tbuckley/cabot-search huggingface dataset:
PDTM-38. ANALYSIS OF PAIRED BRAFV600E MUTANT GLIOMA PATIENT SAMPLES IDENTIFIES NOVEL RESISTANCE MECHANISMS TO TARGETED BRAF INHIBITION
Authors: Jean Mulcahy Levy, Bridget Sanford, Andrew Morin, Adam Green, Patrick Flannery, Kenneth Jones, Anuradha Banerjee, David A Solomon, Theo Nicolaides
Journal: Neuro-Oncology (2017)

BRAFV600E mutations occur in a variety of gliomas including gangliogliomas, epithelioid glioblastomas, pleomorphic xanthroastrocytomas, and pilocytic astrocytomas. The development of BRAFV600E targeted therapies has provided a new treatment option for these patients. Clinical trials in melanoma and colorectal cancer as well as early studies in central nervous system (CNS) tumors indicates a high risk for the development of resistance to these therapies. While the resistance mechanisms in non-CNS tumors has been explored, to date there is little data available for resistance mechanisms in glioma patients treated with BRAFV600E inhibition. To identify molecular and pathway alterations driving resistance in glioma, we performed targeted next-generation DNA sequencing, RNA sequencing, and Ingenuity Pathway Analysis (IPA) on paired pre-treatment and post-resistance primary patient samples (n=4) and cell lines (n=2). Unique genetic alterations likely driving tumor recurrence and resistance to BRAF inhibition were identified in each of the paired samples. Novel mutations identified in the recurrent gliomas included a de novo mutation in the CBL gene that localizes within the RING finger domain of the encoded E3 ubiquitin ligase protein and has been recurrently found in myeloid neoplasms, a frameshift mutation in the RB1 tumor suppressor gene, and a nonsense mutation in ERRFI1, which encodes a negative regulator of EGFR signaling. IPA analysis demonstrated significant pathway activation differences in recurrent samples as well. There was a predominance of up-regulated receptor tyrosine kinase pathways including EGFR, NTRK2, TGFB1, estrogen receptor, ERBB2, and PI3K. Expected up-regulation of the MEK, MAPK1, MAP2k1 and ERK1/2 pathways was also found. The altered pathways were unique for each paired set. These data suggest that pediatric gliomas develop resistance to BRAF inhibition using a multitude of genetic and transcriptional mechanisms that are potentially distinct in each tumor, and with evidence of novel resistance mutations not found in resistant melanoma or colorectal cancers.
EGFR gene copy number detection in non small cell lung cancer: A comparison of chromogenic in situ hybridization (CISH) versus f luorescent in situ hybridization (FISH)
Authors: Marielle Gallegos Ruiz, Karijn Floor, Wim Vos, Katrien Grunberg, Gerrit Meijer, Jose Rodriguez, Giuseppe Giaccone
Journal: Cancer Research (2007)

3770   The Epidermal Growth Factor Receptor (EGFR) is an important target for anti-cancer therapy. In non-small cell lung cancer (NSCLC), mutations in the tyrosine kinase domain of EGFR and EGFR gene copy number have been demonstrated to identify patients who most likely benefit from treatment with EGFR tyrosine kinase inhibitors (TKIs). EGFR gene copy number has been mainly assessed by Fluorescent In Situ Hybridization (FISH), a method that requires the use of a fluorescence microscope, and is limited by the rapid fading of the fluorescent signal. These shortcomings of FISH can be overcome by using Chromogenic In situ Hybridization (CISH), a method that makes use of a chromogenic rather than a fluorescent signal.  In order to test the applicability of CISH for assessing EGFR gene copy number in NSCLC samples, we performed a side-to-side comparison of CISH and FISH with both formalin-fixed, paraffin-embedded (FFPE) specimens (n=27) and frozen tumor samples (n=31). Scoring was done by two independent observers, by counting the hybridization signals (dots) in 200 tumor cells in at least three representative microscopic fields. Samples were considered positive when ≥4 dots per nucleus were present in ≥40% of tumour cells, or when tight EGFR gene clusters were present in ≥10% of cells.  All the frozen samples analyzed by CISH and FISH could successfully be scored, although the number of samples difficult to assess was higher with CISH (14 samples compared to 8 with FISH), due to high background signal. Importantly, when analysing FFPE tissues, all samples could be scored with CISH, but 45% (14 out of 31) could not subsequently be analyzed by FISH due to excessive autofluorescence (4 cases), detachment of tissue (5 cases), unrecognizable morphology (4 cases) or low signal (1 case). Using FISH analysis the concordance between the two observers in the scoring of the samples was 100% (Kappa coefficient = 1). Using CISH, a 93% concordance (Kappa coefficient = 0.74) was found. In 3 out of 4 discordant cases, discrepancy was caused by borderline positivity, and in 1 case by high sample heterogeneity. The concordance between the CISH and FISH results was 93% for the first observer (Kappa coefficient = 0.64) and 95% for the second observer (Kappa coefficient = 0.76). In 3 cases both observers found a discrepancy between the scoring of CISH and FISH. This was due to the strict cut-off value, the samples scoring negative with one of the techniques and borderline positive with the other.  In conclusion, CISH is a suitable alternative to FISH as technique to determine EGFR gene copy number in patients with NSCLC, especially in FFPE samples.
Microscopic Studies of the Early Growth of a Transplantable Melanoma of the Mouse, Using the Transparent-chamber Technique
Authors: Glenn H. Algire
Journal: JNCI Journal of the National Cancer Institute (1943)

Journal Article Microscopic Studies of the Early Growth of a Transplantable Melanoma of the Mouse, Using the Transparent-chamber Technique Get access Glenn H. Algire Glenn H. Algire National Cancer Institute, National Institute of Health, United States Public Health Service Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 4, Issue 1, August 1943, Pages 13–20, https://doi.org/10.1093/jnci/4.1.13 Published: 01 August 1943
The value of trabectedin in the treatment of soft tissue sarcoma: a monoinstitutional retrospective real-life study
Authors: S. Turano, C. Manfredi, S. Conforti, R. Biamonte, A. Rovito, A. Filice, S. Minardi, C.M. Mastroianni, V. Liguori, R. De Simone, A. Piattelli, M.D. Iuvaro, A. Toretti, S. Palazzo
Journal: Annals of Oncology (2017)
NTOX-06. INCREASE OF PSEUDOPROGRESSION AND TREATMENT RELATED EFFECTS IN LOW-GRADE GLIOMA PATIENTS TREATED WITH PROTON RADIATION AND TEMOZOLOMIDE
Authors: Michael Dworkin, William Mehan, Andrzej Niemierko, Sophia Kamran, Jorg Dietrich, Maria Martinez-Lage Alvarez, Kevin Oh, Tracy Batchelor, Patrick Wen, Jay Loeffler, Helen Shih
Journal: Neuro-Oncology (2017)

Chemoradiation with temozolomide (TMZ) can be associated with pseudoprogression (PsP) in glioblastoma. The occurrence of early or delayed treatment effects and pseudoprogression is less well understood in low-grade gliomas (LGG). We hypothesized that adding TMZ to radiotherapy might increase the incidence of treatment related effects or pseudoprogression. Chart review and volumetric MRI-analysis was performed on 109 chemotherapy-naïve patients with grade I-II or IDH1-mutant grade III glioma treated with proton-radiotherapy (RT) between 2005-2015. Progression was defined by tissue-diagnosis or new chemotherapy-initiation. Post-treatment related effects (PTRE) were defined as increase in T2/FLAIR or new/increase in abnormal enhancement without evidence of tumor progression or growth 6-12 months later. PsP was defined if a lesion meeting PTRE-criteria was suspicious for progression or volumetrically increased at least 40% from baseline. Late-PsP was defined as PTRE occurring more than 12 months after RT. Pearson’s chi-squared test was used for statistical analysis. Median RT-dose was 54 Gy (RBE) (range: 45-60). There were 70, 27, and 12 patients who respectively received RT alone, RT with concurrent-TMZ, and RT with adjuvant (sequential)-TMZ. PsP was not more common with concurrent-TMZ versus adjuvant-TMZ (PsP: 67% versus 83%; p=0.29; enhancing-PsP: 52% versus 58%; p=0.710). However, PsP was significantly more frequent with TMZ+RT versus RT alone (PsP: 72% versus 39%; p<0.001; enhancing-PsP: 54% versus 34%; p=0.047). There were no significant inter-group-differences in mean-change from pre-RT-baseline in KPS, MMSE, or seizures during the year following RT-initiation. PsP was significantly more common in presence of p53-mutation (PsP: 62% versus 38%; p=0.048; enhancing-PsP: 48% versus 29%; p=0.124), but unrelated to IDH1-mutant status (PsP: 59% versus 38%; p=0.101; enhancing-PsP: 43% versus 43%; p=1.0) and MGMT promoter methylation (PsP: 66% versus 47%; p=0.296; enhancing-PsP: 50% versus 47%; p=0.876). Treatment with TMZ and p53-mutation status were associated with increased PsP in LGGs treated with proton-radiotherapy.
NCOG-17. COGNITION AND BRAIN STEREOTACTIC RADIOTHERAPY: A PILOT TRIAL
Authors: Emmanuelle Reygagne, Foucaud du Boisgueheneuc, Pierre Ingrand, Antoine Berger
Journal: Neuro-Oncology (2017)

To evaluate a computerised cognitive test for the detection of information processing speed impairment in patients with radiation therapy for brain metastases named Interhemispheric transfer time test (IHTTT). Medical inclusion criteria: patients≥18 years, with 1 to 4 brain metastases treated by stereotactic radiotherapy (SRT) with dose schedule: 33 Gy in 3 fractions, with a solid tumour, ≥70 Karnofsky Performance Status, with Mini-Mental State Evaluation (MMSE) ≥ 24, without medical history of stroke brain injury. 29 patients were recruited to our Center from June 2014 to April 2015. All recruited patients were administered a MMSE, the Frontal Assessment Battery at Bedside (FAB), a IHTTT and a quality of life questionnaire before SRT, and at one month, six months and one year follow up. The primary endpoint was Interhemispheric Transfer Time (IHTT). Secondary endpoints included IHTI (Interhemispheric Transfer Index), MMSE score, FAB score and quality of life. Our results suggest that IHTT and IHTI could detect a significant evolution of cognitive function over time (IHTT=720.3 ms ±26.5 at baseline, 728.0 ± 19.8 at one month follow up, 735.5 ± 36.1 at 6 month, 790.5 ± 109.1 at one year follow up, p=0.04, IHTI=13.1 ± 31.4, 11.5 ± 24.3, 50.6 ± 57.9, 82.2 ± 63.5, p=0.01). There is no significant evolution over time for MMSE and FAB score. This confirms their low sensitivity and specificity for detecting cognitive impairment. No significant evolution over time for quality of life questionnaire. IHTTT could be an interesting cognitive test to include in patients’ evaluation with brain metastases irradiated by SRT.
DDIS-06. ONC206, AN IMIPRIDONE FAMILY MEMBER, SUPPRESSES GLIOMA STEM CELL MAINTENANCE
Authors: Jinkyu Jung, Brent A Reynolds, Joshua E Allen, Mark R Gilbert, Deric M Park
Journal: Neuro-Oncology (2017)

Imipridones selectively target G protein-coupled receptors (GPCRs) that control critical signaling pathways in various cancer cells. Aberrant overexpression of GPCRs has been implicated in tumorigenesis. ONC201, a first generation imipridone that directly antagonizes dopamine receptor D2 (DRD2), continues to be evaluated in clinical trials for advanced cancers. The immediate downstream mechanism(s) of DRD2 inhibition and resulting anti-cancer activity remains an area of active study. Here, we show that ONC206, an analog of ONC201 that shares the same imipridone core chemical structure and selective antagonism of DRD2, potently inhibits patient-derived glioma stem cell (GSC) populations. In silico analysis of a glioma patient database led us to investigate DRD2 signaling in glioma; alteration of DRD2 mRNA expression was directly connected to global gene expression change in glioma patient database. CellTiter-Glo cell viability assay showed that exposure to ONC206 in a dose dependent manner preferentially eliminated GSCs, compared to differentiated glioma cells. Protein array of stem cell markers revealed treatment of ONC206 down-regulated protein expression of oncogenic stem cell markers in the GSCs. Further, in vitro limiting dilution assay and sphere formation analysis showed that ONC206 prevented tumor sphere formation and tumor growth. These observations indicate that ONC206 exhibits promising anti-glioma activity and suggest that elucidating the downstream effects of antagonizing DRD2 signaling with ONC206 in gliomas is warranted.
NIMG-100. USEFULNESS OF 18FET-PET FOR CHEMOTHERAPY MONITORING IN NON-CONTRAST ENHANCING GLIOMA
Authors: Bogdana Suchorska, Marcus Unterrainer, Annamaria Biczok, Nathalie Albert, Joerg-Christian Tonn, Friedrich-Wilhelm Kreth
Journal: Neuro-Oncology (2017)

Monitoring treatment response after chemotherapy of gadolinium (Gd) negative gliomas is challenging as conventional MRI often indicates no radiological changes. We hypothesize that molecular imaging using 18F-FET-PET can be used as a biomarker for response assessment in Gd-negative gliomas undergoing chemotherapy. 61 patients harboring histologically proven Gd-negative WHO grade II (n= 44) or III (n=17) glioma receiving alkylating agents (temozolomide or CCNU/ procarbacine) were included. All patients underwent MRI and 18FET-PET investigations before chemotherapy and 6 months later using a prospective imaging protocol. We calculated T2-volume, 18FET-PET based biological tumour volume (BTV) and maximal tumour-to-brain ratio (TBRmax). A volume decrease >25% of T2-volume and/or BTV and/or a TBRmax reduction of >10% were classified as treatment response, whereas a volume increase >25% and/or a TBRmax increase >10% were categorized as tumour progression. Otherwise, stable disease was assumed. Overall survival (OS) and progression free survival (PFS) were calculated from beginning of chemotherapy. Prognostic factors were obtained from proportional hazards models. At the time of last follow up, 10 patients died and 42 patients experienced tumour progression. 18FET-PET based assessment of treatment response was significantly associated with both PFS (BTV p=0.004; TBRmax p= 0.006) and OS (BTV p<0.001; TBRmax = 0.003), while T2-volume based assessment was not (p=0.84 for PFS and p=0.07 for OS). According to the applied BTV classification scheme, OS was 135.8 months for responders, 92.8 months in case of stable disease, and 40.3 months for non-responders. Lower WHO grade, presence of IDH1/2 mutation with co-deletion 1p/19q and BTV decrease >25% were independently associated with a prolonged PFS in the multivariate analysis. 18FET-PET is a promising biomarker candidate for early response assessment in Gd-negative gliomas undergoing chemotherapy. It might be helpful for timely adjustment of a personalized treatment concept and overcomes limitations of conventional structural imaging.
