tbuckley/cabot-search huggingface dataset:
P11.41 Comparison of fibroblast activation protein expression and localization in glioblastomas and brain metastases
Authors: P Busek, M Zubal, B Chmielova, Z Vanickova, P Hrabal, E Krepela, A Sedo
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Fibroblast activation protein (FAP) is a transmembrane serine protease that is frequently upregulated in the tumor microenvironment. In several cases, FAP protein itself and/or FAP expressing stromal cells have been shown to contribute to cancer progression and to be associated with more aggressive cancer behaviour and shorter patient survival. The aim of this study was to determine FAP expression in glioblastomas and brain metastases and to identify the cell types that express FAP in the microenvironment of these malignancies. MATERIAL AND METHODS FAP enzymatic activity and protein concentration were determined in samples from patients with brain metastases, glioblastomas and pharmacoresistant epilepsy (control non-tumorous brain tissue) by an enzymatic assay using a specific fluorogenic substrate and ELISA, respectively. Immunohistochemical labelling with antibodies against FAP and markers of astroglia, epithelial cancer cells and mesenchymal stromal cells was performed to characterize FAP expressing cells. RESULTS FAP was significantly upregulated in the majority of glioblastomas and brain metastases in comparison to non-tumorous brain tissue. In glioblastomas, FAP was localized perivascularly and in mesenchymal cells, and in part of the tumors also in the glioma cells. In brain metastases, FAP positivity was abundantly present in the stroma and predominantly co-localised with markers of mesenchymal stromal cells (TE-7, SMA, PDGFRbeta, NG2), but there was no overlap between FAP and markers of epithelial cancer cells (EpCAM, pancytokeratin). CONCLUSION FAP is upregulated in the microenvironment of human glioblastomas and brain metastases compared to non-tumorous brain tissue. In glioblastomas, FAP is expressed in part of the glioma cells, in pericytes and mesenchymal stromal cells, whereas no positivity in cancer cells and more abundant FAP+ stroma was detected in brain metastases. The selective expression of FAP in these brain tumors may be useful for the visualization and possibly therapeutic targeting of their tumor microenvironment. GRANT SUPPORT Ministry of Health of the Czech Republic, grant No. 15-31379A, Progres Q28/LF1, 2015064 LM EATRIS and the project,Center for Tumor Ecology - Research of the Cancer Microenvironment Supporting Cancer Growth and Spread” (reg. n. CZ.02.1.01/0.0/0.0/16_019/0000785) supported by the Operational Programme Research, Development and Education.
Renin-Angiotensin-Aldosterone System Modulates Blood Pressure Response During Vascular Endothelial Growth Factor Receptor Inhibition
Authors: Wendy J. Bottinor, Megan M. Shuey, Ali Manouchehri, Eric H. Farber-Eger, Meng Xu, Devika Nair, Joe-Elie Salem, Thomas J. Wang, Evan L. Brittain
Journal: JACC CardioOncology (2019)

This study postulated that antihypertensive therapy with renin-angiotensin-aldosterone system (RAAS) inhibition may mitigate vascular endothelial growth factor inhibitor (VEGFi)–mediated increases in blood pressure more effectively than other antihypertensive medications in patients receiving VEGFi therapy. VEGFi therapy is commonly used in the treatment of cancer. One common side effect of VEGFi therapy is elevated blood pressure. Evidence suggests that the RAAS may be involved in VEGFi-mediated increases in blood pressure. This retrospective cohort analysis was performed using a de-identified version of the electronic health record at Vanderbilt University Medical Center in Nashville, Tennessee. Subjects with cancer who were exposed to VEGFi therapy were identified, and blood pressure and medication data were extracted. Changes in mean systolic and diastolic blood pressure in response to VEGFi therapy in patients receiving RAAS inhibitor (RAASi) therapy before VEGFi initiation were compared with changes in mean systolic and diastolic blood pressure in patients not receiving RAASi therapy before VEGFi initiation. Mean systolic and diastolic blood pressure rose in both groups after VEGFi use; however, patients who had RAASi therapy before VEGFi initiation had a significantly lower increase in systolic blood pressure as compared with patients with no RAASi therapy (2.46 mm Hg [95% confidence interval: 0.7 to 4.2] compared with 4.56 mm Hg [95% confidence interval: 3.5 to 5.6], respectively; p = 0.034). In a real-world clinical population, RAASi therapy before VEGFi initiation may ameliorate VEGFi-mediated increases in blood pressure. Randomized clinical trials are needed to further our understanding of the role of RAASi therapy in VEGFi-mediated increases in blood pressure.
Abstract P279: Circulating Levels of Tissue Inhibitor of Metalloproteinase-2 (TIMP-2) and Matrix Metalloproteinase-2 (MMP-2) in Relation to Cardiovascular Risk Factors and Subclinical and Clinical Atherosclerosis: The Multi-Ethnic Study of Atherosclerosis (MESA) Study
Authors: Suzette J Bielinski, Thanh T Hoang, Cecilia Berardi, Paul A Decker, Phillip S Kirsch, James S Pankow, Michele M Sale, Mariza de Andrade, Hugues Sicotte, Weihong Tang, Naomi Hanson, Joseph F Polak, Michael Tsai
Journal: Circulation (2013)

Atherosclerosis arises from an accumulation of plaque and can develop from an imbalance of proteins that regulate the extracellular matrix (ECM). Matrix metalloproteinases (MMP) are gelatinases tha...
PL2.1 Exploiting the DNAM-1 system for chimeric antigen receptor (CAR) T cell therapy of glioblastoma
Authors: T Weiss, H Meister, M Weller, C Sentman, P Roth
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Cancer immunotherapy with genetically engineered T cells that express a chimeric antigen receptor (CAR) has led to impressive responses in extracranial malignancies and is also explored against glioblastoma. However, CAR T cell strategies that are currently being explored against glioblastoma target single tumor antigens, which are non-homogeneously expressed and are prone to antigen escape. Furthermore, the immunosuppressive brain tumor microenvironment hampers anti-tumor efficacy. METHODS By immunohistochemistry and flow cytometry, we investigated the expression of CD155 and CD112, which are ligands to the activating immune cell receptor DNAX accessory molecule-1 (DNAM-1), in human and mouse glioma cell lines as well as in human glioblastoma samples. To understand their functional role, we generated CD155 or CD112 knock-out glioma cell lines using CRISPR/Cas9 and studied proliferation, sensitivity to irradiation or temozolomide as well as migration. To exploit the promiscuous binding features of DNAM-1, we generated different first or second-generation CAR T cells that use DNAM-1 as a tumor-binding domain. Subsequently, we investigated their anti-tumor activity in vitro in co-culture assays and in vivo in syngeneic orthotopic murine glioma models. RESULTS CD155 and CD112 are homogenously expressed in human and mouse glioma cell lines and human glioblastoma tissues. Knock-out of these ligands affected the migration of tumor cells, but did not affect proliferation or sensitivity to irradition or temozolomide. DNAM-1-based CAR T cells demonstrated high cytolytic activity and effector cytokine secretion in vitro. In vivo, DNAM-1 based CAR T cells reached to the tumor site in the brain upon intravenous administration, prolonged survival of orthotopic glioma-bearing mice and led to a durable anti-tumor response in a fraction of mice. The treatment was tolerated without toxicities. CONCLUSION We elucidated the tumor-intrinisic role of CD155 and CD112 and provide the first systematical preclincal assessment of DNAM-1 CAR T cells against glioma. These findings provide a rationale to test this immunotherapeutic strategy also in human glioma patients.
Probiotics for intestinal decolonization of ESBL-producing Enterobacteriaceae: a randomized, placebo-controlled clinical trial
Authors: O. Ljungquist, C. Kampmann, F. Resman, K. Riesbeck, J. Tham
Journal: Clinical Microbiology and Infection (2019)

Infections with extended spectrum β-lactamase (ESBL)-producing Enterobacteriaceae (EPE) are a major healthcare concern. Our goal was to investigate whether a probiotic mixture could be used for eradication therapy in patients with prolonged intestinal EPE carriage.We performed a randomized, placebo-controlled, single-blinded clinical superiority trial in the south of Sweden between February 2017 and April 2019. Probiotic Vivomixx®, a mixture of 8 different living bacterial strains or placebo was given to adult outpatients intestinally colonized for at least 3 months with EPE. Patients with suspected active infections at the time of evaluation were excluded, and also those with immunosuppression, severe psychiatric disorder, drug abuse or dementia. Each patient in the probiotic arm was administered 2 sachets (9.0 × 1011 live bacteria) twice daily for 2 months. The primary outcome was intestinal EPE eradication at the end of the 1-year follow-up, as shown by 3 consecutive negative EPE rectal swabs during the follow-up year. The per protocol follow-up for all patients was 1, 3, 6 and 12 months after the initiation of the intervention. ClinicalTrials.gov Identifier: NCT03860415.In total, the target size of 80 patients were included. The median age was 68 years in both groups. The number of females in the probiotics group was 23 (58%) and in the placebo group 28 (70%). At the end of the trial, 12.5% (5 out of 40) of the patients in the probiotic group had achieved successful eradication of EPE, as defined by the primary outcome, in the intention to treat analysis. In the placebo group, 5% (2 out of 40) of the patients had achieved successful eradication of EPE (odds ratio 2.71; 95% confidence interval (CI), 0.49-14.9; p 0.24).Successful EPE eradication was observed in very few individuals. This trial did not support Vivomixx® as being superior to placebo for intestinal decolonization in adult patients with chronic colonization of EPE, but was limited in power.
Funding the NHS Can the NHS cope in future?
Authors: A. Harrison, J. Dixon, B. New, K. Judge
Journal: BMJ (1997)

Four potential pressures are likely to determine whether the NHS will be able to cope in future: the change in population structure, changes in level of morbidity, introduction of new technologies, and increasing expectations of patients and NHS providers. New technology and changes in expectations are likely to have the biggest effect and are also the most difficult to quantify. Nevertheless, these pressures are to some extent amenable to control. If the growth in funding continues as it has in the past there is no convincing evidence that the NHS will not continue to cope.
A budget impact analysis of extended adjuvant letrozole following five years of tamoxifen in postmenopausal women with early breast cancer
Authors: A. A. Calabró, M. S. Portella, M. Garcia
Journal: Journal of Clinical Oncology (2006)

646 Background: MA17 study wasa randomized double-blind placebo-controlled trial of 5 years of extended adjuvant therapy with letrozole (Femara) in 5187 postmenopausal women with early breast cancer after adjuvant tamoxifen. MA17 study demonstrated significant improvement in disease-free survival (93% vs. 87% at 4 yrs, HR 0.57) and a similar trend in overall survival (96% vs. 94% at 4 yrs, HR 0.76). Objective: To estimate the budget impact of adding extended adjuvant letrozole in the management of postmenopausal women with early breast cancer after 5 years adjuvant tamoxifen. Methods: A budget impact analysis over 4 years of letrozole vs. no extended adjuvant therapy was developed from the perspective of a health care payer in terms of total treatment costs following the introduction of letrozole. Model inputs included the overall survival, disease-free survival and probabilities of recurrence from the MA17 trial, additional cost of letrozole and the average annual cost to treat a given type of recurrence (contralateral, loncoregional, metastatic). Only direct medical costs were included using the consumer price index. Costs and cost-savings were reported as 2005 US dollars and discounted at 3%. The average annual cost to treat a recurrence was calculated through a retrospective analysis of a healthcare plan database with 147 postmenopausal women and data from published literature. The recurrence cost included chemotherapy in the first year (drug costs, dispensing fee, materials), health professional contacts, laboratory tests, diagnostic procedures, radiotherapy, bisphosphonate (metastatic recurrence), health professional contacts and hospitalization. Surgery costs were not considered in the study. Results: The average annual cost to treat a recurrence was estimated in US$83,064. For the base-case analysis of 100 patients, savings due to reduced recurrence were $1,006,446, in the letrozole patients. Subtracting the cost of letrozole treatment for 100 patients from savings yielded projected net savings of $36,314. Conclusions: In post-menopausal women who have completed 5 years adjuvant tamoxifen therapy, extended adjuvant letrozole is a cost-saving use of healthcare resources in additional to its clinical benefits. [Table: see text]
Inducing Different Neuronal Subtypes from Astrocytes in the Injured Mouse Cerebral Cortex
Authors: Nicola Mattugini, Riccardo Bocchi, Volker Scheuss, Gianluca Luigi Russo, Olof Torper, Chu Lan Lao, Magdalena Götz
Journal: Neuron (2019)

Astrocytes are particularly promising candidates for reprogramming into neurons, as they maintain some of the original patterning information from their radial glial ancestors. However, to which extent the position of astrocytes influences the fate of reprogrammed neurons remains unknown. To elucidate this, we performed stab wound injury covering an entire neocortical column, including the gray matter (GM) and white matter (WM), and targeted local reactive astrocytes via injecting FLEx switch (Cre-On) adeno-associated viral (AAV) vectors into mGFAP-Cre mice. Single proneural factors were not sufficient for adequate reprogramming, although their combination with the nuclear receptor-related 1 protein (Nurr1) improved reprogramming efficiency. Nurr1 and Neurogenin 2 (Ngn2) resulted in high-efficiency reprogramming of targeted astrocytes into neurons that develop lamina-specific hallmarks, including the appropriate long-distance axonal projections. Surprisingly, in the WM, we did not observe any reprogrammed neurons, thereby unveiling a crucial role of region- and layer-specific differences in astrocyte reprogramming.
Revisiting the initial diagnosis and blood staging of mycosis fungoides and Sézary syndrome with the <scp>KIR</scp> 3 <scp>DL</scp> 2 marker
Authors: M. Roelens, A. Masson, C. Ram‐Wolff, G. Maki, J‐M. Cayuela, A. Marie‐Cardine, A. Bensussan, A. Toubert, M. Bagot, H. Moins‐Teisserenc
Journal: British Journal of Dermatology (2019)

The early diagnosis of Sézary syndrome (SS) is challenging. Loss of CD7 and CD26 expression on CD4+ T cells is the currently used criterion in the initial diagnosis and staging of patients with SS.Our aim was to evaluate the respective value of CD26, CD7 and KIR3DL2 expression on CD4+ T cells and total lymphocytes at initial diagnosis of SS.This prospective study included 254 patients with clinical features consistent with cutaneous T-cell lymphoma seen at our institution between March 2014 and February 2019. Peripheral blood analysis by flow cytometry was performed for each patient at the time of diagnosis and during follow-up. The diagnosis of SS was based on ISCL/EORTC criteria.The presence of KIR3DL2+ Sézary cells (SCs) ≥ 200 μL-1 correlated with the diagnosis of SS, with sensitivity of 88·6% and specificity of 96·3%. All 154 patients with either inflammatory skin disease or other haematological disease had KIR3DL2+ cells < 200 μL-1 , while eight of them had CD4+ CD26- T cells ≥ 1000 μL-1 . Of five patients with SS and lymphopenia, four had CD4+ CD7- T cells < 1000 μL-1 and three had CD4+ CD26- T cells < 1000 μL-1 . However, all of them had KIR3DL2+ CD4+ T cells ≥ 200 μL-1 . Among patients with available samples during evolution, all B1-staged patients with ≥ 200 μL-1 KIR3DL2+ SCs at diagnosis evolved to B2 stage within 7 months.KIR3DL2 expression on T cells is highly specific and helps the early diagnosis of SS, especially in those patients with lymphopenia. What's already known about this topic? In the ISCL/EORTC cutaneous T-cell lymphoma (CTCL) categorization of blood involvement (B0-B2), B2 is defined as a T-cell receptor clonal rearrangement in blood, associated with high blood-smear Sézary cell (SC) count. Flow cytometry was developed to circumvent interobserver variability of SC manual counts; however, it mostly relies on detection of cells lacking CD7 and/or CD26 expression. We previously reported the reliability of KIR3DL2 as the first positive SC marker. What does this study add? Based on our analysis of 254 patients, we propose that KIR3DL2 be added to the ISCL/EORTC criteria for initial diagnosis of Sézary syndrome (SS) and B2 staging. This marker improved sensitivity of SS B2-stage CTCL diagnosis with a specificity > 95%, especially for patients with lymphopenia. We found KIR3DL2 helped early diagnosis of SS and was more reliable than CD26 in assessing blood tumour burden during therapy. What is the translational message? SC quantification is the major means of staging at initial diagnosis and monitoring blood tumour burden in a clinical trials setting. We recommend using a threshold value of KIR3DL2+ SCs ≥ 200 μL-1 or KIR3DL2+ SCs/lymphocytes ≥ 10% in the diagnostic criteria of SS and propose a novel algorithm for CTCL B2 blood staging.
P13.12 Development and validation of a radiomic model for the preoperative prediction of transsphenoidal surgical response in patients with acromegaly
Authors: Y Fan, M Feng, R Wang
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND The preoperative prediction of transsphenoidal surgical (TSS) response is important for determining individual treatment strategies for acromegaly. Therefore, this study aimed to predict TSS response in a non-invasive way based on radiomic analysis. MATERIAL AND METHODS 273 patients with acromegaly were enrolled and divided into primary (n=180) and validation cohorts (n=93) according to time point. Radiomic features were extracted from the MR images and determined using the ‘Elastic Net’ feature selection algorithm. A radiomic signature was built using a support vector machine. Subsequently, multivariable logistic regression analysis was used to select the most informative clinical features, and a radiomic model, incorporating the radiomic signature and selected clinical features, was constructed and used as the final predictive model. The performance of this radiomic model was validated using receiver operating characteristics analysis, and its calibration, discriminating ability, and clinical usefulness were assessed. RESULTS The radiomic signature, which was constructed with six radiomic features selected using the primary cohort, showed a favorable discriminatory ability in the validation cohort. The radiomic model incorporating the radiomic signature and three selected clinical features showed good discrimination abilities and calibration, with an area under the curve (AUC) of 0.93 for the primary cohort and 0.89 for the validation cohort. The radiomic model better estimated the treatment responses of patients with acromegaly than did the clinical features. Decision curve analysis showed the radiomic model was clinically useful. CONCLUSION This radiomic model could aid neurosurgeons in the preoperative prediction of TSS response in patients with acromegaly, and could contribute to determining individual treatment strategies.
Baseline Characteristics of Patients with Paroxysmal Nocturnal Hemoglobinuria Identified in the Department of Defense Database
Authors: Marianne Ulcickas Yood, Susan Jick, Catherine Vasilakis-Scaramozza, Bonnie M.K. Donato, Ioannis Tomazos, Gilbert L'Italien, Nicholas Sicignano, Brian L. Feldman
Journal: Blood (2018)
Activity limitation and clustering of symptoms in breast cancer patients
Authors: R. Sawhney, M. E. Sehl, H. Sanati, W. A. Satariano, A. Naeim
Journal: Journal of Clinical Oncology (2006)

8540 Background: While previous cancer symptom research has been focused on individual symptoms, more recent studies have attempted to identify symptom clusters in breast cancer patients. However, there has been no large study that has examined both clustering of symptoms and activity limitation in breast cancer patients. Methods: Data were taken from a survey study of 1,011 patients found to have histologically confirmed breast cancer, identified by the Metropolitan Detroit Cancer Surveillance System. Patients were surveyed at both 3 and 12 months after diagnosis. Survey data on 1,054 control participants were also obtained for matching variables. Participants were asked whether or not they had each of 21 symptoms, and whether or not they attributed any activity limitation to each symptom. Results: Of 21 symptoms examined, prevalence of symptoms listed in Table 1 was significantly higher in cancer patients than in controls (p&lt;0.05) at baseline. Though the prevalence of each symptom decreased significantly at follow up, each symptom remained significantly more prevalent than in the control group, with the exception of depression. Activity limitation attributed to 4 of the 5 symptoms listed in Table 1 was significantly higher than that of controls, and this difference persisted at follow up. Symptoms tended to cluster together amongst breast cancer patients. For example, at baseline, 73% of patients with depression also reported fatigue, and 30% of patients with pains in chest area also reported both fatigue and depression. These associations persisted at follow up. Symptoms were significantly correlated with each other at baseline (p&lt;0.00005), with correlation coefficients ranging from 0.13 to 0.26, with most correlations remaining significant at follow up. Conclusion: In a large survey of breast cancer patients, symptoms were found to be associated with significant activity limitation, and tended to cluster together. This correlation persists at 12 months after diagnosis, even after treatment is complete. [Table: see text] No significant financial relationships to disclose.
Pulmonary Illness Related to E-Cigarette Use in Illinois and Wisconsin — Final Report
Authors: Jennifer E. Layden, Isaac Ghinai, Ian Pray, Anne Kimball, Mark Layer, Mark W. Tenforde, Livia Navon, Brooke Hoots, Phillip P. Salvatore, Megan Elderbrook, Thomas Haupt, Jeffrey Kanne, Megan T. Patel, Lori Saathoff-Huber, Brian A. King, Josh G. Schier, Christina A. Mikosz, Jonathan Meiman
Journal: New England Journal of Medicine (2019)

E-cigarettes are battery-operated devices that heat a liquid and deliver an aerosolized product to the user. Pulmonary illnesses related to e-cigarette use have been reported, but no large series has been described. In July 2019, the Wisconsin Department of Health Services and the Illinois Department of Public Health received reports of lung injury associated with the use of e-cigarettes (also called vaping) and launched a coordinated public health investigation.
Blockade of IL-2 and IL-15 Gamma Chain Receptor Signaling Decreases Leukemic Cell Viability in T-Cell Large Granular Lymphocyte Leukemia and Adult T-Cell Leukemia
Authors: Tracy Tiffany Wang, Jun Yang, Yong Zhang, Meili Zhang, Kevin C Conlon, Yutaka Tagaya, Thomas L Olson, David J Feith, Nazli Azimi, Thomas A. Waldmann, Thomas P Loughran
Journal: Blood (2017)
Predicting Response to BET Inhibitors Using a Computational Model and Its Validation: A Beat AML Project Study
Authors: Leylah M. Drusbosky, Robinson Vidva, Saji Gera, Anjanasree V. Lakshminarayana, Vijayashree P. Shyamasundar, Ashish Kumar Agrawal, Anay Talawdekar, Taher Abbasi, Shireen Vali, Cristina E. Tognon, Stephen E Kurtz, Jeffrey W. Tyner, Brian J. Druker, Christopher R. Cogle
Journal: Blood (2017)