tbuckley/cabot-search huggingface dataset:
SCDT-17. DECREASED OPERATIVE COMPLICATIONS WITH IMAGE-GUIDED OMMAYA RESERVOIR INSERTION: SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Jonathan Lau, Suzanne Kosteniuk, Tom Walker, Alla Iansavichene, David Macdonald, Joseph Megyesi
Journal: Neuro-Oncology (2017)

One of the classic technologies facilitating therapeutic drug delivery to the central nervous system (CNS) is the Ommaya reservoir. Subcutaneous Ommaya reservoir insertion (ORI) has been available as a treatment option for targeted intraventricular pharmacotherapy since the 1960’s. The intraventricular catheter has conventionally been inserted freehand. However, advancements in image-guidance (IG) over the past two decades has enabled IG-ORI as a viable, and arguably preferred, alternative to blind insertion. In this study, we sought to compile evidence from the literature about surgical outcome in ORI to assess the impact of IG on safety and efficacy. A systematic review and meta-analysis of operative outcomes from ORI was performed using Medline and Embase databases in compliance with standard guidelines. Patient demographics, surgical details, and peri-operative outcomes (hemorrhage, infection, malposition, malfunction, overall morbidity and mortality) were extracted from the full-text of included articles. Study quality was assessed via MINORS criteria. Random effects and heterogeneity analysis were performed. 45 studies met study criteria, for a total of 2075 independent ORIs. Pooled rates of outcome for IG compared to non-IG were 6.0% versus 13.0% for overall complications; 2.1% compared to 2.9% for catheter malfunction; 1.7% compared to 3.0% for catheter malposition; 0.8% compared to 4.2% for early post-operative infection; 0.4% compared to 1.4% for mortality. Interestingly, post-operative hemorrhage was increased at 3.8% compared to 2.3%. There was an overall trend towards decreased complications with date of publication (Pearson correlation = -0.606). The reported analyses all met the threshold for statistical significance (p-value < 0.05). IG was associated with decreased overall complication, catheter malfunction/malposition, and early post-operative infection rates. Increased hemorrhage rates are likely the result of increased routine post-operative imaging concurrent with the IG era. Although the overall quality of evidence is low, this meta-analysis provides objective support for IG-ORI.
P1.17-019 B7-H3 Protein Expression in Thymic Epithelial Tumor Subtypes and Its Association with PD-L1 and Clinical Characteristics
Authors: S. Gennatas, A. Mandal, J. Robertus, A. Bowman, A. Nicholson, S. Popat, A. Bowcock
Journal: Journal of Thoracic Oncology (2017)
ACTR-91. NUMERICAL SIMULATIONS OF TTFIELDS DISTRIBUTION IN PATIENT MODELS REVEALS A CONNECTION BETWEEN FIELD INTENSITY AND PATIENT OUTCOME
Authors: Noa Urman, Gitit Lavy-Shahaf, Avital Frenkel, Shay Levi, Ariel Naveh, Manzur Doron, Cornelia Wenger, Uri Weinberg, Eilon D Kirson, Ze’ev Bomzon
Journal: Neuro-Oncology (2017)

Preclinical studies show that the efficacy of TTFields increases with field intensity. However, studies investigating the connection between field distribution and patient outcome have yet to be performed. We have developed a novel technique that enables rapid numerical simulation of TTFields distribution within the heads of patients. We are utilizing this technique to investigate the connection between TTFields distribution and patient outcome in patients treated with TTFields during the EF-14 trial (n=466). To date, n=57 cases have been simulated and field intensity distributions in a tumor bed comprising the Gross Tumor Volume (GTV) and a zone extending 1 cm from the GTV were derived. To account for compliance, field values for each patient were multiplied by their average compliance over the first six months of treatment. To test the hypothesis that patient outcome correlates with field intensities, we defined E95 such that 95% of the tumor bed receives field intensities above this value. The patients were split into two groups E95>1.3V/cm (n=13) and E95<1.3V/cm (n=44). E95=1.3V/cm, is the threshold that yielded the most statistically significant difference in OS between the groups. Demographics of the two groups were similar to the demographics of the entire EF-14 trial population and similar to each other. The median OS and PFS were superior when E95>1.3.V/cm OS (35.8 months vs. 23.0 months, p=0.04, HR=0.43) and PFS (11.5 months vs 8.1 months, p=0.12, HR=0.57). Within the E95>1.3V/cm group, a higher percentage of patients showed clinical benefit (stable disease/ partial response, 100% vs 75% p=0.045). OS in both groups is superior to OS in the EF-14-control-arm (16.0 months, p=0.049), indicating that patients benefited from treatment even when field intensities were lower. These preliminary results suggest that field intensity at the tumor bed correlates with patient outcome. Analysis of the full patient group will further elucidate this connection.
