tbuckley/cabot-search huggingface dataset:
P2.03-015 Efficacy of EGFR-TKIs for EGFR Mutant NSCLC Patients with Central Nervous System Metastases: A Retrospective Analysis
Authors: K. Koyama, Y. Saida, T. Abe, M. Satokata, Y. Mishina, K. Sato, S. Shoji, T. Tanaka, K. Nozaki, K. Ichikawa, T. Miyabayashi, T. Ota, F. Fujimori, R. Ito, R. Kondo, T. Hiura, M. Okajima, S. Miura, S. Watanabe, N. Matsumoto, H. Tanaka, T. Kikuchi
Journal: Journal of Thoracic Oncology (2017)
DRES-06. PRIMARY RESISTANCE TO EGFR INHIBITION IN GLIOBLASTOMA IS MEDIATED BY A TNF-JNK-Axl-ERK SIGNALING AXIS
Authors: Gao Guo, Ke Gong, Amyn Habib
Journal: Neuro-Oncology (2017)

Aberrant EGFR signaling is widespread in various forms of cancer, but EGFR inhibition seems to be primarily effective only in a subset of lung cancers that harbor EGFR activating mutations and are oncogene addicted. Most cancers with aberrant EGFR signaling are not oncogene addicted and exhibit a primary resistance to EGFR inhibition. EGFR gene amplification and mutation are common in glioblastoma (GBM), but EGFR inhibition is not effective in treating this tumor. Primary resistance to EGFR inhibition could occur because the EGFR does not drive survival/proliferation of these cells or because adaptive signals prevent cell death. Our data suggest that EGFR expressing glioma cells exhibiting primary resistance are potentially oncogene addicted and that primary resistance results from a rapid adaptive response to EGFR inhibition that mediates cell survival. We show that in primary GBM neurospheres or cell lines expressing either EGFRwild type or the mutant EGFRvIII, erlotinib triggers a rapid adaptive response that is driven by tumor necrosis factor (TNF) and protects cells from a loss of EGFR signaling. Increased TNF secretion leads to JNK activation, which serves as a key regulator of this survival response. JNK activation results in increased levels of GAS6 and activation of Axl, leading to ERK activation. We propose that this TNFα-JNK-Axl-ERK signaling axis mediates primary resistance to EGFR inhibition in GBM. Inhibition of this adaptive response at multiple nodes renders glioma cells with primary resistance sensitive to EGFR inhibition. Moreover, combined treatment of erlotinib and thalidomide as a TNF inhibitor resulted a highly significant improved survival in intracranial mouse model using patient derived samples (n=8, p<0.01), whereas erlotinib or thalidomide alone were not effective. Our findings suggest a new approach to the treatment of GBM using a combination of EGFR and TNF inhibition.
Abstract 15119: Consumption of a Defined Plant Based Diet Reduces Lp(a) and Other Atherogenic Lipoproteins and Particles in Four Weeks
Authors: Rami S Najjar, Frank A Laws, Carolyn E Moore, Baxter D Montgomery
Journal: Circulation (2017)

Introduction: Lipoprotein(a) [Lp(a)] is a highly atherogenic lipoprotein and is minimally effected by lifestyle changes. No medical therapy has consistently shown definitive reduction of Lp(a). The...
RARE-30. ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMA WITH LEPTOMENINGEAL DISSEMINATION RESPONSIVE TO BRAF INHIBITION AND BEVACIZUMAB
Authors: Alissa Thomas, Suzanne Tucker, Carl Nelson, Joshua Nickerson, Susan Durham, Alan Homans
Journal: Neuro-Oncology (2017)

Anaplastic pleomorphic xanthoastrocytoma (PXA) is a newly recognized entity in the 2016 WHO classification of CNS tumors, characterized by elevated mitotic activity with or without necrosis, and shorter survival when compared with WHO grade II PXAs. BRAF V600E mutations are frequent. While grade II PXAs can often be managed surgically, there is no consensus on the optimal treatment for anaplastic PXA. Rarely, anaplastic PXA can present with leptomeningeal dissemination (LMD), which is associated with poor prognosis. We present a case of a 16-year-old girl diagnosed with a left frontal anaplastic PXA with BRAF V600E mutations and high grade features of necrosis. Following subtotal resection, cranial radiation, and temozolomide chemotherapy her tumor recurred with bulky, nodular LMD throughout the cervical, thoracic, and lumbar spine. She received palliative radiation to the thoracic spine and then started targeted therapy with dabrafenib with a partial radiographic response and then trametinib was added to dabrafenib with sustained response for 5 months. When the leptomeningeal tumor progressed, bevacizumab was added to the dabrafenib and trametinib therapy, and the patient remained stable for an additional 4 months. The combined therapy was very well tolerated; the patient experienced a grade II rash with initiation of dabrafenib, but no other side effects. To our knowledge this is the first time dabrafenib, trametinib, and bevacizumab have been combined to treat a pediatric high grade glioma. This is also the first report of BRAF inhibition in glial LMD. Our experience suggests that targeted therapy with dabrafenib and trametinib can be safely combined with anti-angiogenic therapy and may improve quality of life and survival in patients with LMD associated with high grade PXA. The growing experience with targeted therapy in rare pediatric gliomas may justify a need for a larger clinical trial.
Ziv-aflibercept in combination with FOLFIRI for the second-line treatment of patients with metastatic colorectal cancer: Third interim safety data from the global aflibercept safety and quality-of-life program (ASQoP and AFEQT studies).
Authors: Roberto Bordonaro, Alberto F. Sobrero, Rosario Vincenz Iaffaioli, Hendrik Kroening, Pilar Garcia Alfonso, Luca Frassineti, Libero Ciuffreda, Evaristo Maiello, Giuseppe Aprile, Anne L. Thomas, Yan Moore, Chiara Zilocchi, Sandrine Brette, Emmanuelle Dochy, Gérard Lledo, Julien Taïeb
Journal: Journal of Clinical Oncology (2014)

e14562 Background: Results from the phase 3 VELOUR study of ziv-aflibercept (Z, known as aflibercept outside the United States) supported initiation of the global Aflibercept Safety and Quality-of-Life (QoL) Program composed of 2 clinical studies (ASQoP [NCT01571284]; AFEQT [NCT01670721]) to capture QoL and safety data from a target population similar to that of VELOUR in a real-life setting. We report updated safety data from this 3rd interim analysis in the overall population and patients (pts) pretreated with bevacizumab (B). Methods: ASQoP and AFEQT are single-arm, open-label trials in metastatic colorectal cancer pts previously treated with an oxaliplatin-containing regimen. Eligible pts receive Z (4 mg/kg) q2wks on day 1 of each cycle followed by FOLFIRI until disease progression, unacceptable toxicity, death, or investigator/pt decision. Initial starting doses of FOLFIRI and subsequent dose modifications are at the treating physician’s discretion. Interim analyses were preplanned to evaluate safety in a real-life setting. Percentages of pts with grade (G) 3/4 adverse events (AEs) in the combined safety population of ASQoP and AFEQT and in B-pretreated pts are compared with those of the ITT population and B-pretreated pts, respectively, in VELOUR. Results: At the preplanned data cutoff date, the safety population comprised 450 pts with ≥1 completed treatment cycle; 238 were pretreated with B. At least 1 G3/4 AE was experienced by 63.8% of pts vs 83.5% in VELOUR. Most reported G3/4 AEs were G3. There were no reports of G4 hypertension. Conclusions: This3rdinterim safety analysis from ASQoP and AFEQT has identified no new safety signals. This updated analysis provides additional safety data and suggests an acceptable toxicity profile in this real-life setting, including B-pretreated pts. Clinical trial information: NCT01571284. Overall Pretreated with bevacizumab Grade 3/4 AE, % ASQoP/AFEQT n=450 VELOUR n=611 ASQoP/AFEQT n=238 VELOUR* n=171 Proteinuria (PT) 0.9 2.9 0.8 1.8 Stomatitis (PT) 8.0 12.8 8.8 10.5 Diarrhea (PT) 14.0 19.3 15.5 18.7 Infections (SOC) 8.4 12.3 8.4 13.5 Hypertension (PT) 18.4 19.1 14.3 16.4 *Per eCRF.
Abstract 16221: Therapeutic Lymphangiogenesis Ameliorates Cardiac Dysfunction in the Setting of Ischemic-induced Heart Failure
Authors: Yuuki Shimizu, Rohini Polavarapu, Toyoaki Murohara, John Calvert
Journal: Circulation (2016)

