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Purpose: Glioblastoma is the most aggressive brain tumor in adults and has few therapeutic options. The study of molecular subtype classifications may lead to improved prognostic classification and identification of new therapeutic targets. The Cancer Genome Atlas (TCGA) subtype classification has mainly been applied in U.S. clinical trials, while the intrinsic glioma subtype (IGS) has mainly been applied in European trials. Experimental Design: From paraffin-embedded tumor samples of 432 patients with uniformly treated, newly diagnosed glioblastoma, we built tissue microarrays for IHC analysis and applied RNA sequencing to the best samples to classify them according to TCGA and IGS subtypes. Results: We obtained transcriptomic results from 124 patients. There was a lack of agreement among the three TCGA classificatory algorithms employed, which was not solely attributable to intratumoral heterogeneity. There was overlapping of TCGA mesenchymal subtype with IGS cluster 23 and of TCGA classical subtype with IGS cluster 18. Molecular subtypes were not associated with prognosis, but levels of expression of 13 novel genes were identified as independent prognostic markers in glioma-CpG island methylator phenotype-negative patients, independently of clinical factors and MGMT methylation. These findings were validated in at least one external database. Three of the 13 genes were selected for IHC validation. In particular, high ZNF7 RNA expression and low ZNF7 protein expression were strongly associated with longer survival, independently of molecular subtypes. Conclusions: TCGA and IGS molecular classifications of glioblastoma have no higher prognostic value than individual genes and should be refined before being applied to clinical trials.

Background Results from a phase 2 trial of the TPEx chemotherapy regimen (docetaxel-platinum-cetuximab) showed promising results, with a median overall survival of 14.0 months in first-line recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). We therefore aimed to compare the efficacy and safety of the TPEx regimen with the standard of care EXTREME regimen (platinum-fluorouracil-cetuximab) in this setting. Methods This was a multicentre, open-label, randomised, phase 2 trial, done in 68 centres (cancer centres, university and general hospitals, and private clinics) in France, Spain, and Germany. Eligible patients were aged 18-70 years with histologically confirmed recurrent or metastatic HNSCC unsuitable for curative treatment; had at least one measurable lesion according to Response Evaluation Criteria in Solid Tumors version 1.1; and had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less. Participants were randomly assigned (1:1) using the TenAlea website by investigators or delegated clinical research associates to the TPEx regimen or the EXTREME regimen, with minimisation by ECOG performance status, type of disease evolution, previous cetuximab treatment, and country. The TPEx regimen consisted of docetaxel 75 mg/m(2) and cisplatin 75 mg/m(2), both intravenously on day 1, and cetuximab on days 1, 8, and 15 (intravenously 400 mg/m(2) on day 1 of cycle 1 and 250 mg/m(2) weekly subsequently). Four cycles were repeated every 21 days with systematic granulocyte colony-stimulating factor (G-CSF) support at each cycle. In case of disease control after four cycles, intravenous cetuximab 500 mg/m(2) was continued every 2 weeks as maintenance therapy until progression or unacceptable toxicity. The EXTREME regimen consisted of fluorouracil 4000 mg/m(2) on day 1-4, cisplatin 100 mg/m(2) on day 1, and cetuximab on days 1, 8, and 15 (400 mg/m(2) on day 1 of cycle 1 and 250 mg/m(2) weekly subsequently) all delivered intravenously. Six cycles were delivered every 21 days followed by weekly 250 mg/m(2) cetuximab as maintenance therapy in case of disease control. G-CSF support was not mandatory per the protocol in the EXTREME regimen. The primary endpoint was overall survival in the intention-to-treat population; safety was analysed in all patients who received at least one dose of chemotherapy or cetuximab. Enrolment is closed and this is the final analysis. This study is registered at ClinicalTrials.gov, NCT02268695. Findings Between Oct 10, 2014, and Nov 29, 2017, 541 patients were enrolled and randomly assigned to the two treatment regimens (271 to TPEx, 270 to EXTREME). Two patients in the TPEx group had major deviations in consent forms and were not included in the final analysis. Median follow-up was 34.4 months (IQR 26.6-44.8) in the TPEx group and 30.2 months (25.5-45.3) in the EXTREME group. At data cutoff, 209 patients had died in the TPEx group and 218 had died in the EXTREME group. Overall survival did not differ significantly between the groups (median 14.5 months [95% CI 12.5-15.7] in the TPEx group and 13.4 months [12.2-15.4] in the EXTREME group; hazard ratio 0.89 [95% CI 0.74-1.08]; p=0.23). 214 (81%) of 263 patients in the TPEx group versus 246 (93%) of 265 patients in the EXTREME group had grade 3 or worse adverse events during chemotherapy (p

