A Bockerstett, Scott A Lewis, Kyle J Wolf, Christine N Noto, Nicholas M Jackson, Eric L Ford, Tae-Hyuk Ahn, Richard J DiPaolo
Journal: Gut (2019)

Spasmolytic polypeptide-expressing metaplasia (SPEM) is a regenerative lesion in the gastric mucosa and is a potential precursor to intestinal metaplasia/gastric adenocarcinoma in a chronic inflammatory setting. The goal of these studies was to define the transcriptional changes associated with SPEM at the individual cell level in response to acute drug injury and chronic inflammatory damage in the gastric mucosa.Epithelial cells were isolated from the gastric corpus of healthy stomachs and stomachs with drug-induced and inflammation-induced SPEM lesions. Single cell RNA sequencing (scRNA-seq) was performed on tissue samples from each of these settings. The transcriptomes of individual epithelial cells from healthy, acutely damaged and chronically inflamed stomachs were analysed and compared.scRNA-seq revealed a population Mucin 6 (Muc6)+gastric intrinsic factor (Gif)+ cells in healthy tissue, but these cells did not express transcripts associated with SPEM. Furthermore, analyses of SPEM cells from drug injured and chronically inflamed corpus yielded two major findings: (1) SPEM and neck cell hyperplasia/hypertrophy are nearly identical in the expression of SPEM-associated transcripts and (2) SPEM programmes induced by drug-mediated parietal cell ablation and chronic inflammation are nearly identical, although the induction of transcripts involved in immunomodulation was unique to SPEM cells in the chronic inflammatory setting.These data necessitate an expansion of the definition of SPEM to include Tff2+Muc6+ cells that do not express mature chief cell transcripts such as Gif. Our data demonstrate that SPEM arises by a highly conserved cellular programme independent of aetiology and develops immunoregulatory capabilities in a setting of chronic inflammation.
MET-PET and NGS Targeted Sequencing Guides Precision Medicine in a CNS Relapsed MM Patient
Authors: Matteo Da Via, Susanne Strifler, Santiago Barrio Garcia, Andoni Garitano Trojaola, Eva Teufel, Silvia Nerreter, A. Keith Stewart, Andreas Rosenwald, Anke Heidemeier, Constantin Lapa, Hermann Einsele, K. Martin Kortüm
Journal: Blood (2017)
P11.43 Deletions on Y chromosome are associated with shorter survival in glioblastoma
Authors: M Lysiak, A Malmström, K R Roodakker, E Sandberg, A Dimberg, M Mudaisi, C Bratthäll, M Strandéus, P Milos, M Hallbeck, A Smits, P Söderkvist
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Apart from few exceptions, men are more likely to be diagnosed with cancer during their lifetime, including glioblastoma (GBM), but the gender-related differences in GBM are poorly understood. Loss of chromosome Y (LOY) in peripheral blood cells is associated with physiological ageing, but also with disorders like cardiovascular disease, Alzheimer’s disease and different cancer types. In this study, we determined deletions on Y chromosome in tumor tissue of male patients with GBM, and studied the impact of LOY on survival. MATERIAL AND METHODS Ten genes, serving as markers, were selected on both arms of chromosome Y for copy number analysis with droplet digital PCR (ddPCR), enabling detection of loss of a marker in a fraction of the tumor cells used for DNA extraction. A total of 114 tumor samples from male patients were used, derived from a cohort of IDH wild type GBM patients treated with standard radio-chemo therapy. For 61 of these 114 patients, corresponding blood samples were available and analyzed. Different cut-off values were tested for each marker and Kaplan-Meier log-rank analysis was used to estimate overall survival. The mRNA expression for nine of the ten tested genes was available in TCGA, and 225 IDH wild type male GBM were included in a separate survival analysis, where median value of expression was used as group separator. RESULTS Fractional loss, as well as gain of markers was detected. Decreased copy number of the following markers was associated with significantly shorter survival; amelogenin Y-linked (AMELY) (13.5 vs. 19.3 months, p=0.017), neuroligin 4 Y-linked (NLGN4Y) (11.8 vs. 18.9 months, p=0.03) and sex determining region Y (SRY) (10.3 vs. 18.7 months, p=0.002). Additional analysis of SRY in the blood samples verified that copy number alterations were predominantly present in tumors. Survival analysis using mRNA expression data from TCGA showed that reduced expression of SRY was associated with significantly shorter OS (13.8 vs. 19.8 months, p=0.008), but no significant correlation with OS for any of the other markers. CONCLUSION Our data suggests a clonal or at least sporadic occurrence of fractional loss of Y chromosome markers in GBM, as detected with ddPCR. Interestingly, such dosage changes may contribute to shorter survival in men and explain some of the sex disparity seen in GBM. More research is needed to elucidate the molecular mechanisms of LOY and the role of specific Y-linked genes in GBM but also other diseases.
Functional Logic of Layer 2/3 Inhibitory Connectivity in the Ferret Visual Cortex
Authors: Benjamin Scholl, Daniel E. Wilson, Juliane Jaepel, David Fitzpatrick
Journal: Neuron (2019)

Highlights•GABAergic boutons have diverse orientation preferences within orientation domains•Single-neuron inhibitory input fields originate from diverse orientation domains•Conductance measurements show inhibition and excitation are not strictly co-tunedSummaryUnderstanding how cortical inhibition shapes circuit function requires identifying the connectivity rules relating the response properties of inhibitory interneurons and their postsynaptic targets. Here we explore the orientation tuning of layer 2/3 inhibitory inputs in the ferret visual cortex using a combination of in vivo axon imaging, functional input mapping, and physiology. Inhibitory boutons exhibit robust orientation-tuned responses with preferences that can differ significantly from the cortical column in which they reside. Inhibitory input fields measured with patterned optogenetic stimulation and intracellular recordings revealed that these inputs originate from a wide range of orientation domains, inconsistent with a model of co-tuned inhibition and excitation. Intracellular synaptic conductance measurements confirm that individual neurons can depart from a co-tuned regime. Our results argue against a simple rule for the arrangement of inhibitory inputs supplied by layer 2/3 circuits and suggest that heterogeneity in presynaptic inhibitory networks contributes to neural response properties.
Cardiovascular assessment II
Authors: A. Rigoli, B. Allaria, B. Brunetti, G. DeFilippi, V. Reina, E. Sansone, H. Brock, S. Necsk, B. Rapf, F. Kern, E. Weiss, H. Chromy, H. Dan, R. Bonato, F. Merlo, D. Pittarello, L. Lacquaniti, L. Andriolo, H. Mentec, S. Terré, P. Legrand, A. Felices Nieto, J. M. Cruz Fernández, M. Pavón García, J. Giménez Raurell, M. Guerrero de Mier, F. J. Ortega Vinuesa, L. Fayos, J. A. Lopez, J. E. Belenguer, R. Oltra, A. Cabadés, M. Ruano, V. Palacios, J. M. Palencia
Journal: Intensive Care Medicine (1992)
NKT Cells Coexpressing a GD2-Specific Chimeric Antigen Receptor and IL15 Show Enhanced <i>In Vivo</i> Persistence and Antitumor Activity against Neuroblastoma
Authors: Xin Xu, Wei Huang, Andras Heczey, Daofeng Liu, Linjie Guo, Michael Wood, Jingling Jin, Amy N. Courtney, Bin Liu, Erica J. Di Pierro, John Hicks, Gabriel A. Barragan, Ho Ngai, Yuhui Chen, Barbara Savoldo, Gianpietro Dotti, Leonid S. Metelitsa
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Vα24-invariant natural killer T cells (NKT) are attractive carriers for chimeric antigen receptors (CAR) due to their inherent antitumor properties and preferential localization to tumor sites. However, limited persistence of CAR-NKTs in tumor-bearing mice is associated with tumor recurrence. Here, we evaluated whether coexpression of the NKT homeostatic cytokine IL15 with a CAR enhances the in vivo persistence and therapeutic efficacy of CAR-NKTs. Experimental Design: Human primary NKTs were ex vivo expanded and transduced with CAR constructs containing an optimized GD2-specific single-chain variable fragment and either the CD28 or 4-1BB costimulatory endodomain, each with or without IL15 (GD2.CAR or GD2.CAR.15). Constructs that mediated robust CAR-NKT cell expansion were selected for further functional evaluation in vitro and in xenogeneic mouse models of neuroblastoma. Results: Coexpression of IL15 with either costimulatory domain increased CAR-NKT absolute numbers. However, constructs containing 4-1BB induced excessive activation-induced cell death and reduced numeric expansion of NKTs compared with respective CD28-based constructs. Further evaluation of CD28-based GD2.CAR and GD2.CAR.15 showed that coexpression of IL15 led to reduced expression levels of exhaustion markers in NKTs and increased multiround in vitro tumor cell killing. Following transfer into mice bearing neuroblastoma xenografts, GD2.CAR.15 NKTs demonstrated enhanced in vivo persistence, increased localization to tumor sites, and improved tumor control compared with GD2.CAR NKTs. Importantly, GD2.CAR.15 NKTs did not produce significant toxicity as determined by histopathologic analysis. Conclusions: Our results informed selection of the CD28-based GD2.CAR.15 construct for clinical testing and led to initiation of a first-in-human CAR-NKT cell clinical trial (NCT03294954).