Background: Lymphatic vessels exist throughout the body in the same manner as blood vessels. They interconnect with blood vessels to form an elaborate system that function in interstitial fluid dra...
CMET-11. IMPACT OF TUMOR SIZE AND MOLECULAR PROFILE ON LOCAL CONTROL IN PATIENTS WITH BREAST CANCER BRAIN METASTASES: UNDERSTANDING TUMOR BIOLOGY AND RADIOSURGERY DOSING
Authors: Rupesh Kotecha, Jacob Miller, Alireza Mohammadi, Erin Murphy, John Suh, Gene Barnett, Michael Vogelbaum, Lilyana Angelov, Manmeet Ahluwalia, Samuel T Chao
Journal: Neuro-Oncology (2017)

Studies in the breast cancer literature have demonstrated that recurrence rates after surgery and adjuvant whole-breast irradiation differ based on tumor subtype. The hypothesis of this study was to clarify the relationship between tumor biology and dose in patients undergoing stereotactic radiosurgery (SRS) for breast cancer brain metastases (BCBM). The records of 222 patients who underwent SRS to 864 BCBM at a single tertiary care institution from 1997–2015 were reviewed. The primary outcome was the cumulative incidence of local failure, with death as a competing risk. Cohorts were defined by either RTOG prescription dosing (24 Gy for ≤2 cm, 18 Gy for 2–3 cm, and 15 Gy for >3 cm sized lesions) or non-RTOG prescription dosing (12–23 Gy for ≤2 cm, 12–17 Gy for 2–3 cm, and 10–14 Gy for 3–4 cm sized lesions) and breast cancer tumor subtype. For lesions ≤ 2 cm, luminal A and luminal B subtypes were the most radiosensitive, with the smallest magnitude of differences based on dosing strategy (1.8% and 2.5% absolute difference in local control, respectively). Larger luminal A BCBM showed only a 4% difference in local control, even for the largest BCBM (>3 cm). Alternatively, triple-negative and Her-2/neu positive BCBM >2 cm showed the highest differences in local failure based on dosing strategy (>5% difference regardless of size). Dose de-escalation can be considered for patients with BCBM from favorable subtypes without significant differences in local control. Dose-escalation or strategies incorporating targeted therapy in combination with SRS should be considered for larger triple-negative or Her-2/neu positive BCBM, given the high local failure rates with dose de-escalation approaches. Further work is needed to understand the molecular underpinnings driving differences in radiosensitivity among tumor subtypes.
DRES-17. BCL3 IS A 19q PASSENGER THAT PREDICTS RESPONSE TO ALKYLATING CHEMOTHERAPY IN GBM
Authors: Longtao Wu, Giovanna Bernal, Kirk Cahill, Peter Pytel, Bakhtiar Yamini
Journal: Neuro-Oncology (2017)