BACKGROUND: Standard treatment for glioblastoma is radiation with concomitant and adjuvant temozolomide for six cycles, although the optimal number of cycles of adjuvant temozolomide has long been a subject of debate. We performed a phase II randomized, trial investigating whether extending adjuvant temozolomide for more than six cycles improved outcome.; METHODS: Glioblastoma patients treated at 20 Spanish hospitals who had not progressed after six cycles of adjuvant temozolomide were centrally randomized to stop (control arm) or continue (experimental arm) temozolomide up to a total of twelve cycles at the same doses they were receiving in cycle 6. Patients were stratified by MGMT methylation and measurable disease. The primary endpoint was differences in 6-month progression-free survival (PFS). Secondary endpoints were PFS, overall survival (OS) and safety. (Clinicaltrials.gov NCT02209948).; RESULTS: From August 2014 to November 2018, 166 patients were screened, seven of whom were ineligible. Seventy-nine patients were included in the stop arm and 80 in the experimental arm. All patients were included in the analyses of outcomes and of safety. There were no differences in 6-month PFS (control 55.7%; experimental 61.3%), PFS, or OS between arms. MGMT methylation and absence of measurable disease were independent factors of better outcome. Patients in the experimental arm had more lymphopenia (P < 0.001), thrombocytopenia (P < 0.001), and nausea and vomiting (P = 0.001).; CONCLUSIONS: Continuing temozolomide after six adjuvant cycles is associated with greater toxicity but confers no additional benefit in 6-month PFS. © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

The original version of this article unfortunately contained a mistake. Figure 3 was incorrect.

Sunitinib is a tyrosine kinase inhibitor with direct anti-tumor and anti-angiogenesis activity targeting VEGFR 1-2, PDGFR alpha-beta, c-kit, bFGF, (CSF-1), FLT3 and RET. The present trial examined the activity of sunitinib in 12 patients with newly diagnosed, non-resectable glioblastoma. Patients (= 2 and minimental status [MMS] >= 25) were treated post-biopsy with sunitinib 37.5 mg daily for 8 weeks pre-radiotherapy, during radiotherapy (60 Gy, 6 weeks) and post-radiotherapy until disease progression. The primary endpoints were overall response rate (ORR; RANO criteria) after 8 weeks of sunitinib and patient tolerance. Secondary endpoints were percentage of patients free of neurological deterioration pre-radiotherapy, percentage of patients completing radiotherapy, progression-free survival (PFS), overall survival (OS), and 1-year survival. A Simon 2-stage design (12 -> 20) based on ORR was applied to calculate the number of patients needed to detect at least 10 % response with a error of 0.05 and beta error of 0.10. The trial was closed because it did not meet minimal activity criteria. ORR was 0 % with only 1/12 patients (8.3%) achieving stable disease after sunitinib treatment. No patient showed reduction in gadolinium enhancement. The most frequent G3/4 toxicities were fatigue (24.9 %) and diarrhea (16.6 %); one patient died of a CNS hemorrhage; 10/12 patients (83.3 %) deteriorated neurologically before radiation therapy; median PFS was 7.7 weeks (95 % CI: 7.2-8.2); median OS was 12.8 weeks (95 % CI: 0.5-23.8 weeks); 1-year survival was 0 %. Sunitinib has no activity as monotherapy in glioblastoma, and further investigation of its efficacy in this setting is unwarranted.