P14.12 The cost-effectiveness of tumor-treating fields in patients with newly diagnosed glioblastoma
Authors: X Armoiry, P Auguste, C Dussart, J Guyotat, M Connock
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND The addition of novel therapy “Tumor-Treating fields” (TTF) to standard radio-chemotherapy with Temozolomide (TMZ) has recently shown superiority over conventional TMZ regimen in patients with glioblastoma. Despite the clinical benefit of TTF, there is a strong concern regarding the cost of this new treatment. A first cost-effectiveness analysis, which was published in 2016, was based on effectiveness outcomes from an interim analysis of the pivotal trial and used a “standard” Markov model. Here, we aimed to update the cost-effectiveness evaluation using a partitioned survival model design and using the latest effectiveness data. MATERIAL AND METHODS A partitioned survival model was developed with three mutually exclusive health states: stable disease, progressive disease, and dead. Parametric models were fitted to the Kaplan-Meier data for overall and progression-free survival. These generated clinically plausible extrapolations beyond the observed data. The perspective of the French national health insurance was adopted and the time horizon was 20 years. Base case results were expressed as cost/life-years (LY) gained (LYG). Secondary analyses were undertaken, with the results presented as cost/per quality adjusted life years (QALY) gained. Last, we undertook deterministic and probabilistic sensitivity analyses. RESULTS After applying 4% annual discounting of benefits and costs, the base case model generated incremental benefit of 0.507 LY at a incremental cost of €258,695 yielding an incremental cost effectiveness ratio (ICER) of €510,273 / LYG. Secondary analyses yielded an ICER of €667,173/QALY. Sensitivity analyses and bootstrapping methods showed the model was relatively robust. The model was sensitive to TTF device costs and the parametric model fitted to the Kaplan-Meier data for overall survival. The cost-effectiveness acceptability curve showed TTF has 0% of being cost-effective under conventional thresholds. CONCLUSION Using a partitioned survival model, uprated costs and more mature survival outcomes, TTF when compared to standard radio-chemotherapy with TMZ is not likely to be cost-effective. This has major implications in terms of access of newly eligible patients
Association of the reduced expression of NR4A1 and NR4A3 with poor survival in patients with aggressive lymphomas.
Authors: Alexander Josef Deutsch, Martin Pichler, Sonja Reitter, Katharina Troppan, Christine Beham-Schmid, Peter Neumeister
Journal: Journal of Clinical Oncology (2012)

e18525 Background: NR4A1 and NR4A3 belong to the orphan nuclear receptors. Their function as critical tumour suppressor genes was demonstrated by the rapid development of acute myeloid leukemia (AML) in NR4A1 and NR4A3 double knock-out mice and by their reduced expression in leukemic blasts from human AML patients. The aim of our study is to comprehensively study and functionally characterize NR4A1 and NR4A3 expression in Non-Hodgkin's Lymphomas (NHL). Methods: NR4A1 and NR4A3 expression were determined on mRNA- and protein levels in most lymphoid malignancies of B cell type. Additionally direct sequencing, methylation specific PCR and microRNA analyses of potential interacting NR4A partners were performed. For functional characterization NR4A1was over expressed in a Sc-1 lymphoma cell line by using an inducible lentiviral construct, and treated with Cytosporone-B (Csn-B), a non physiological NR4A1 ligand, followed by apoptotic assays (cleaved caspase 3, Sub-G1 peak determination, and the Annexin V staining). Results: We found a more than 50% reduction of both, NR4A1 and NR4A3, in B-CLL (71%) and Follicular Lymphoma (70%), and more pronounced in diffuse large B cell lymphoma (DLBCL) (74%) compared to normal controls. Mutational analyses in selected cases revealed four of 16 aggressive lymphoma samples mutated (one misssense- and three silent mutations (=25%)). Induction of NR4A1 expression in the transduced Sc-1 lymphoma cell line led to apoptosis in a significantly higher proportion of induced cells compared to their uninduced controls. Additionally, Csn-B treatment of an immortalized B cell line and three lymphoma cell lines caused NR4A1 mediated apoptosis. In a patient cohort of 83 DLBCL, NR4A1 and NR4A3 were more than 50% down-regulated in 88% and 74% of patients, respectively. A low expression of NR4A1 was significantly associated with non-germinal center B-cell like subtype (p&lt;0.001) and with poor overall survival (p=0.042, HR=2.2, CI=1.01-4.9). Conclusions: Our data indicates that NR4A1 has pro-apoptotic functions and that Csn-B induces NR4A1 mediated apoptosis in lymphoma cells. Hence, regulation of NR4A1 by Csn-B is a promising target for the development of new therapeutic drugs.