Despite the universal use of temozolomide (TMZ) in GBM, many patients experience minimal benefit. Moreover, TMZ can be deleterious due to its mutagenic nature. These findings underline the importance of predicting which patients will benefit from TMZ. DATA: Bcl-3 was identified as being involved in cytotoxicity by TMZ due to its unique interaction with NF-κB residues modified following treatment. Up- and down-regulation of Bcl-3 in patient-derived glioma stem-like cells (GSCs) demonstrates that Bcl-3 blocks cytotoxicity by TMZ in vitro and in an intracranial PDX. Analysis of multiple public GBM datasets demonstrates that BCL3 mRNA expression is a marker of outcome, a finding confirmed on multivariate analysis incorporating MGMT promoter methylation, age and IDH mutation among other variables. Most notably, separation of patients in TCGA by treatment modality demonstrates that BCL3 is only informative in patients who received alkylating chemotherapy not untreated patients or those receiving ionizing radiation (IR) alone, a finding significant on multivariate analysis and validated in REMBRANDT. To examine Bcl-3 protein, TMAs were constructed incorporating 86 GBMs. Bcl-3 immunohistochemistry graded on a 4-tier system and dichotomized significantly separates patients into survival groups (P<0.0001; HR, 5.418; 95%CI, 2.747–9.647). In GBM, Bcl-3 mRNA and protein level is regulated by gene copy number determined in public datasets and in TMAs by FISH. CNAs of BCL3 occur due to changes directed to a broad region of 19q13, an area deleted in 20–40% of all types of glioma. Mechanistically, Bcl-3 promotes resistance by inducing mesenchymal differentiation via promoter-specific NF-κB dimer exchange, shown in GSCs and confirmed in TCGA GBM. BCL3 is an independent predictor of response to TMZ in GBM whose expression is regulated by CNA targeted to 19q13 that inadvertently affect BCL3. Bcl-3 expression level represents a cell-intrinsic modulator of NF-κB activity that promotes mesenchymal differentiation and resistance to therapy.
QLIF-05. A SINGLE INSTITUTION’S EXPERIENCE EXPLORING THE ASSOCIATION OF INTEGRATIVE MEDICINE AND SURVIVORSHIP IN GLIOBLASTOMA
Authors: Dina Randazzo, Frances McSherry, James E Herndon, Mary Lou Affronti, Patrick Healy, Eric S Lipp, Annick Desjardins, Henry S Friedman, Katherine B Peters
Journal: Neuro-Oncology (2017)

Complementary and Alternative Medicine (CAM) uses diverse practices and products that are not a part of standard of care while Integrative Medicine combines both CAM and conventional medicine. Given the poor prognosis of glioblastoma (GBM), many patients will explore other options to improve survival or quality of life. We sought to examine the association between CAM modalities and survivorship. In this cross-sectional retrospective analysis, data about CAM treatment and self-help practices were obtained from the modified International Complementary and Alternative Medicine Questionnaire (I-CAM-Q). CAM treatment included modalities such as vitamins/supplements, massage, energy work, or acupuncture, while CAM self-help practices consisted of praying, exercise, visualization, meditation, relaxation, or diet. Survival was defined by date of questionnaire completion to date of death. There were 365 GBM patients (31% censored) with a median overall survival (mOS) of 14.1months, 95% CI: 12.2, 17.0. Those patients who used CAM self-help practices (n=188, mOS =16.2 months, 95% CI: 12.2, 18.1) and CAM treatments (n=237, mOS = 15.5 months, 95% CI: 9.9, 18.1) did not have any association with survival compared to those who did not use self-help (n=65; mOS = 20.9 months, 95% CI: 12.7, 39.1) or CAM treatments (n=74, mOS = 15.5 months, 95% CI: 9.9, 18.1). The most popular modalities used, prayer (n=171, 15.1 vs 22.7 months) and supplements (n=220; 14.7 vs 16.5 months) were also not associated with survival. The use of CAM was not a predictor of survival whereas those who were multifocal, grade IV, older than 55, or had recurrent disease had significantly poorer survival. It is difficult to accurately predict survival benefit because of this study’s cross-sectional design. Due to the increased interest in CAM in the primary brain tumor population, a prospective analysis utilizing some of these self- help practices or treatments may be warranted.
EPID-07. ALTERATIONS IN PERIPHERAL BLOOD COUNTS AND INDICES IN PATIENTS WITH INTRA-AXIAL BRAIN TUMORS
Authors: Subeikshanan Venkatesan, Akshat Dutt, Venkatesh Madhugiri
Journal: Neuro-Oncology (2017)

Elevation in the neutrophil-lymphocyte ratio (NLR) has been shown to be of prognostic significance in several solid cancers. The brain is considered an immune-privileged site. Moreover, most brain tumors do not metastasize outside the central nervous system. We therefore attempted to examine if brain tumors caused any measurable alterations in peripheral blood counts and indices. This was a combined prospective-retrospective study. All consecutive patients with newly diagnosed intra-axial brain tumors (IABT) who were steroid-naive were included in the study. A healthy control population who had undergone blood tests for occupational health screening was compared with the tumor group. 318 subjects were included - 145 patients with IABT and 173 healthy controls. The median age of the control group was 24 years and that of the IABT group was 40 years. The mean Hb in the control group was 14.5 ± 1.6 gm% and that for the IABT group was 13.5 ± 2.1 gm% (p<0.001). The mean platelet count (per cu mm) was significantly higher in the IABT group (263035.9 ± 80738.6) than in the control group (225912.8 ± 73591.6, p<0001). The mean total leucocyte count was also higher in the IABT group (9187.5 ± 3894.7 per cu mm) compared to the control group (7794.9 ± 1867.5, p=0.001). The median NLR of the IABT group (2.53, IQR-2.54) was significantly higher than that of the control group (1.77, IQR-0.9, p<0.001). One way ANOVA showed that the NLR was significantly higher for grade IV tumors than other lower grade IABTs. IABTs cause definite alterations in peripheral blood counts and indices. Thrombocytopenia and elevated NLR have been described to be indicative of poor prognosis in other solid tumors; this pattern was observed with IABTs as well, especially in grade 4 tumors.
Evaluation de la classification des cas d’encéphalites à tiques en Pologne
Authors: P Stefanoff, M Eidson, D L Morse, A Zielinski
Journal: Eurosurveillance (2005)

L’encephalite a tiques d’Europe centrale est une atteinte virale du systeme nerveux central. Bien qu’un systeme de surveillance de cette encephalite existe en Pologne depuis 1970, il n’y a pas de definition de cas standardisee et les tests de diagnostic u
GPs lose millions from mis-sold financial products
Authors: Gareth Iacobucci
Journal: BMJ (2017)

General practices have had to pay out millions of pounds after they bought interest rate hedging products mis-sold to them by banks, The BMJ has learnt.

In some cases the deals have left GPs struggling to retire or to sell their practices.

Interest rate hedging products, or “swaps,” are designed to help buyers manage fluctuations in interest rates with fixed rate deals. They were sold to small businesses seeking loans from 2001.

But in 2013 the Financial Conduct Authority found that there had been “serious failings” in the sale of these products and that 90% had been mis-sold.1

The BMJ has learnt of at least 10 medical centres hit by the scandal, with experts predicting that dozens or even hundreds may have been affected.

One affected practice, the Ridge Medical Practice in Bradford, paid out an estimated £3.6m (€4m; $4.7m) to the Royal Bank of Scotland in interest between 2007 and 2015 after it took out a 26 year swap along with a £9.5m loan to fund new premises. The bank has refused to pay any compensation to the practice.

Nick Nurden, the Ridge practice’s business manager, who oversaw the deal in 2008, told The BMJ , “We were presented with what was effectively a fait accompli by the bank. They presented it to us as really the only option, but from what I now know there were far better products that would have been easily affordable and would’ve actually still done the same job of providing that security. …
Crizotinib in ROS1 rearranged or MET deregulated non-small-cell lung cancer (NSCLC): final results of the METROS trial
Authors: L. Landi, R. Chiari, C. Dazzi, M. Tiseo, A. Chella, A. Delmonte, L. Bonanno, D. Cortinovis, F. de Marinis, G. Minuti, R. Buosi, A. Morabito, P. Maione, D. Galetta, F. Barbieri, F. Grossi, S. Novello, R. Bruno, G. Fontanini, L. Crinò, F. Cappuzzo
Journal: Annals of Oncology (2017)
Rughetta di importazione, in parte responsabile dell’aumentata incidenza di casi di epatite A in Svezia, 2000-2001
Authors: K Nygård, Y Andersson, P Lindkvist, C Ancker, I Asteberg, E Dannetun, R Eitrem, L Hellström, M Insulander, L Skedebrant, K Stenqvist, J Giesecke
Journal: Eurosurveillance (2001)

