tbuckley/cabot-search huggingface dataset:
P12.07 Long term follow-up of cavernous sinus meningiomas after stereotactic radiosurgery
Authors: R. Daniel, F. Fritsche, S. Grau, H. Treuer, M. Kocher, M. Ruge
Journal: Neuro-Oncology (2017)

Introduction: Microsurgical resection of cavernous sinus meningiomas (CSM) is challenging with a high percentage of recurrence due to incomplete resection (>10% reported recurrence rate after Simpson Grade II and >20% after Grade III resections) and/or permanent, partly severe cranial nerve deficits. Stereotactic radiosurgery (SRS) has evolved as alternative first-line treatment for SCM. Here, we report about the long term clinical and radiological follow-up of an unique cohort of patients with CSM treated with LINAC based SRS. MATERIAL AND METHODS: In this single center retrospective analysis we included all patients with SCM who underwent single fraction LINAC SRS between 1993 and 2012 and had a minimum follow-up of 3 months. We evaluated tumor control (no further intervention needed) by the Kaplan-Meier method. Additionally, patient data were analyzed in terms of clinical symptom control and incidence of complications or unexpected side effects rated by Common Terminology Criteria for Adverse Events (CTCAE; v4.03). Results: 82 patients with 83 tumors (f/m =62/20, median age 53 ± 11, range 33-81 years) were identified. Mean tumor volume was 5.8 ± 3.5 cm3 (range, 0.6-16 cm3), the mean marginal dose was 12 ± 2 Gy (range, 7.0-18.75 Gy) at isodose levels of 64 ± 17% (range, 30-85%). Median follow-up (FU) was 57 months (range, 3-226 months). Tumor control was 100% after 6 and 12 months, 97% after 5-years and 94% after 10 years. Symptoms prior to SRS remained stable in 88% (n=73), improved in 3.6% (n=3) and deteriorated in 2.4% (n=2) at last follow-up. Four patients (4.8%) report about adverse events CTCAE grade 1 (headache n=2, somnolence n=1, trigeminus disorder n=1). Conclusions: SRS for SCM provides reliable long term tumor control without considerable permanent side effects. Thus, SRS should be taken into account when counselling patients harbouring CSM.
NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma
Authors: Donnele Daley, Vishnu R. Mani, Navyatha Mohan, Neha Akkad, Gautam S.D. Balasubramania Pandian, Shivraj Savadkar, Ki Buom Lee, Alejandro Torres-Hernandez, Berk Aykut, Brian Diskin, Wei Wang, Mohammad S. Farooq, Arif I. Mahmud, Gregor Werba, Eduardo J. Morales, Sarah Lall, Benjamin J. Wadowski, Amanda G. Rubin, Matthew E. Berman, Rajkishen Narayanan, Mautin Hundeyin, George Miller
Journal: The Journal of Experimental Medicine (2017)

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance, which enables disease to progress unabated by adaptive immunity. However, the drivers of this tolerogenic program are incompletely defined. In this study, we found that NLRP3 promotes expansion of immune-suppressive macrophages in PDA. NLRP3 signaling in macrophages drives the differentiation of CD4+ T cells into tumor-promoting T helper type 2 cell (Th2 cell), Th17 cell, and regulatory T cell populations while suppressing Th1 cell polarization and cytotoxic CD8+ T cell activation. The suppressive effects of NLRP3 signaling were IL-10 dependent. Pharmacological inhibition or deletion of NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD complex), or caspase-1 protected against PDA and was associated with immunogenic reprogramming of innate and adaptive immunity within the TME. Similarly, transfer of PDA-entrained macrophages or T cells from NLRP3-/- hosts was protective. These data suggest that targeting NLRP3 holds the promise for the immunotherapy of PDA.
P09.40 Clinical behavior of the glioblastomas showing a radiation necrosis and tumor mixed pathology in recurrence or progression
Authors: J. Park, Y. Lee
Journal: Neuro-Oncology (2017)

The current standard treatment for newly diagnosed glioblastoma patients is surgical resection followed by concurrent chemoradiotherapy with temozolomide. When progression is suspected during the treatment protocol, surgical resection is considered. Focal tumor cells can be found within extensive radiation necrosis specimens, and whether to categorize this finding as tumor progression or radiation necrosis is debatable. From June 2006 to June 2016, 115 patients were diagnosed as glioblastoma and 93 of them completed their concurrent chemoradiotherapy. During follow up, 31 patients underwent surgery due to radiologic progression. While 23 patients were diagnosed as recurrent glioblastoma, 8 patients’ specimen showed extensive radiation necrosis with a few tumor cells. Four patients who showed 1p19q codeletion positive and 4 patients who did not have available study results were excluded from the study according to the recent change in CNS tumor diagnosis from the 2016 WHO classification. Among the 6 patients in the mixed pathology group, 5 of them were discontinued from the primary treatment. Overall survival (OS) and survival after radiologic progression (SARP) was measured, and analyzed using the Kaplan-Meier method. Comparing the recurrence group and the mixed pathology group, MGMT methylation PCR results showed positive findings in 6/17 (35.3%) and 4/6 (66.7%), respectively. Although this finding suggests superior outcome on the mixed pathology group, the mean OS was 25.86 (SD 3.15, 95% CI 19.70-32.02) and 25.20 (SD 5.34, 95% CI 14.74-35.66) for recurrence and mixed pathology groups, respectively, with no statistical significance (p=0.875). The mean SARP was 9.63 (SD 1.06, 95% CI 7.56-11.7) and 13.20 (SD 2.05, 95% CI 9.19-17.22) for recurrence and mixed pathology groups. The survival curve showed superior outcome in the mixed pathology group, but failed to obtain statistical significance (p=0.110). The tendency of longer SARP in the mixed pathology group suggests the possibility of a better prognosis group within the previously known recurrence cases. The decision of treatment failure may have been premature in selected patients, and further study is warranted in order to define the exact patient group.
P17.14 Connecting radiotherapy with targeted anti-glioma therapy using superparamagnetic nanoparticles conjugated with Granzyme B
Authors: M. Shevtsov, S. Stangl, W. Sievert, M. Parr, B. Nikolaev, R. Illarionov, Y. Marchenko, L. Yakovleva, V. Ryzhov, G. Multhoff
Journal: Neuro-Oncology (2017)

Introduction: 70-kDa heat shock protein (Hsp70) is overexpressed on the membrane of the glioblastoma cells, but not on corresponding normal cells. Membrane-bound Hsp70 (i.e., mHsp70) is rapidly internalized into tumor cells and thus targeting the protein might provide a promising strategy for theranostics. Superparamagnetic iron oxide nanoparticles (SPIONs) are contrast negative agents that are used for the detection of tumors with MRI. In the presented study we conjugated the protease Granzyme B which is known to recognize mHsp70 to superparamagnetic iron nanoparticles to assess tumor-specific theranostic targeting before and after radiotherapy. Materials and Methods: Synthesized superparamagnetic iron oxide nanoparticles covered with Granzyme B protease (GrB-SPIONs) were characterized using transmission electron microscopy (TEM), dynamic light scattering, NMR relaxometry. Cellular interactions of the GrB-SPIONs conjugates with tumor cell lines (i.e., U87, LN229, C6, K562, HeLa) were assessed using confocal microscopy, flow cytometry and TEM. Brain tumor targeting was analyzed in the orthotopic C6 glioma model in rats, human U87 and LN229 gliomas in nu/nu mice. Following intravenous administration retention of the nanoparticles in the tumor site was assessed using high-field 11.0 T magnetic resonance imaging (MRI) with subsequent histological assay. Biodistribution studies of the SPIONs were performed by NLR-M2 measurements. Combination of the nanoparticle targeting with radiotherapy of the brain tumors was performed at small animal radiation research platform (SARRP) (Xstrahl Inc., UK) using single of fractionated irradiation. Results:In vitro experiments demonstrated the selectivity of GrB-SPIONs conjugates to free and mHsp70 in different tumor cell types in a dose-dependent manner. High-resolution MRI on T2-weighted images showed the retention of the conjugates in C6 glioma model in rats, and U87 and LN229 human orthotopic glioma models in nu/nu mice. Accumulation of GrB-SPION nanoparticles in the glioma resulted in many-fold drop of T2* values in comparison to non-conjugated SPIONs. Biodistribution analysis using NLR-M2 measurements showed an increase in the tumor-to-background (normal brain) uptake ratio of GrB-SPIONs conjugates in glioma-bearing animals in comparison to SPIONs. Accumulation within Hsp70-positive glioma was enhanced after a single dose (10 Gy) of ionizing radiation. Combination of the radiotherapy and application of the GrB-SPIONs significantly increased the survival of the glioma-bearing animals. Conclusions: Elevated accumulation of the functionalized magnetic nanoparticles in the tumor due to radiosensitization proves the combination of radiotherapy and application of Hsp70-targeted agents such as Granzyme B in the theranostics of brain tumors.
P04.20 Hyperspectral imaging for brain tumour identification and boundaries delineation in real-time during neurosurgical operations
Authors: J. F. Piñeiro, D. Bulters, S. Ortega, H. Fabelo, S. Kabwama, C. Sosa, S. Bishop, A. Martínez-González, A. Szolna, G. M. Callico
Journal: Neuro-Oncology (2017)

Introduction: More extensive surgical resection is associated with longer life expectancy for newly diagnosed gliomas. Current intraoperative techniques to delineate the limits and characteristics of gliomas, such as Immunofluorescence or Intraoperative Magnetic Resonance Imaging (iMRI), have limitations. iMRI is allows only a few images to be obtained and is costly. Immunofluorescence requires preoperative administration and is poor in low grade lesions. Hyperspectral imaging (HSI) is an emerging technology in the medical field that combines the benefits of digital imaging and spectroscopy, allowing to simultaneously exploit both the morphology and the chemical composition of the materials that are presented in a scene. Here we set out to apply this technique for the first time to identify and delineate brain tumour boundaries in real-time during neurosurgical operations. Materials and methods: Using a new hyperspectral acquisition system covering the spectral range from 400 nm to 1700 nm, a hyperspectral library of human brain affected by different types of tumours was generated (more than 250.000 spectral signatures). The images were acquired intraoperatively from 30 different patients after performing craniotomy and durotomy. Biopsies were taken in defined areas of the image and assessed by neuropathology. These pixels were used as the gold standard to generate a Support Vector Machine classifier. Results: Supervised learning algorithms show that it is possible to automatically distinguish between tumour tissue, normal tissue, hypervascularized tissue and other elements present in the brain surface using a previously captured database. Quantitative results computed employing the pixels used as the gold standard provide an overall accuracy above 95% in most cases. Using the developed hyperspectral brain cancer detection system, classification maps, where each type of tissue is represented using different colours, are provided to neurosurgeons as an aid-visualization tool for delimiting the tumour margins during a neurosurgical operation in real-time. Conclusions: A novel non-invasive medical imaging technique has been developed for delimiting the tumour margins during neurosurgical operations. HSI is a promising new technique to help neurosurgeons during brain tumour surgery, avoiding leaving unintentional tumour residuum or the excessive resection of normal brain. FUNDING: European Commission FP7 FET Open programme ICT-2011.9.2, European Project HELICoiD "HypErspectral Imaging Cancer Detection" under Grant Agreement 618080.
Polo‐like‐kinase 1 is a proviral host factor for hepatitis B virus replication
Authors: Ahmed Diab, Adrien Foca, Floriane Fusil, Thomas Lahlali, Pascal Jalaguier, Fouzia Amirache, Lia N'Guyen, Nathalie Isorce, François‐Loïc Cosset, Fabien Zoulim, Ourania Andrisani, David Durantel
Journal: Hepatology (2017)