This study analyzed the effects of temperature and transmembrane pressure on the crossflow microfiltration process of arazá (Eugenia stipitata) juice treated with a commercial pectic enzyme preparation, thus finding the appropriate operation values of the process. Clarified arazá juice was obtained with a crossflow microfiltration pilot plant equipped with ceramic membranes with a 0.48 m² total effective filtration area and mean pore diameter of 0.2 µm. The juice was evaluated at transmembrane pressures 1.5, 3.0 and 4.5 bar, and at temperatures of 30, 35 and 40ºC at different volumetric reduction factors. The tests were carried out using three systems (total recirculation, concentration, and continuous mode). In total recirculation, it was found that the most influential variable was the transmembrane pressures, and that the partial enzymatic liquefaction of the arazá juice, prior to microfiltration, produced an unusual pattern of permeate flux, characterized by an increase following an abrupt decrease at 4.5 bar and 6.5 m/s. In this case, the highest values of the flux were obtained when compared with those obtained during the crossflow microfiltration in concentration mode. After reaching the value of volumetric reduction factor (3.2), during the crossflow microfiltration in continuous mode, it was not necessary to stop the process as the volumetric reduction factor remained constant for the continuous removal of retained, achieving a high permeate flux in a short period of time 319 L/(h·m²), thus adding to the economic viability of the process. En este trabajo se analizaron los efectos de la temperatura y la presión transmembrana sobre el proceso de microfiltración tangencial de jugo de arazá (Eugenia stipitata) tratado con una preparación comercial de enzimas pectolíticas, encontrando los valores adecuados de operación. Se obtuvo un jugo clarificado de arazá con un equipo piloto de microfiltración tangencial provisto de membranas cerámicas de 0,48 m² de área total efectiva de filtración, diámetro promedio de poro de 0,2 µm, evaluado a diferentes presiones transmembrana de 1,5; 3,0 y 4,5 bar y temperaturas de 30, 35 y 40ºC, a diferentes factores de reducción volumétrica. Las pruebas fueron llevadas a cabo utilizando tres modos de operación: recirculación total, concentración y continuo. En recirculación total, se encontró que la variable más influyente sobre el proceso fue la presión transmembrana y que la licuefacción enzimática parcial realizada al jugo de arazá, previo a la microfiltración, produjo un patrón inusual del flux de permeado, caracterizado por un incremento después de una disminución abrupta cuando se trabajó a 4,5 bar y 6,5 m/s. En este caso se encontraron los valores más altos del flux al compararse con los obtenidos durante la microfiltración tangencial en modo de concentración. Una vez alcanzado el valor de factor de reducción volumétrica (3,2) durante la microfiltración tangencial en modo continuo no fue necesario detener el proceso, ya que el factor de reducción volumétrica se mantuvo constante durante la eliminación continua de retenido, lográndose altos flujos de permeado en corto tiempo (319 L/(h·m²)), facilitando la viabilidad económica del proceso.

The Cerro Cóndor depocenter represents the most complete stratigraphic sequence of the continental Jurassic of the Cañadón Asfalto basin and southern South America. It is situated in extraandean Patagonia, on both sides of the middle Chubut river valley. The sedimentation in this pull-apart basin begins early in the Middle Jurassic, accompanied by effusions of olivinic basalts. The prevailing lacustrine deposits are characterized by carbonatic and siliciclastic facies associations, interfingering with volcanic deposits grading from lavic in the base to predominantly pyroclastic towards the top. The facies evolution from north to south is described, embracing the sections of farm El Torito and the canyons of Los Loros, Las Chacritas, Carrizal, Asfalto and Lahuincó. The carbonatic facies/microfacies are represented by mudstones, wackestones, packstones, grainstones and microbialitic limestones, characteristic of littoral/marginal and palustrine environments. In the Cañadón Asfalto Formation are distinguished a lower member (Las Chacritas composed by limestones, shales, sandstones and conglomerates intercalated with olivinic basalts, and an upper member (Puesto Almada) composed by tuffs, tuffites, shales and sandstones. The first is bearing a palynologic assemblage of Bajocian-Bathonian age and the second dinosaurs of Tithonian age. The stratigraphic sections of both members of the formation are described and illustrated at their type localities cañadón Las Chacritas and farm El Torito and the paleoenvironments of the depocenter, from the Aalenian to the Tithonian are described and illustrated. The age of the Puesto Almada Member at its type locality was obtained by radiometric dating (K/Ar) of biotites from a thin layer of volcanic tuff (147.1 + 3.3 Ma, Tithonian) from the upper part of the unit. Fil:Cabaleri, N. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Armella, C. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Silva Nieto, D. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Cagnoni, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Ramos, A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Panarello, H. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Koukharsky, M. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina.