tbuckley/cabot-search huggingface dataset:
Nonadherence to Statins and Antihypertensives and Hospitalizations Among Elderly Medicare Beneficiaries With Incident Cancer
Authors: Ishveen Chopra, Nilanjana Dwibedi, Malcolm D. Mattes, Xi Tan, Patricia Findley, Usha Sambamoorthi
Journal: Journal of the National Comprehensive Cancer Network (2017)

Background: Incident cancer diagnosis may increase the risk of coronary artery disease (CAD)–related hospitalizations, especially in older individuals. Adherence to statins and/or angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs)/β-blockers reduces CAD-related hospitalizations. This study examined the relationship between medication adherence and CAD-related hospitalizations immediately following cancer diagnosis. Patients and Methods: A retrospective observational longitudinal study was conducted using SEER-Medicare data. Elderly Medicare fee-for-service beneficiaries with preexisting CAD and incident breast, colorectal, or prostate cancer (N=12,096) were observed for 12 months before and after cancer diagnosis. Hospitalizations measured every 120 days were categorized into CAD-related hospitalization, other hospitalization, and no hospitalization. Medication adherence was categorized into 5 mutually exclusive groups: adherent to both statins and ACEIs/ARBs/β-blockers (reference group), not adherent to both statins and ACEIs/ARBs/β-blockers, adherent to either statins or ACEIs/ARBs/β-blockers, use of one medication class and adherent to that class, and use of one medication class and not adherent to that class. The relationship between medication adherence and hospitalization was analyzed using repeated measures multinomial logistic regressions. Inverse probability treatment weights were used to control for observed group differences among medication adherence categories. Results: Adherence to both statins and ACEIs/ARBs/β-blockers was estimated at 31.2% during the 120-day period immediately following cancer diagnosis; 13.7% were not adherent to both medication classes during the same period, and 27.4% had CAD-related hospitalizations immediately after cancer diagnosis, which declined to 10.6% during the last 4 months of the postdiagnosis period. In the adjusted analyses, those not adherent to both statins and ACEIs/ARBs/β-blockers were more likely to have CAD-related hospitalization compared with those adherent to both medication classes (adjusted odds ratio, 1.82; 95% CI, 1.72–1.92; P<.0001). Conclusions: Given the complexity of interaction between CAD and cancer, it is important to routinely monitor medication adherence in general clinical practice and to provide linkages to support services that can increase medication adherence.
P1.02-059 Molecular Characteristics of SMARCA4 Mutations Detection in Chinese Non-Small Cell Lung Cancer Patients
Authors: X. Chen, C. Xu, W. Wang, W. Zhuang, Z. Song, Y. Zhu, R. Chen, Y. Guan, X. Yi, Y. Chen, G. Chen, T. Lv, Y. Song
Journal: Journal of Thoracic Oncology (2017)
EXTH-80. ENHANCED THERAPEUTIC RESPONSE IN MURINE MEDULLOBLASTOMA TUMOR MODEL USING ADENANTHIN AND TRANSIENT MODULATION OF THE BLOOD-BRAIN BARRIER WITH CADHERIN PEPTIDE
Authors: Ngoc H On, Sajesh Babu, Refaat Omar, Samaa Alrushaid, Yan Wang, Jian-Xin Pu, Han-Dong Sun, Neil Davies, Teruna Siahaan, Magimairajan Issaivanan, Donald W Miller
Journal: Neuro-Oncology (2017)