EXTH-51. PI3K/mTOR INHIBITION LEADS TO REDUCTION IN 2HG PRODUCTION AND CELL PROLIFERATION IN IDH1 MUTANT CELLS
Authors: Georgios Batsios, Pavithra Viswanath, Joanna J Phillips, Russell O Pieper, Sabrina Ronen
Journal: Neuro-Oncology (2017)

Mutations in isocitrate dehydrogenase (IDH1) drive tumorigenesis in 70–90% of low-grade gliomas and secondary glioblastomas. The mutant IDH1 enzyme produces the oncometabolite 2-hydroxyglutarate (2HG), which, in addition to driving tumorigenesis, also induces significant metabolic reprogramming. Dual phosphoinositide-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibition is one of the therapeutic options under consideration for mutant IDH1 gliomas. The goal of the current study was to investigate the effect of one such inhibitor, namely XL765 (Voxtalisib), on mutant IDH1 glioma cells. We used two cell models genetically-engineered to express mutant IDH1: a U87 glioblastoma-based model and an immortalized normal human astrocyte (NHA)-based model. In both of our models we found that XL765 significantly inhibited cell proliferation to ~50% following treatment with 12uM and 32uM for 24h and 72h for U87 and NHA respectively. We then used magnetic resonance spectroscopy (MRS) to investigate the impact of treatment on cell metabolism. Using 1H-MRS, we observed that XL765 induced a significant ~70% and ~50% reduction in steady-state levels of 2HG and glutamate respectively in U87 while in NHA the drop was ~90% and ~70% for 2HG and glutamate respectively. Using 13C-MRS, we observed a reduction in flux from [1-13C]-glucose to [4-13C]-2HG and to [4-13C]-glutamate, indicating reduced flux to the tricarboxylic acid (TCA) cycle in both models. We also observed a reduction of [3-13C]-glutamine flux to [3-13C]-2HG and [3-13C]-glutamate in the treatment group. Finally, the treatment group presented reduced glucose and glutamine uptake from the media compared to control. Collectively, our results indicate that treatment with a PI3K/mTOR inhibitor is associated with response in mutant IDH1 models that is accompanied by inhibition in the synthesis of 2HG and glutamate from both glucose and glutamine. The metabolic changes are detectably by MRS and could be used as biomarkers of response for patients undergoing treatment with PI3K/mTOR inhibitors.
P3.01-007 Heterogeneous Resistance Mechanisms in Rebiopsies from EGFR-Mutated NSCLC: Transformation to SCLC; FGFR3 and T790M Mutations
Authors: E. Urbanska, M. Grauslund, L. Melchior, J.B. Sørensen, E. Santoni-Rugiu
Journal: Journal of Thoracic Oncology (2017)
OA 14.07 Progress in Lung Squamous Cell Carcinoma from the Lung-MAP Master Protocol (S1400) Sub-Studies S1400A, S1400B, S1400C and S1400D
Authors: R. Herbst, M. Redman, D.R. Gandara, F.R. Hirsch, P. Mack, H. Borghaei, C. Langer, J. Wade, J. Engelman, M. Edelman, K. Albain, P. Lara, C. Aggarwal, M. Socinski, S. Gettinger, L. Bazhenova, S. Waqar, F. Robert, G. Kiefer, J. Bradley, J. Crawford, E. Mcgary, N. Rafique, D. Petro, P. Hoffman, Y. Zhou, J. Miao, K. Griffin, S. Mcdonough, C. Miwa, S. Malik, V. Miller, E. Sigal, S. Adam, C. Blanke, K. Kelly, V. Papadimitrakopoulou
Journal: Journal of Thoracic Oncology (2017)
P1.07-004 Predictive Biomarkers of Response to Nivolumab in Non–Small Cell Lung Cancer: A Multicenter Retrospective Cohort Study
Authors: Y. Kataoka, K. Hirano, T. Narabayashi, S. Hara, D. Fujimoto, T. Tanaka, N. Ebi, K. Tomii, H. Yoshioka
Journal: Journal of Thoracic Oncology (2017)
Impatto del vaccino coniugato contro il meningococco C in Spagna: una decisione epidemiologica e microbiologica
Authors: R Cano, A Larrauri, S Mateo, B Alcalá, C Salcedo, J A Vázquez
Journal: Eurosurveillance (2004)