A Biophysical Model Uncovers the Size Distribution of Migrating Cell Clusters across Cancer Types
Authors: Federico Bocci, Mohit Kumar Jolly, José Nelson Onuchic
Journal: Cancer Research (2019)

Migration from the primary tumor is a crucial step in the metastatic cascade. Cells with various degrees of adhesion and motility migrate and are launched into the bloodstream as single circulating tumor cells (CTC) or multicellular CTC clusters. The frequency and size distributions of these clusters have been recently measured, but the underlying mechanisms enabling these different modes of migration remain poorly understood. We present a biophysical model that couples the phenotypic plasticity enabled by the epithelial-mesenchymal transition (EMT) and cell migration to explain the modes of individual and collective cancer cell migration. This reduced physical model captures how cells undergo a transition from individual migration to collective cell migration and robustly recapitulates CTC cluster fractions and size distributions observed experimentally across several cancer types, thus suggesting the existence of common features in the mechanisms underlying cancer cell migration. Furthermore, we identify mechanisms that can maximize the fraction of CTC clusters in circulation. First, mechanisms that prevent a complete EMT and instead increase the population of hybrid epithelial/mesenchymal (E/M) cells are required to recapitulate CTC size distributions with large clusters of 5 to 10 cells. Second, multiple intermediate E/M states give rise to larger and heterogeneous clusters formed by cells with different epithelial-mesenchymal traits. Overall, this biophysical model provides a platform to continue to bridge the gap between the molecular and biophysical regulation of cancer cell migration and highlights that a complete EMT might not be required for metastasis. SIGNIFICANCE: A biophysical model of cancer cell invasion integrates phenotypic heterogeneity and cell migration to interpret experimental observations of circulating tumor cell clusters and provides new predictions.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/21/5527/F1.large.jpg.
P14.05 Treatment of relapsing patients with intracranial germ cell tumors: the French experience
Authors: L Callec, C Patte, A Lardy-Cleaud, L Vignon, C Alapetite, P Chastagner, C Faure Conter, D Frappaz
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Optimal strategy for treatment of relapsing intracranial malignant germ cell tumors remains ill-defined. Authors describe the French experience over a 25-year period. MATERIAL AND METHODS Relapsing patients were retrieved by their participation in the SFOP-TGM 90-92 or GCT 96 protocols or from National Childhood Solid Tumour Registry. RESULTS The cohort included Group A: documented germinomas (n=14), Group B: patients treated as germinomas without histopathological proof (n=5) and Group C: secreting germ cell tumours (n=25). Patients all received standard dose chemotherapy, and some high dose chemotherapy (VP16 Thiotepa with stem cell rescue) and/or various type of radiation. The 5 year EFS and OS post relapse are: 79%[47 to 93%] and 86% [54 to 96%] respectively in group A, 20% [1 to 58%] and 80% [20 to 97%] respectively in group B, 56% [35 to 73%] and 60% [38 to 76%] respectively in group C. Among 14 Group A patients, 7/12 receiving high dose versus 3/3 receiving standard dose chemotherapy, and 9/11 re-irradiated versus 1/3 not re-irradiated are CR2. Among 21 Group C patients. who had received radiation in first line, 10/15 receiving high dose versus 1/6 receiving standard dose chemotherapy, and 7/11 re-irradiated versus 4/10 not re-irradiated are CR2. CONCLUSION The outcome of relapsing germinoma is favourable and intensity of second line remains matter of debate. High dose chemotherapy with radiotherapy, when feasible, should remain the reference for treatment of a relapsed non germinoma, though more active treatments are warranted.
Right Atrial Mechanisms of Atrial Fibrillation in a Rat Model of Right Heart Disease
Authors: Roddy Hiram, Patrice Naud, Feng Xiong, Doa’a Al-u’datt, Vincent Algalarrondo, Martin G. Sirois, Jean-François Tanguay, Jean-Claude Tardif, Stanley Nattel
Journal: Journal of the American College of Cardiology (2019)