Chronic hepatitis B virus (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC) and current treatments for chronic hepatitis B and HCC are suboptimal. Herein, we identified cellular serine/threonine Polo-like-kinase 1 (PLK1) as a positive effector of HBV replication. The aim of this study was to demonstrate the proviral role of PLK1 in HBV biosynthesis and validate PLK1 inhibition a potential antiviral strategy. To this end, we employed physiologically relevant HBV infection models of primary human hepatocytes (PHHs) and differentiated HepaRG cells in conjunction with pharmacologic PLK1 inhibitors, small interfering RNA (siRNA)-mediated knockdown, and overexpression of constitutively active PLK1 (PLK1
Identification of a polygalacturonase (Cup s 2) as the major <scp>CCD</scp>‐bearing allergen in <i>Cupressus sempervirens</i> pollen
Authors: Y. Shahali, J.‐P. Sutra, C. Hilger, K. Swiontek, I. Haddad, J. Vinh, L. Guilloux, D. Charpin, H. Sénéchal, P. Poncet
Journal: Allergy (2017)

As IgE glyco-epitopes, also referred to as cross-reactive carbohydrate determinants (CCDs), can share significant structural homologies between different plants, they are prone to extensive cross-reactivity among allergen pollen extracts. Here, cypress pollen allergens, especially a polygalacturonase (PG), were further characterized using double one-dimensional electrophoresis (D1-DE). The presence of specific IgE directed against CCDs was investigated by bromelain IgE inhibition and concanavalin A binding assays using sera of cypress pollen-sensitized patients. Our results showed that IgE reactivity to CCDs in Cupressus sempervirens pollen extracts is mainly related to bromelain-type epitopes of a newly identified cypress PG. This glycoprotein has been further characterized through an immunoproteomic approach and officially indexed as Cup s 2 by the WHO/IUIS allergen nomenclature. Cup s 2 could thus be associated with the increased prevalence of IgE reactivity to cypress pollen extracts because of CCD interference.
Activity of distinct growth factor receptor network components in breast tumors uncovers two biologically relevant subtypes
Authors: Mumtahena Rahman, Shelley M. MacNeil, David F. Jenkins, Gajendra Shrestha, Sydney R. Wyatt, Jasmine A. McQuerry, Stephen R. Piccolo, Laura M. Heiser, Joe W. Gray, W. Evan Johnson, Andrea H. Bild
Journal: Genome Medicine (2017)