In Spagna e disponibile il nuovo vaccino coniugato contro il meningococco del sierogruppo C che e stato incluso nel programma di vaccinazione del 2000. E stato attuata una vasta campagna di vaccinazione nei bambini di eta inferiore a sei anni, grazie alla quale l'incidenza delle patologie meningococciche determinate dal batterio del sierogruppo C e diminuita notevolmente negli ultimi tre anni in Spagna. Il rischio di contrarre la patologia meningococcica determinata dal sierogruppo C nel 2002/2003 e diminuita del 58% rispetto alla stagione precedente a quella in cui e stato introdotto l'impiego del vaccino coniugato. Si e anche assistito alla diminuzione della mortalita. Nel 2002/2003 si sono verificati tre decessi dovuti al batterio del sierogruppo C nei gruppi di bambini di eta prevista dal programma di vaccinazione, rispetto ai 30 decessi registrati negli stessi gruppi di eta nella stagione precedente alla vasta campagna di vaccinazione. Durante il programma di vaccinazione la copertura ha raggiunto valori pari al 92%. Negli anni 2001, 2002 e 2003 i valori relativi alla copertura del programma di immunizzazione dell'infanzia di routine variarono dal 90% al 95%. Durante gli ultimi tre anni sono stati riportati 111 casi di patologie da sierogruppo C in pazienti destinati al programma di vaccinazione. La maggior parte degli insuccessi del vaccino furono registrati negli dell'epidemia 2002/2003. Otto (53%) di questi insuccessi interessarono i bambini sottoposti ai programmi di immunizzazione di routine dell'infanzia e sono pertanto imputabili alla perdita di protezione che si verifica con il passare del tempo in seguito alla vaccinazione. L'isolamento di differenti ceppi B:2a:P1.5 (citogenia ST-11) e degno di nota e puo avere origine nei ceppi C:2a:P1.5 che in seguito a ricombinazione genetica a livello dell'aperone capsulare, esprimono una capsula del sierogruppo B. Questi ceppi del sierogruppo B possono avere un potenziale epidemico rilevante.
Vigilancia de la sífilis en Francia, 2000-2003
Authors: E Couturier, A Michel, M Janier, N Dupin, C Semaille
Journal: Eurosurveillance (2004)

Este articulo describe las tendencias de la sifilis y las caracteristicas de los pacientes en Francia desde 2000 a 2003, asi como las tendencias de las ventas de Extencilline® (bencilpenicilina benzatina) 2,4 MUI, de 2001 a 2003. Desde 2001 existe un sistema de vigilancia de sifilis basado en la notificacion voluntaria, procedente principalmente de centros que suministran tratamiento para las infecciones de transmision sexual y que pertenecen al sistema publico. Los datos clinicos se complementan con datos sobre conducta sexual, recogidos por medio de un auto-cuestionario.
De 2000 a 2003, se declararon 1.089 casos de sifilis, pasando de 37 casos en 2000 a 428 en 2003. Los casos de sifilis eran en su mayoria hombres (96%), de edad media 36,5 anos. El 70% de los casos habian nacido en Francia. La proporcion de casos de sifilis co-infectados por el VIH disminuyo en el tiempo, bajando de 60% en 2000 a 33% en 2003. 
La region mas afectada por el brote de sifilis era la region Ile-de-France, principalmente Paris. En esta region, la mayoria de los casos de sifilis fueron diagnosticados en homosexuales (87%) comparado con el 75% en otras regiones. Entre los pacientes que completaron el auto-cuestionario sobre conducta sexual, el 83% declararon tener parejas ocasionales en los tres meses previos al diagnostico de sifilis. 
Las tendencias de las ventas de Extencilline® 2,4 MUI en farmacias privadas son semejantes a las observadas en el sistema de vigilancia, con un incremento entre 2001 y 2003. En conclusion, la transmision de la sifilis continua en Francia en 2003. Es necesario insistir en el papel que juega el sexo oral sin proteccion en la transmision de esta enfermedad.