Peroxiredoxin1 (PRDX1) is overexpressed in medulloblastoma (MBL) causing resistance to therapy. Adenanthin (PRDX1 inhibitor) had been validated as a therapeutic target in MBL. However, adenanthin does not cross the blood-brain barrier (BBB). The objective of this study was to examine the efficacy of adenanthin in conjunction with Hav peptide (to transiently modulate the BBB) in an MBL tumor model. Effects of HAV6 on BBB permeability to gadolinium contrast-agent (Gd-DTPA) and adenanthin were examined in healthy mice using MRI and LC/MS respectively. The response of MBL tumor mice to adenanthin was also examined under control conditions and following the BBB disruption using HAV6. Brain tumors in mice were induced by stereotaxic injection of D425 tumor cells. A 5-cycle treatment regimen began 10 days following tumor induction. For each cycle, the mice received 3-consecutive days of either vehicle, adenanthin (10mg/kg), or a combination of adenanthin (10mg/kg) and Hav (0.010mmol/kg) peptide followed by a 1 day of rest. The mice were then monitored for signs of tumor progression. Under control conditions, very little Gd-DTPA and adenanthin entered the brain. In contrast, mice treated with HAV6 showed a significant increase of BBB permeability to both Gd-DTPA (3-fold) and adenanthin (100-fold) compared to control. All mice injected with D425 cells developed tumors within 7 days as seen by bioluminescence imaging. Tumor volume increased at similar rate with median survival of 16 and 18 days for placebo and adenanthin treatment groups respectively. In contrast, tumor bearing mice treated with the combination of Hav and adenanthin showed significant reduction in tumor size and extended survival (>32 days) with little to no symptoms of tumor burden or toxicity related to treatment. Transient disruption of BBB using HAV6 provided therapeutically relevant adenanthin brain concentrations, thereby improving the response to treatment in tumor bearing mice.
P2.16-025 Accuracy of Multidisciplinary Evaluation of Small Solitary Pulmonary Nodules in a Portuguese Private Hospital
Authors: M.O. Fernandes, M.M. Felizardo, M. Grafino, J. Reis, A. Catarino, F. Mascarenhas, C. Loewenthal, M. Pantarotto, F. Martelo
Journal: Journal of Thoracic Oncology (2017)
SCDT-25. INSIGHT INTO THE CYTOTOXIC EFFECTS OF TUMOR INFILTRATING LYMPHOCYTES (TILs) TO CD133+ GLIOBLASTOMA STEM CELLS (GSCs)
Authors: Han-Chung Lee, Yin-Cheng Huang, Yueh-Sheng Chen, Wen-Kuang Yang
Journal: Neuro-Oncology (2017)

Glioblastoma multiforme (GBM) is the most prevalent and high malignant primary brain tumors, and contains a small cohort of self-renewing, tumorigenic glioblastoma stem cells (GSCs) that contribute to tumor relapse and therapeutic resistance. GSCs are typically recognized by the expression of cell surface marker, CD133, encoded from prominin-1 (PROM1) gene. Recent studies have indicated CD133+ cancer stem-like cells are enriched after the treatment of ionizing radiation (IR). To investigate the effect of cytotoxic TILs to glioblastoma cells experienced irradiation, we used post-vaccination TILs treat with glioblastoma cells derived from patient’s tissue specimens without experienced and experienced irradiation respectively. The effect of cytotoxic TILs was not evident in glioblastoma cells experienced IR until 120 hours later. To further investigate whether immune cytokines have cytotoxicity in CD133+ glioblastoma cells, we observed that TNF-α and IFN-γ have the cytotoxic effects in CD133+ glioblastoma cells, implicating the reason why the cytotoxic of CD8+ TILs were delayed to 120 hours. These data provide the framework for understanding the radioresistance in glioblastoma cells that can be used to develop an efficient vaccine.
Ophthalmologists should be able to prescribe bevacizumab, says royal college
Authors: Deborah Cohen
Journal: BMJ (2017)

Ophthalmologists should be able to prescribe the most appropriate treatment for wet age-related macular degeneration, including off-label bevacizumab (Avastin), provided that patients give their informed consent, the Royal College of Ophthalmologists has said.

The college said that it has long petitioned for a review to find out how bevacizumab could be more widely available in the NHS to treat wet AMD.

Using bevacizumab rather than the far more expensive ranibizumab or aflibercept would have “the potential to release funds for much-needed reinvestment into over-stretched hospital eye services,” it said.

Mike Burdon, the college’s president, called for all relevant parties to come together to resolve the issues.

Ophthalmologists have said that the General Medical Council’s guidance, which says that doctors cannot …
PDTM-24. THE PROTEOGENOMICS OF MEDULLOBLASTOMA
Authors: Ling San Lau, Mojca Stampar, Samuel Rivero-Hinojosa, Jerome Staal, Huizhen Zhang, Heather Gordish-Dressman, Kristy Brown, Brian Rood
Journal: Neuro-Oncology (2017)

The genomic characterization of medulloblastoma at the level of the chromosome, epigenome and transcriptome has radically redefined diagnostic classifications and reoriented disease definitions toward a biological underpinning. However, it still remains a challenge to leverage this wealth of data toward a true understanding of disease biology and subsequently to capitalize on the promise of biologically based therapies. One reason for this difficulty is the loose correlation between the genetic and the functional aspects of the cancer cell resulting from multilayered regulatory mechanisms governing protein production, the predominant functional moiety of the cell. To better actualize the promise of genomics, it is necessary to add an understanding of the proteomic dimension to cancer cell biology. We have undertaken a super-SILAC based quantitative proteomics survey of 42 tissue samples spanning the 4 genomic subgroups of medulloblastoma and control cerebellum. We have identified and quantitated thousands of proteins across these groups and find that we are able to recapitulate the genomic subgroups based upon subgroup restricted and differentially abundant proteins while also identifying one additional subgroup. Employing a custom built RNA-seq based searchable proteome database, we are also able to use peptide sequence data to discover medulloblastoma specific protein isoforms. Adding array gene expression data to this analysis, we calculate a relatively poor correlation between mRNA and protein abundance with the best concordance found among stable proteins. From the quantitative proteomic data, we are able to discern networks of functional pathways with differential activation between the medulloblastoma subgroups and normal control cerebellum yielding potential avenues for clinical intervention. This work demonstrates that quantitative proteomics can further elucidate the biology inherent in a genomically based classification regime.
Breve resumen de Swedres 2005, un informe sobre la utilización de antibióticos y la resistencia en Suecia
Authors: O Cars, B Olsson-Liljequist, K Lundh
Journal: Eurosurveillance (2007)

Swedres 2005, el quinto informe sobre la utilizacion de antibioticos y la resistencia en medicina humana en Suecia, se presento en mayo de 2006. En comparacion con los demas paises europeos, el consumo de antibioticos y el grado de resistencia son relativamente bajos en Suecia.
GENE-08. PHARMACOLOGIC MODULATION OF MYC AND PDGFRA BY TARGETING TOPOISOMERASE II ON GLIOMAS
Authors: Edgar Gonzalez-Buendia, Eric Feldstein, Junfei Zhao, Aayushi Mahajan, Ronald Realubit, Charles Karan, Raul Rabadan, Adam M Sonabend
Journal: Neuro-Oncology (2017)

Topoisomerase II (TOP2B) A/B regulate transcription by inducing double-strand DNA breaks and enhancing chromatin accessibility in other contexts, but their role in gliomas has not been elucidated. We investigated the effect of TOP2A/B on epigenetic regulation in glioma cell lines and explored the targeting of this process as a therapeutic strategy. We performed ChIP-qPCR/seq for TOP2A/B chromatin binding. RNA-seq and WB were used to evaluate gene expression. TOP2 inhibition was achieved with ICRF-193 and confirmed by decatenation assays. Susceptibility to TOP2 inhibitor MST-16 was evaluated by area under the curve (AUC) of dose response curves. TOP2A/B inhibition with ICRF-193 led to significant down-regulation of oncogenes PDGFRA and MYC on BT-142 (adj. p<7E-14), and similar results on TS543 glioma cell line. Concurrent with the decrease in transcript expression, PDGFRA protein decreased following ICRF-193 inhibition (p<0.001). Both TOP2A and TOP2B binding were enriched on the promoters of these oncogenes on TS543 and BT-142 as opposed to cell lines SNB19 and 0777A, which do not express PDGFRA or MYC. MYC down-regulation was associated with a trend for lower expression of its transcriptional targets following TOP2 inhibition (p=0.054). Susceptibility to the TOP2 inhibitor MST-16 (e.g. AUC) had a high correlation with the transcript levels of PDGFRA (Rho= -0.91, p=0.0014) and MYC (Rho= -0.7554, p=0.03) across 8 human glioma cell lines. TOP2 elicits epigenetic regulation of oncogene transcription in a subset of glioma cell lines and in those cases, its pharmacological targeting leads to simultaneous modulation of PDGFRA and MYC. The expression level of oncogenes modulated by TOP2 might serve as biomarkers to predict susceptibility and personalize the use of drugs that target this enzyme.
P1.03-009 A Lung Adenocarcinoma with a STRN-ALK Rearrangement Was Poorly Responsive to Alectinib Treatment
Authors: Y. Iida, Y. Nakanishi, N. Takahashi, H. Nishimaki, T. Nishizawa, Y. Nakagawa, T. Shimizu, Y. Gon, S. Masuda, S. Hashimoto
Journal: Journal of Thoracic Oncology (2017)
RTHP-29. DEVELOPMENT OF A NOVEL PROGNOSTIC SCORING SYSTEM FOR PATIENTS RECEIVING RE-IRRADIATION FOR RECURRENT HIGH GRADE GLIOMA
Authors: Cord Peters, Jason Cheng, Holly Ning, Mary Hawes, Barbara Arora, Theresa Cooley Zgela, Megan Mackey, Kevin Camphausen, Andra Krauze
Journal: Neuro-Oncology (2017)

Despite mounting evidence for the use of re-irradiation (re-RT) in recurrent high grade glioma, optimal patient selection criteria for re-RT remain unknown. We present a novel scoring system based on radiobiology principles including target independent factors, the likelihood of target control, and the anticipated organ at risk (OAR) toxicity for proper patient selection for re-RT of recurrent glioma. 31 patients with recurrent glioma who received re-RT (2008-2016) at NCI–NIH were included in the analysis. A novel scoring system was designed to include: 1) independent factors (age, KPS, histology, presence of symptoms), 2) target control tumor size, recurrence location, diffuse disease), and 3) OAR toxicity risk (OAR location, previous OAR dose, disease-free interval). Kaplan-Meier analysis was performed for overall survival (OS) and progression free survival (PFS) for comparison amongst variables. 31 patients, median age 46 (18 -73), with original diagnosis of (18 GBM, 5 anaplastic astrocytoma, 8 other) were analysed. Mean recurrence GTV and PTV were 29 cm3 (0.3-313) and 124 cm3 (0.5–511), respectively. Mean initial RT dose was 60 Gy (18-60) with a disease-free interval of 4.28 years (0.95-14.51). Re-RT dose was 30 Gy (15-54). Median PFS and OS from re-RT were 4 months (0.5-103) and 6 months (0.7-103), respectively. The independent factor and target control scores were each statistically significant for OS and in combination for both OS (p=0.02) and PFS (p=0.006). The anticipated toxicity risk score was not statistically significant. Our scoring system, which utilizes a radiobiological rationale in terms of target control, OAR toxicity risk, and patient factors, represents a novel in-depth approach to patient selection for re-RT in recurrent high grade glioma. Further validation in larger patient cohorts including compilation of doses to tumor and OAR may help refine this further for inclusion into clinical trials and practice surrounding re-RT.
CSIG-04. WNT SIGNALING REGULATES ALDEHYDE DEHYDROGENASE 3A1 (ALDH3A1) TO INDUCE TEMOZOLOMIDE RESISTANCE IN GLIOBLASTOMA CELLS
Authors: Abigail K Suwala, Katharina Koch, Rene Deenen, Karl Köhrer, Jörg Felsberg, Guido Reifenberger, Ulf Kahlert, Jaroslaw Maciaczyk
Journal: Neuro-Oncology (2017)

Glioma stem cells (GSCs) are considered to be responsible for glioblastoma’s dismal prognosis. The Wingless (WNT) signaling pathway promotes stemness and resistance towards chemo- and radiotherapy in glioblastoma. We have previously shown that pharmacological WNT inhibition using the porcupine inhibitor LGK974 reduces stem cell properties in glioblastoma in vitro. Here, we demonstrate that LGK974 acts synergistically with temozolomide (TMZ) and γ-radiation, the therapeutic modalities currently used as standard treatment for glioblastoma, to suppress in vitro growth of glioma cells. Synergistic growth inhibition was independent of the O6-alkylguanine DNA alkyltransferase (MGMT) promoter methylation status. In order to find genetic mechanisms that reveal WNT’s function in promoting chemoresistance we performed transcriptomic analysis. Aldehyde dehydrogenase 3A1 (ALDH3A1), an oxidative enzyme, was found to be significantly downregulated when cells were treated with LGK974 and TMZ. Using genetic approaches we verified a proportional correlation between WNT signaling and ALDH3A1 expression. Furthermore, ALDH3A1 knockdown cells were less viable and more sensitive towards TMZ treatment. Investigating pairs of primary and recurrent tumor samples from glioblastoma patients, we found that ALDH3A1 mRNA expression levels increased upon tumor recurrence following radiochemotherapy in some of the patients. Taken together, our study supports a novel role of ALDH3A1 in promoting TMZ resistance related to aberrant WNT signaling in glioblastoma cells.
NCOG-02. PRETREATMENT VOLUME OF MRI-DETERMINED WHITE MATTER INJURY (WMI) PREDICTS COGNITIVE DECLINE AFTER HIPPOCAMPAL AVOIDANT (HA) WBRT FOR BRAIN METASTASES: SECONDARY ANALYSIS OF NRG ONCOLOGY RTOG 0933
Authors: Joseph Bovi, Stephanie L Pugh, David Sabsevitz, Clifford G Robinson, Eric Paulson, Minesh P Mehta, Vinai Gondi, Vijayananda Kundapur, Wayne H Pinover, Samuel T Chao, Mitch Machtay, Albert S DeNittis, Nadia N Laack, Jeffrey N Greenspoon, Robert S Mannel, Jiayi Huang, Michael M Dominello, Lisa A Kachnic
Journal: Neuro-Oncology (2017)

RTOG 0933 demonstrated benefits to memory following HA-WBRT, supporting the hypothesis of hippocampal radiosensitivity and associated memory specificity. However, some patients demonstrated cognitive decline, suggesting mechanisms outside hippocampal radiosensitivity playing a role. WMI has been implicated in RT-induced cognitive decline. This secondary analysis explored the relationship between pre-treatment WMI and memory following HA-WBRT. 113 patients received HA-WBRT. Standardized cognitive assessments were performed at baseline, 2, 4, and 6 months. The primary endpoint was Hopkins Verbal Learning Test Delayed Recall (HVLT-DR) at 4 mos. Secondary endpoints included HVLT Total Recall (HVLT-TR) and Recognition (HVLT-Recog). Of 113 patients, 34 underwent pre-treatment and 4-month post-treatment HVLT testing and pre-treatment post-contrast volumetric T1 and axial T2/FLAIR MRI. Volumetric analysis of metastatic disease burden and disease-unrelated WMI was conducted on the pre-treatment MRI. Correlational analyses were performed examining the relationship between pre-treatment WMI and HVLT outcomes following HA-WBRT. Correlation was found between larger volumes of pre-treatment WMI and decline in HVLT-Recog (r=.54, p<.05) and a correlational trend was observed between larger volume of pre-treatment WMI and decline in HVLT-DR (r=.31, p=.08). Patients with higher pre-treatment disease burden experienced a greater magnitude of stability/positive shift in HVLT-TR and HVLT–DR following HA-WBRT. (r=-.36 and r=-.36, p’s <.05), compared to the magnitude of stability/positive shift in those with lesser disease burden. In patients receiving HA-WBRT, pre-treatment WMI predicts memory decline, suggesting white matter integrity pre-treatment contributes to the pathogenesis of post-WBRT cognitive toxicity independent of hippocampal stem cell radiosensitivity. Less decline/improvement in HVLT following HA-WBRT for patients with higher pre-treatment intracranial metastatic burden supports the importance of WBRT-induced intracranial control on cognition. These imaging biomarkers for cognitive toxicity will be further explored on NRG CC001 and CC003, phase III trials of WBRT with or without HA. Supporting NCI grants: U10CA180868, U10CA180822, U24CA180803, UG1CA189867.
La rabia en Europa en 2005
Authors: H Bourhy, L Dacheux, C Strady, A Mailles
Journal: Eurosurveillance (2005)

En 2005 la rabia sigue presente en Europa. Su incidencia humana sigue siendo limitada (menos de cinco casos al ano) por medio de la aplicacion estricta de medidas de profilaxis (tratamientos antirrabicos) y de medidas de control veterinario de la rabia en las poblaciones animales salvajes y domesticas. Los principales reservorios animales autoctonos son: el perro en los paises del este de Europa y en las fronteras con el Medio-Oriente, el zorro en el centro y el este de Europa, el mapache en el nordeste de Europa y los murcielagos insectivoros en todo el territorio. Finalmente, cada ano se describen casos de animales rabiosos importados de areas enzooticas, demostrando la permeabilidad de las fronteras y la falta de conciencia del riesgo de rabia en los viajeros. Esas importaciones son una amenaza permanente para el estatus libre de rabia de los animales terrestres de los paises de Europa occidental y complican la decision terapeutica de los medicos cuando no hay informacion sobre el animal mordedor.
EXTH-79. INITIAL EXPERIENCES WITH COMPASSIONATE-USE CUSP9v3/v4 FOR RECURRENT GLIOBLASTOMA
Authors: Marc-Eric Halatsch, Michael Salacz, Bernd Schmitz, Georg Karpel-Massler, Richard Kast
Journal: Neuro-Oncology (2017)

CUSP9v3/v4 uses 9 re-purposed drugs having preclinical data indicating antiglioma effects. We offered compassionate-use CUSP9v3 to 7, CUSP9v4 to 1, heavily pretreated low Karnofsky Performance Score patients with recurrent glioblastoma. CUSP9v3 uses aprepitant, a neurokinin-1 receptor blocker marketed to treat nausea; auranofin, a thioredoxin reductase inhibitor marketed to treat rheumatoid arthritis; captopril, an ACE inhibitor marketed to treat hypertension; celecoxib, an analgesic COX-2 inhibitor; disulfiram, an ALDH inhibitor marketed to treat alcoholism; itraconazole, an antifungal that inhibits Hedgehog; minocycline, an antibiotic that inhibits MMP-9; ritonavir, an antiviral that induces ER stress; sertraline, an antidepressant - all with low-dose temozolomide. CUSP9v4 substituted quetiapine, a RANKL inhibitor marketed to treat psychiatric illnesses for ritonavir (Patient A below). RATIONALE: 1) CUSP9v3/v4 drugs have ancillary attributes that block previously identified growth-stimulating pathways. 2) When one pathway is pharmacologically blocked, glioblastomas use other unblocked pathways. 3) Since we treat today's illnesses with today's tools, polypharmacy with already-marketed drugs is required to block multiple cross-covering pathways. RESPONSES: Changes in T1-weighted MRI were seen in recurrent glioblastomas in 6 of 8 patients during CUSP9v3/v4 treatment. Patient A, RANO PR by day 311 after initiation. Patient B, CR by day 189, resection for recurrence on day 288, restart of modified (m)CUSP9v3 on day 399 (progression along corpus callosum), PR on day 83 of mCUSP9v3. Patient C, PR by day 66 with decreasing diameters of necrotic cores and regression of fronto-caudal contrast enhancement. Patient D, PR on day 50, diminished lateral ventricle compression. Patient E, SD on day 39 with decreased contrast enhancement. Patient F and G, PR on days 63 and 39. There were 10 grade 3 and 1 grade 4 (infection) adverse events. CUSP9v3/v4 showed enough MRI evidence of potential activity in heavily pre-treated patients with low enough adverse events to warrant further study.