Un aumento dell’incidenza di epatite A in Svezia, senza nessuna causa ovvia di infezione, ed una epidemia circoscritta durante la primavera del 2001, hanno portato ad intraprendere uno studio caso-controllo. Il consumo di rughetta importata e stato associato alla malattia (essendo gli odds ratio pari a 9,1; intervallo di confidenza al 95% 1,5- 69). L’importazione di vegetali da paesi dove l’epatite A e endemica in paesi dove invece non lo e, continua a costituire un problema di salute pubblica.
Seizures and Encephalitis in Myelin Oligodendrocyte Glycoprotein IgG Disease vs Aquaporin 4 IgG Disease
Authors: Shahd H. M. Hamid, Dan Whittam, Mariyam Saviour, Amal Alorainy, Kerry Mutch, Samantha Linaker, Tom Solomon, Maneesh Bhojak, Mark Woodhall, Patrick Waters, Richard Appleton, Martin Duddy, Anu Jacob
Journal: JAMA Neurology (2017)

<h3>Importance</h3> Antibodies to myelin oligodendrocyte glycoprotein IgG (MOG-IgG) are increasingly detected in patients with non–multiple sclerosis–related demyelination, some of whom manifest a neuromyelitis optica (NMO) phenotype. Cortical involvement, encephalopathy, and seizures are rare in aquaporin 4 antibody (AQP4-IgG)–related NMO in the white European population. However, the authors encountered several patients with seizures associated with MOG-IgG disease. <h3>Objective</h3> To compare incidence of seizures and encephalitis-like presentation, or both between AQP4-IgG–positive and MOG-IgG–positive patients. <h3>Design, Setting, and Participants</h3> Retrospective case series of all patients who were seropositive for MOG-IgG (n = 34) and the last 100 patients with AQP4-IgG disease (NMO spectrum disorder) seen in the NMO service between January 2013 and December 2016, and analysis was completed January 4, 2017. All patients were seen in a tertiary neurological center, The Walton Centre NHS Foundation Trust in Liverpool, England. <h3>Main Outcomes and Measures</h3> The difference in seizure frequency between the AQP4-IgG–positive and MOG-IgG–positive patient groups was determined. <h3>Results</h3> Thirty-four patients with MOG-IgG disease (20 female) with a median age at analysis of 30.5 years (interquartile range [IQR], 15-69 years), and 100 AQP4-IgG–positive patients (86 female) with a median age at analysis of 54 years (IQR, 12-91 years) were studied. Most patients were of white race. Five of the 34 patients with MOG-IgG (14.7%) had seizures compared with 1 patient with AQP4-IgG (2-sided<i>P</i> &lt; .008, Fisher test). On magnetic resonance imaging, all 5 MOG-IgG–positive patients had inflammatory cortical brain lesions associated with the seizures. In 3 of the 5 MOG-IgG–positive patients, seizures occurred as part of the index event. Four of the 5 presented with encephalopathy and seizures, and disease relapsed in all 5 patients. Four of these patients were receiving immunosuppressant medication at last follow-up, and 3 continued to take antiepileptic medication. In contrast, the only AQP4-IgG–positive patient with seizures had a diagnosis of complex partial epilepsy preceding the onset of NMO by several years and experienced no encephalitic illness; her magnetic resonance imaging results demonstrated no cortical, subcortical, or basal ganglia involvement. <h3>Conclusions and Relevance</h3> Patients with MOG-IgG–associated disease were more likely to have seizures and encephalitis-like presentation than patients with AQP4-IgG–associated disease.