P1.01-054 PD-L1 Expression in Patients with Non-Small Cell Lung Cancer According to Underlying Pulmonary Disease: A Retrospective Study
Authors: S. Ohara, A. Saihara, Y. Matsumoto, R. Furukawa, Y. Taniguchi, A. Sato, M. Hojo, K. Usui
Journal: Journal of Thoracic Oncology (2017)
Accurate hepatitis C virus genotyping and selection of optimal therapy: lessons from a St Petersburg strain infection
Authors: E. Knops, E. Heger, C. Koenig, U. Moebius, N. Lübke, R. Kaiser, V. Di Cristanziano, L. Hüsgen, C. Kocyigit, J. Rupp, S. Sierra
Journal: Clinical Microbiology and Infection (2017)
PDTM-07. SYSTEMATIC DRUG IDENTIFIES DIGOXIN AS A DRUG THAT PROLONGS SURVIVAL IN PDOX MODELS OF GROUPS 3 AND 4 MEDULLOBLASTOMA AT CLINICALLY RELEVANT DOSES
Authors: Sarah Injac, Lei Huang, Hong Zhao, Lin Qi, Mari Kogiso, Chris Man, Xiao-Nan Li, Ching Lau, Stephen Wong
Journal: Neuro-Oncology (2017)

Medulloblastoma (MB) is the most common malignant brain tumor of childhood. While the current standard care for MB leads to long term survival in approximately 75 % of patients; recurrent and refractory MB continues to have dismal outcomes and long term survivors face significant treatment-related sequelae. Drug repositioning for known drugs is a promising potential strategy which allows for accelerated translation into the clinical setting. A non-parametric, bootstrapping based simulated annealing (NPBSA) algorithm was employed to identify driver signaling pathways for over 1,800 patients with Group 3 and Group 4 MB through an integrative analysis on their mRNA expression, DNA-copy number, DNA-methylation and DNA-seq profiles. Drug functional networks then were constructed based on gene expression profiles under drug treatment and chemical structures. These were clustered into drug modules with potential mechanisms of action. By evaluating the targeted effects of 1,309 drugs from connectivity map database, we identified multiple cardiac glycosides as potential drug candidates for Group 3 and 4 MB subtypes. These findings were first validated in multiple MB-derived cell lines which showed high rates of growth inhibition by cardiac glycosides compared to controls. Patient-derived orthotopic-xenograft (PDOX) models of Group 3 (ICb-2555MB) and 4 MB (ICb-1078MB) were subsequently treated with digoxin (2 mg/kg i.p.) for 2 cycles of 14 days. Digoxin treatment significantly prolonged survival in both models compared to untreated controls (p=0.001; p=0.031). Studies using the Group 3 model further demonstrated that the observed survival benefit is synergistic with radiation and that prolonged dosing (daily treatment for 60 days) further improves median survival. Finally, average digoxin trough levels in treated mice (2.4 ng/mL +/- 0.4) were similar to target levels used in heart failure patients taking digoxin (0.8- 2 ng/mL) suggesting the potential for rapid translation of these findings into a clinical setting.
Localized Synchrotron Irradiation of Mouse Skin Induces Persistent Systemic Genotoxic and Immune Responses
Authors: Jessica Ventura, Pavel N. Lobachevsky, Jason S. Palazzolo, Helen Forrester, Nicole M. Haynes, Alesia Ivashkevich, Andrew W. Stevenson, Christopher J. Hall, Andreas Ntargaras, Vasilis Kotsaris, Gerasimos Ch. Pollakis, Gianna Potsi, Konstantinos Skordylis, Georgia Terzoudi, Ioannis S. Pateras, Vassilis G. Gorgoulis, Alexandros G. Georgakilas, Carl N. Sprung, Olga A. Martin
Journal: Cancer Research (2017)

The importance of nontargeted (systemic) effects of ionizing radiation is attracting increasing attention. Exploiting synchrotron radiation generated by the Imaging and Medical Beamline at the Australian Synchrotron, we studied radiation-induced nontargeted effects in C57BL/6 mice. Mice were locally irradiated with a synchrotron X-ray broad beam and a multiplanar microbeam radiotherapy beam. To assess the influence of the beam configurations and variations in peak dose and irradiated area in the response of normal tissues outside the irradiated field at 1 and 4 days after irradiation, we monitored oxidatively induced clustered DNA lesions (OCDL), DNA double-strand breaks (DSB), apoptosis, and the local and systemic immune responses. All radiation settings induced pronounced persistent systemic effects in mice, which resulted from even short exposures of a small irradiated area. OCDLs were elevated in a wide variety of unirradiated normal tissues. In out-of-field duodenum, there was a trend for elevated apoptotic cell death under most irradiation conditions; however, DSBs were elevated only after exposure to lower doses. These genotoxic events were accompanied by changes in plasma concentrations of macrophage-derived cytokine, eotaxin, IL10, TIMP1, VEGF, TGFβ1, and TGFβ2, along with changes in tissues in frequencies of macrophages, neutrophils, and T lymphocytes. Overall, our findings have implications for the planning of therapeutic and diagnostic radiation treatments to reduce the risk of radiation-related adverse systemic effects. Cancer Res; 77(22); 6389-99. ©2017 AACR.
ACTR-07. LIMITED IMPACT OF EXTENDED ADJUVANT TEMOZOLOMIDE BEYOND 12 CYCLES IN PATIENTS WITH NEWLY DIAGNOSED GLIOBLASTOMAS
Authors: Makoto Ohno, Yasuji Miyakita, Masamichi Takahashi, Yuko Matsushita, Yosuke Kitagawa, Takahiro Yamauchi, Natsuko Kitamura, Koichi Ichimura, Yoshitaka Narita
Journal: Neuro-Oncology (2017)

Radiotherapy combined with concomitant/adjuvant temozolomide (TMZ) is the standard treatment for patients with newly diagnosed glioblastomas (GBM). However, the optimal cycles of adjuvant TMZ remains controversial. Until December 2013 we treated patients with GBM with maximum 24 cycles of adjuvant TMZ (24C group, N=122), and after January 2014 changed our treatment policy to maximum 12 cycles (12C group, N=26). The aim of this study was to explore an impact of extended TMZ treatment on outcome with comparison between 12C group and 24C group. Between May 2006 and March 2016 we included 148 patients with newly diagnosed GBM whose number of cycles of adjuvant TMZ was available. In 119 patients, IDH1/2 mutations and MGMT promoter methylation status were analyzed by direct sequencing and pyrosequencing, respectively. Methylation was defined as positive when the mean level of methylation at the 16 CpG sites examined was greater than 16%. The median survival time (MST) and progression free survival (mPFS) were 18.1 months and 9.9 months, respectively. The median number of adjuvant TMZ cycles was 6, and 31 patients (20.9%) received 13 cycles or more. The MST and mPFS did not differ significantly between 12C group and 24C group (30.3 vs 18.1 months, p=0.26, 12.3 vs 9.6 months, p=0.23, respectively). The time from the end of 12 cycles to progression did not differ between patients who completed 12 cycles and stop and those who continued more than 12 cycles (progression free survival rate at 6 months: 62.5% vs 66.7%, p=0.65). Multivariate analysis indicated that age, extent of resection, postoperative Karnofsky performance status, and MGMT promoter methylation were associated with prolonged survival time, but not the number of adjuvant TMZ cycles (p=0.28). Extended TMZ beyond 12 cycles did not prevent tumor recurrence and was not associated with improved outcome.
Bisogna armonizzare la gestione dell'esposizione all'HIV in Europa
Authors: R Tubiana
Journal: Eurosurveillance (2004)

Gia da tempo si e sentita la necessita di armonizzare le raccomandazioni europee per la gestione dell'esposizione all'HIV. Due gruppi di esperti di 14 paesi hanno compiuto importanti e significativi lavori, e le loro conclusioni e raccomandazioni sono riportate nei due articoli di Jesus Almeda et al e Vincenzo Puro et al [1,2]. 
Sono specificate due situazioni, sebbene la differenza tra di loro sia argomento di dibattito, se l'importante sia di impedire o di prevenire una infezione gia verificatasi dopo esposizione a HIV (o, anche, HCV o HBV). Come gli autori fanno notare, la profilassi post-esposizione (PPE) costituisce lo standard di cura per gli operatori sanitari (OS) in quasi tutti i paesi, compresi gli Stati Uniti, ma non per la gestione degli altri casi di esposizione all'HIV, sessuale, utilizzatori di droghe iniettabili o altre esposizioni non occupazionali. 
Nel caso dell'esposizione degli operatori sanitari, il compito degli autori e stato quello di standardizzare diverse raccomandazioni e strategie nazionali. Per le esposizioni non occupazionali, lo scopo e stato quello di stabilire delle linee guida europee, dal momento che esistono molto poche raccomandazioni nazionali.
Come mostrano questi articoli, in entrambe le situazioni sono molto simili il razionale, il background, la gestione e la scelta del trattamento per le PPE.
P1.02-003 Prevention of Adriamycin-induced Cardiac Damage by NAD-Modulation Prevention of Adriamycin-induced Cardiac Damage by NAD-Modulation
Authors: S. Yang, K. Kwon, D. Khadka, G. Oh, H. Kim, S. Lee, A. Pandit, S. Lee, H. So
Journal: Journal of Thoracic Oncology (2017)
Vigilancia de la prevalencia del VIH y el comportamiento de hombres que tienen relaciones sexuales con hombres en Barcelona, España
Authors: K Pérez, A Rodes, J Casabona Barbarà
Journal: Eurosurveillance (2002)

Recientemente, los diversos estudios realizados en hombres que tienen relaciones sexuales con hombres (HRSH) ponen de manifiesto un aumento de la incidencia de VIH y de las infecciones de transmision sexual, asi como de los comportamientos sexuales de riesgo. El optimismo ocasionado por los tratamientos antirretrovirales podria favorecer en un futuro proximo una mayor relajacion de las medidas de proteccion.
Obstructive Sleep Apnea Severity Affects Amyloid Burden in Cognitively Normal Elderly. A Longitudinal Study
Authors: Ram A. Sharma, Andrew W. Varga, Omonigho M. Bubu, Elizabeth Pirraglia, Korey Kam, Ankit Parekh, Margaret Wohlleber, Margo D. Miller, Andreia Andrade, Clifton Lewis, Samuel Tweardy, Maja Buj, Po L. Yau, Reem Sadda, Lisa Mosconi, Yi Li, Tracy Butler, Lidia Glodzik, Els Fieremans, James S. Babb, Kaj Blennow, Henrik Zetterberg, Shou E. Lu, Sandra G. Badia, Sergio Romero, Ivana Rosenzweig, Nadia Gosselin, Girardin Jean-Louis, David M. Rapoport, Mony J. de Leon, Indu Ayappa, Ricardo S. Osorio
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Rationale: Recent evidence suggests that obstructive sleep apnea (OSA) may be a risk factor for developing mild cognitive impairment and Alzheimer's disease. However, how sleep apnea affects longitudinal risk for Alzheimer's disease is less well understood.Objectives: To test the hypothesis that there is an association between severity of OSA and longitudinal increase in amyloid burden in cognitively normal elderly.Methods: Data were derived from a 2-year prospective longitudinal study that sampled community-dwelling healthy cognitively normal elderly. Subjects were healthy volunteers between the ages of 55 and 90, were nondepressed, and had a consensus clinical diagnosis of cognitively normal. Cerebrospinal fluid amyloid β was measured using ELISA. Subjects received Pittsburgh compound B positron emission tomography scans following standardized procedures. Monitoring of OSA was completed using a home sleep recording device.Measurements and Main Results: We found that severity of OSA indices (AHIall [F1,88 = 4.26; P < 0.05] and AHI4% [F1,87 = 4.36; P < 0.05]) were associated with annual rate of change of cerebrospinal fluid amyloid β42 using linear regression after adjusting for age, sex, body mass index, and apolipoprotein E4 status. AHIall and AHI4% were not associated with increases in ADPiB-mask (Alzheimer's disease vulnerable regions of interest Pittsburg compound B positron emission tomography mask) most likely because of the small sample size, although there was a trend for AHIall (F1,28 = 2.96, P = 0.09; and F1,28 = 2.32, not significant, respectively).Conclusions: In a sample of cognitively normal elderly, OSA was associated with markers of increased amyloid burden over the 2-year follow-up. Sleep fragmentation and/or intermittent hypoxia from OSA are likely candidate mechanisms. If confirmed, clinical interventions for OSA may be useful in preventing amyloid build-up in cognitively normal elderly.
P3.01-004 The Underestimated Role of Bronchial Washing Fluid in the Detection of EGFR Mutation from Lung Cancer Patients
Authors: X. Zhang, M. Ye, C. Li, Q. Hu, M. Du, X. Wang, Z. Gong, D. Zhang, J. Hu, Q. Hong, L. Mei, X. Yin, Y. Hou, X. Zhang
Journal: Journal of Thoracic Oncology (2017)
CBIO-12. GTP METABOLIC SWITCH LEADS TO NUCLEOLAR TRANSFORMATION AND MALIGNANT GROWTH OF GLIOBLASTOMA
Authors: Kofuji Satoshi, Akiyoshi Hirayama, Naoya Sakamoto, Kazutaka Sumita, Hirofumi Yoshino, Mikako Warren, Risa Kawaguchi, Tatsuya Ozawa, Nobuyuki Onishi, Kara Wolfe, Koichi Okumura, Annmarie Ramkissoon, Lionel M L Chow, Akshiv Malhotra, Jumpei Terakawa, Takiko Daikoku, Trisha Wise-Draper, Nazanin Majd, Kaori Kofuji, Mika Sasaki, Masaru Mori, Dimitrios Anastasiou, Hiroaki Wakimoto, Holger Bierhoff, Craig M Horbinski, Wataru Yasui, Hideyuki Saya, Tomoyoshi Soga, Eric Holland, Ingrid Grummt, Paul Mischel, Atsuo Sasaki
Journal: Neuro-Oncology (2017)

Nucleolar mass is frequently increased in malignant cells, pointing to a prominent role for aberrant rRNA transcription in highly anabolic cells. ATP and GTP, fundamental energy currencies and building blocks for DNA and RNA, are synthesized by the energy-efficient salvage pathway and energy-demanding de novo pathway. While purine nucleotide biosynthesis is upregulated in malignant cancers, distinctive role(s) of de novo ATP and GTP biosynthesis in cancer cell proliferation remains elusive. Here, we show that the highly lethal brain cancer glioblastoma rewires purine metabolism to activate de novo GTP biosynthesis for rRNA transcription and nucleolar transformation, whereas de novo ATP biosynthesis is commonly utilized in glioblastoma and primary glial cells. Transcriptome screening followed by two cohort analyses identified upregulation of inosine monophosphate dehydrogenase-2 (IMPDH2) in glioblastoma patients. Pharmacological and genetic inhibition of IMPDH2 abolished de novo GTP biosynthesis and growth of glioblastoma cells in vitro and in vivo without affecting de novo ATP biosynthesis. This GTP metabolic switch in glioblastoma cells is critical for enhanced RNA Pol I-dependent nucleolar transcription, but not for RNA Pol II and Pol III transcription. Increased IMPDH2 expression correlates with enlarged nucleoli in human glioma patients, and inhibition of IMPDH2 leads to decreased nucleolar mass. Abnormal nucleolar morphology in many cancer types has long been recognized by pathologists and de novo purine biosynthesis was discovered in 1885. Our data connect these dots of long observed features in cancer by demonstrating a glioblastoma-specific shift in glucose flux to increase de novo GTP biosynthesis, which is required for enhanced ribosome biosynthesis and growth of tumor cells. Our results propose new strategies for the detection and treatment of the incurable glioblastoma, and perhaps other tumors, with minimum impact on normal tissues.
TMOD-49. ANTITUMOR EFFICACY OF ANTI-PDL1 IN ACTH-SECRETING PITUITARY ADENOMAS: AN IMMUNOTHERAPEUTIC APPROACH FOR CUSHING’S DISEASE
Authors: Aladine A Elsamadicy, S Harrison Farber, Pakawat Chongsathidkiet, Hanna Kemeny, Karolina Woroniecka, Xiuyu Cui, Ian Dunn, Peter Fecci
Journal: Neuro-Oncology (2017)

Cushing’s disease (CD) is caused by an ACTH-secreting pituitary adenoma that causes severe patient morbidity. First-line treatment for CD is surgical adenomectomy, but 25% of these patients will recur within 5-years. Targeting immune checkpoint Program Death Ligand-1 (PDL1) has emerged as a viable immunotherapeutic approach. The expression of PD-L1 on pituitary adenomas is recently demonstrated by our group and others, making PD-L1 a potential immunologic target. Immunohistochemistry (IHC) was used to determine the expression of PD-L1 on 19 human pituitary adenoma samples, including 9 ACTH-secreting adenomas. For murine in-vitro studies, the ACTH-secreting pituitary adenoma ATT20/D16v.2 cell line was assessed by flow cytometry. For in-vivo studies, a murine-model of CD was established. ATT20/D16v.2 cells were implanted into the flank of A/HeJ x C57L/J F1 mice, and continued PD-L1 expression confirmed on harvested tumors. Plasma ACTH was assessed by EIA at baseline and 6-weeks after tumor implantation. Tumor-bearing mice were then treated intraperitoneally(i.p.) with anti-PDL1 or isotype control every 3 days x 12 doses. Tumor volume, mouse weight, and ACTH levels were assessed. Our data reveal the upregulated expression of ACTH-secreting PD-L1 on pituitary adenomas of both patients and mice compared to normal pituitary. Human pituitary adenomas demonstrate significant (i.e.≥1% staining) PD-L1 expression in 32% of samples, including 22% of ACTH-secreting adenomas. Similar findings are observed in mice, where the ATT20/D16v.2 cell line, as well as tumor grown subcutaneously in flank both demonstrates elevated PD-L1 expression, as well as elevated plasma ACTH concentration. Anti-PDL1 treated mice demonstrated significant reductions to both tumor volume and plasma ACTH levels. PD-L1 is found significantly elevated on ACTH-secreting pituitary adenomas in patients and mice. Furthermore, there is a significant antitumor effect with the administration of anti-PDL1. These results demonstrate a promising immunotherapeutic approach for CD. A multi-institution clinical trial is being planned.