The growth factor receptor network (GFRN) plays a significant role in driving key oncogenic processes. However, assessment of global GFRN activity is challenging due to complex crosstalk among GFRN components, or pathways, and the inability to study complex signaling networks in patient tumors. Here, pathway-specific genomic signatures were used to interrogate GFRN activity in breast tumors and the consequent phenotypic impact of GRFN activity patterns. Novel pathway signatures were generated in human primary mammary epithelial cells by overexpressing key genes from GFRN pathways (HER2, IGF1R, AKT1, EGFR, KRAS (G12V), RAF1, BAD). The pathway analysis toolkit Adaptive Signature Selection and InteGratioN (ASSIGN) was used to estimate pathway activity for GFRN components in 1119 breast tumors from The Cancer Genome Atlas (TCGA) and across 55 breast cancer cell lines from the Integrative Cancer Biology Program (ICBP43). These signatures were investigated for their relationship to pro- and anti-apoptotic protein expression and drug response in breast cancer cell lines. Application of these signatures to breast tumor gene expression data identified two novel discrete phenotypes characterized by concordant, aberrant activation of either the HER2, IGF1R, and AKT pathways ("the survival phenotype") or the EGFR, KRAS (G12V), RAF1, and BAD pathways ("the growth phenotype"). These phenotypes described a significant amount of the variability in the total expression data across breast cancer tumors and characterized distinctive patterns in apoptosis evasion and drug response. The growth phenotype expressed lower levels of BIM and higher levels of MCL-1 proteins. Further, the growth phenotype was more sensitive to common chemotherapies and targeted therapies directed at EGFR and MEK. Alternatively, the survival phenotype was more sensitive to drugs inhibiting HER2, PI3K, AKT, and mTOR, but more resistant to chemotherapies. Gene expression profiling revealed a bifurcation pattern in GFRN activity represented by two discrete phenotypes. These phenotypes correlate to unique mechanisms of apoptosis and drug response and have the potential of pinpointing targetable aberration(s) for more effective breast cancer treatments.
NIH Consortium to Study Biomarkers for Dementia
Authors: Jennifer Abbasi
Journal: JAMA (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
P08.19 Resistance towards the MDM2 inhibitor idasanutlin is mediated via the NFkB pathway and IGFBP1 upregulation in glioblastoma
Authors: A. Hertenstein, S. Chiblak, T. Hielscher, S. Ciprut, D. Lemke, C. Thomé, T. Kessler, A. Abdollahi, M. Platten, W. Wick
Journal: Neuro-Oncology (2017)

Background: Dysregulation of p53 pathway is common in glioma. Frequent causes are p53 mutations or overexpression of the oncogene MDM2 in p53 wildtype tumors. Idasanutlin is a MDM2 inhibitor, which is currently under investigation for multiple myeloma and acute myeloid leukemia, but of principal interest also for other p53 mutated solid tumors. Therefore, preclinical data and molecular understanding about treatment effects and resistance mechanisms are important. Methods: Treatment effects of idasanutlin monotherapy and combination with radiotherapy were analyzed on cell viability, proliferation and clonogenicity in p53 wildtype cell lines (U87MG, A172) and glioma-initiating cells (GICs, S24, T1) at radiation doses of 2 and 4 Gray (photons). Toxicity assays were performed on freshly isolated murine astrocytes and cerebellum granule neurons. Idasanutlin resistant cells were generated by treatment of U87MG cells with increasing doses of idasanutlin for 3 months. Resistance mechanisms were analyzed by microarray analysis and confirmed via qRT-PCR, immuno blots and treatment with the nuclear factor (NF)kB inhibitor JSH-23 and transient knockdown of insulin-like growth factor binding protein (IGFBP)1 via siRNA. Results: Idasanutlin reduced cell viability and clonogenicity in p53 wildtype glioblastoma cell lines and GICs. Combined treatment with radiotherapy showed synergistic effects on clonogenicity and proliferation at clinically relevant doses without toxicity on normal brain cells. Long-term treatment with idasanutlin resulted in resistance against the drug in U87MG cells and led to a more clonogenic, invasive and proliferative phenotype of the cells. Microarray analysis revealed an activation of NFkB and ERK1/2 pathway and an upregulation of IGFBP1 expression in idasanutlin resistant cells. While radiotherapy did not overcome resistance conferred by idasanutlin, inhibition of NFkB pathway by JSH23 treatment and transient knockdown of IGFBP1 by siRNA partly restored sensitivity towards idasanutlin. Transient knockdown of IGFBP1 additionally reduced the invasiveness of idasanutlin resistant cells. Conclusions: Combination of idasanutlin treatment and radiotherapy showed synergistic effects on glioblastoma cells in a clinically relevant setting. However, long-term treatment with idasanutlin resulted in resistance against the drug mediated by activation of NFkB pathway and upregulation of IGFBP1. Targeting these pathways may provide strategies to overcome idasanutlin resistance.
A More Common Massive Retroperitoneal Mass—Reply
Authors: Kyle J. Van Arendonk, Jin He
Journal: JAMA Surgery (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal