Safety and Efficacy of Durvalumab With or Without Tremelimumab in Patients With PD-L1-Low/Negative Recurrent or Metastatic HNSCC The Phase 2 CONDOR Randomized Clinical Trial

IMPORTANCE: Dual blockade of programmed death ligand 1(PD-L1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) may overcome immune checkpoint inhibition. It is unknown whether dual blockade can potentiate antitumor activity without compromising safety in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) and low or no PD-L1 tumor cell expression. OBJECTIVE :To assess safety and objective response rate of durvalumab combined with tremelimumab. DESIGN, SETTING, AND PARTICIPANTS: The CONDOR study was a phase 2, randomized, open-label study of Durvalumab, Tremelimumab, and Durvalumab in Combination With Tremelimumab in Patients With R/M HNSCC. Eligibility criteria included PD-L1-low/negative disease that had progressed after 1 platinum-containing regimen in the R/M setting. Patients were randomized (N = 267) from April 15, 2015, to March 16, 2016, at 127 sites in North America, Europe, and Asia Pacific. INTERVENTIONS: Durvalumab (20 mg/kg every 4 weeks) + tremelimumab (1 mg/kg every 4 weeks) for 4 cycles, followed by durvalumab (10 mg/kg every 2 weeks), or durvalumab (10 mg/kg every 2 weeks) monotherapy, or tremelimumab (10 mg/kg every 4 weeks for 7 doses then every 12 weeks for 2 doses) monotherapy. MAIN OUTCOMES AND MEASURES: Safety and tolerability and efficacy measured by objective response rate. RESULTS: Among the 267 patients (220 men [82.4%]), median age (range) of patients was 61.0 (23-82) years. Grade 3/4 treatment-related adverse events occurred in 21 patients (15.8%) treated with durvalumab + tremelimumab, 8 (12.3%) treated with durvalumab, and 11 (16.9%) treated with tremelimumab. Grade 3/4 immune-mediated adverse events occurred in 8 patients (6.0%) in the combination arm only. Objective response rate (95% CI) was 7.8% (3.78%1339%) in the combination arm (n =129), 9.2% (3.46%-19.02%) for durvalumab monotherapy (n = 65), and 1.6% (0.04%-8.53%) for tremelimumab monotherapy (n = 63); median overall survival (95% CI) for all patients treated was 7.6 (4.9-10.6), 6.0 (4.0-11.3), and 5.5 (3.9-7.0) months, respectively. CONCLUSIONS AND RELEVANCE: In patients with R/M HNSCC and low or no PD-Lt tumor cell expression, all 3 regimens exhibited a manageable toxicity profile. Durvalumab and durvalumab + tremelimumab resulted in clinical benefit, with minimal observed difference between the two. A phase 3 study is under way

A física dos relâmpagos – Uma sequência didática referenciada na aprendizagem significativa de Ausubel

The phenomenon of lightning in the atmosphere is very rich from a conceptual point of view. To describe it, even at the basic level, one must understand the relationship between several concepts of physics. Even so, the theme is absent or dealt with peripherally in most of the Physics High School textbooks used in Brazil. Therefore, we present in this work a didactic sequence to deal with this theme that is anchored in Ausubel’s Theory of Meaningful Learning and it uses a text about the physics of lightning in the atmosphere as a didactic tool. This didactic text is also presented in this work. Since the sequence was systematically applied in several High School classes of the Instituto Federal do Rio de Janeiro, results and conclusions are also presented and discussed. These suggest that the sequence can promote a meaningful learning of the theme and it can be adjusted to the most diverse school realities.O fenômeno dos relâmpagos na atmosfera é riquíssimo do ponto de vista conceitual. Para descreve-lo, ainda que em nível básico, é preciso compreender a relação entre uma série de conceitos de física. Ainda assim, o tema é ausente ou tratado de forma periférica em boa parte dos livros didáticos mais utilizados no Brasil no ensino médio. Diante disso, apresentamos neste trabalho uma sequência didática para abordar este tema que se ancora na Teoria da Aprendizagem Significativa de Ausubel e utiliza como ferramenta didática um texto didático sobre a física dos relâmpagos na atmosfera especialmente desenvuelto para este fim. Este texto didático também é apresentado neste trabalho. Haja vista que a sequência foi sistematicamente aplicada em turmas do ensino médio do Instituto Federal do Rio de Janeiro, resultados e conclusões são também apresentados e discutidos. Estes sugerem que a sequência pode promover um aprendizado significativo do tema em questão e pode ser ajustada às mais diversas realidades escolares

Waveshapes of continuing currents and properties of M-components in natural positive cloud-to-ground lightning

This work analyses the waveshapes of continuing currents and parameters of M-components in positive cloud-to-ground (CG) flashes through high-speed GPS synchronized videos. The dataset is composed of only long continuing currents (with duration longer than 40 ms) and was selected from more than 800 flashes recorded in Sao Jose dos Campos (45.864 degrees W, 23.215 degrees S) and Uruguaiana (29.806 degrees W, 57.005 degrees S) in Southeast and South of Brazil, respectively, during 2003 to 2007 summers. The videos are compared with data obtained by the Brazilian Lightning Location System (BrasilDAT) in order to determine the polarity of each flash and select only positive cases. There are only two studies of waveshapes of continuing currents in the literature. One is based on direct current measurements of triggered lightning, in which four different types of waveshapes were observed; and the other is based on measurements of luminosity variations in high-speed videos of CG negative lightning, in which besides the four types above mentioned two additional types were observed. The present work is an extension of the latter, using the same method but now applied to obtain the waveshapes of positive CG lightning. As far as the authors know, this is the first report on M-components in positive continuing currents. We also have used the luminosity-versus-time graphs to observe their occurrence and measure some parameters (duration, elapsed time and time between two successive M-components), whose statistics are presented and compared in detail to the data for negative flashes. We have plotted a histogram of the M-components elapsed time over the total duration of the continuing current for positive flashes, which presented an exponential decay (correlation coefficient: 0.83), similar to what has been observed for negative flashes. (C) 2008 Elsevier B.V. All rights reserved

High-speed video observations of positive ground flashes produced by intracloud lightning

High-speed video recordings of two lightning flashes confirm that positive cloud-to-ground (CG) strokes can be produced by extensive horizontal intracloud (IC) discharges within and near the cloud base. These recordings constitute the first observations of CG leaders emanating from IC discharges of either polarity. In one case, the discharge began with a negative leader that propagated horizontally, went upward and produced an IC discharge. After the beginning of the IC discharge, a positive leader emanated from the lowest portion of the IC discharge, and initiated a positive return stroke. In the other case, the IC discharge began with a positive leader and then initiated a downward-propagating positive leader that contained recoil processes and produced a bright return stroke followed by a long continuing luminosity. These observations help to understand the complex genesis of positive CG flashes, why IC lightning commonly precedes them and why extensive horizontal channels are often involved. Citation: Saba, M. M. F., L. Z. S. Campos, E. P. Krider, and O. Pinto Jr. (2009), High-speed video observations of positive ground flashes produced by intracloud lightning, Geophys. Res. Lett., 36, L12811, doi: 10.1029/2009GL038791.Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP