Cloud thermodynamic phase inferred from merged POLDER and MODIS data

International audienceThe global spatial and diurnal distribution of cloud properties is a key issue for understanding the hydrological cycle, and critical for advancing efforts to improve numerical weather models and general circulation models. Satellite data provides the best way of gaining insight into global cloud properties. In particular, the determination of cloud thermodynamic phase is a critical first step in the process of inferring cloud optical and microphysical properties from satellite measurements. It is important that cloud phase be derived together with an estimate of the confidence of this determination, so that this information can be included with subsequent retrievals (optical thickness, effective particle radius, and ice/liquid water content). In this study, we combine three different and well documented approaches for inferring cloud phase into a single algorithm. The algorithm is applied to data obtained by the MODIS (MODerate resolution Imaging Spectroradiometer) and POLDER3 (Polarization and Directionality of the Earth Reflectance) instruments. It is shown that this synergistic algorithm can be used routinely to derive cloud phase along with an index that helps to discriminate ambiguous phase from confident phase cases. The resulting product provides a semi-continuous confidence index ranging from confident liquid to confident ice instead of the usual discrete classification of liquid phase, ice phase, mixed phase (potential combination of ice and liquid particles), or simply unknown phase clouds. This approach is expected to be useful for cloud assimilation and modeling efforts while providing more insight into the global cloud properties derived from satellite data

Metastatic Renal Cell Carcinoma Rapidly Progressive to Sunitinib: What to Do Next?

Background: From 10% to 26% of patients with metastatic renal cell carcinoma (mRCC) experience rapidly progressive disease (PD) on treatment with sunitinib. Objective: To investigate the benefit of subsequent treatment with another tyrosine kinase inhibitor (TKI) or a mammalian target of rapamycin (mTOR) inhibitor in such primary refractory patients. Design, setting, and participants: A total of 150 mRCC patients with rapidly PD on first- line sunitinib (within two cycles, n = 93, or four cycles, n = 57) were identified: median age 59 yr; nephrectomy 86%; histological subtypes: clear cell (77.8%), papillary (14%), and sarco- matoid features (18%); according to the Memorial Sloan-Kettering Cancer Center and French classifications: good risk (11% and 7%, respectively), intermediate (68% and 63%, respectively), and poor (21% and 29%, respectively). Outcome measurements and statistical analysis: Data were retrospectively collected by a questionnaire from 19 European oncology centers between March 2005 and March 2011. Pro- gression-free survival (PFS) and overall survival (OS) were calculated (Kaplan-Meier method). Results and limitations: Median OS from the start of first-line treatment was 7.4 mo. Second-line treatment was administered to 86 (57%) patients (44 mTOR inhibitors: 23 ever- olimus and 21 temsirolimus; 39 TKIs alone or in combination; three chemotherapy). Second- line PFS was not significantly different between TKIs and mTOR inhibitors (2.0 vs 0.9 mo; p = 0.536). Median OS from the start of second-line treatment was 5.0 mo for mTOR inhibitors and 6.6 mo for TKIs (p = 0.15). Conclusions: Treatment with further TKIs or mTOR inhibitors for mRCC patients primarily refractory to first-line sunitinib in the observed time period achieved very minimal benefit, suggesting avoiding TKI rechallenge and possibly preferring alternative strategies, such as immune checkpoint inhibitors, after PD to a treatment line including a TKI in this setting. Patient summary: The present work collected data about 150 patients affected by meta- static renal cell carcinoma, who received one of the current standard of care as first-line treatment, namely, the antiangiogenic drug sunitinib, and experienced rapid worsening of the disease. We investigated and described the subsequent outcome of such patients treated with two different types of drug, administered as second-line therapy, to better understand the best strategy to adopt for patients who got no benefit from sunitinib and to describe the current therapeutic approach in such cases

Outcomes in Patients With Metastatic Renal Cell Carcinoma Who Develop Everolimus-Related Hyperglycemia and Hypercholesterolemia: Combined Subgroup Analyses of the RECORD-1 and REACT Trials

In this study we examined the outcome of metastatic renal cell cancer patients with everolimus treatment-related hyperglycemia and hypercholesterolemia. All patients were treated in 2 large, international prospective trials, RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily) and REACT (RAD001 Expanded Access Clinical Trial in RCC). Patients who experienced these events might have experienced an improved response to everolimus. Background Hyperglycemia and hypercholesterolemia are class effects of mammalian target of rapamycin inhibitors. The purpose of this study was to characterize safety and efficacy of patients with metastatic renal cell carcinoma (mRCC) treated with everolimus in RECORD-1 (REnal Cell cancer treatment with Oral RAD001 given Daily) and REACT (RAD001 Expanded Access Clinical Trial in RCC) who developed these events. Patients and Methods Adults with vascular endothelial growth factor–refractory mRCC received everolimus 10 mg/d in the randomized RECORD-1 (n = 277) and open-label REACT (n = 1367) studies. Outcomes included safety, treatment duration, overall response, and progression-free survival for patients who developed hypercholesterolemia or hyperglycemia. Results In RECORD-1, 12% (33 of 277) and 20% (55 of 277) of patients developed any grade hyperglycemia or hypercholesterolemia, respectively, with only 6% (78 of 1367) and 1% (14 of 1367) of the same events, respectively, in REACT. Median everolimus treatment duration was similar for patients with hyperglycemia or hypercholesterolemia (RECORD-1, 6.2 and 6.2 months, respectively; REACT, 4.4 and 4.5 months, respectively), but longer than the overall populations (RECORD-1, 4.6 months; REACT, 3.2 months). In RECORD-1/REACT, 82%/68% of patients with hyperglycemia and 75%/71% of patients with hypercholesterolemia achieved partial response or stable disease. The incidence of clinically notable Grade 3 or 4 adverse events, other than anemia and lymphopenia, appeared to be similar across trials and subgroups. Although there was a trend for improved progression-free survival with development of hyperglycemia or hypercholesterolemia, the association was not statistically significant. Conclusion Hyperglycemia and hypercholesterolemia were observed in low numbers of patients, and although these events might be associated with improved response to everolimus, the differences were not significant. These findings should be validated with prospective biomarker studies

Непрямое сравнение эффективности и безопасности апалутамида и даролутамида для лечения неметастатического кастрационнорезистентного рака предстательной железы по результатам двух независимых исследований с поправкой на разницу между популяциями пациентов

.Введение. Апалутамид и даролутамид являются ингибиторами андрогенных рецепторов нового поколения, которые продемонстрировали превосходную эффективность у пациентов с неметастатическим кастрационно-резистентным раком предстательной железы, получающих андрогендепривационную терапию (АДТ). На сегодняшний день нет исследований по прямому сравнению этих 2 препаратов.Цель исследования – непрямое сравнение эффективности и переносимости апалутамида и даролутамида.Материалы и методы. Был применен метод согласованного скорректированного непрямого сравнения (matchingadjusted indirect comparison, MAIC) данных рандомизированного плацебо-контролируемого исследования III фазы SPARTAN (апалутамид + АДТ), которые были уравновешены по основным исходным клиническим параметрам, с опубликованными обобщенными данными исследования ARAMIS (даролутамид + АДТ) для их сопоставления. Для оценки всех конечных точек эффективности, включая выживаемость без метастазирования, повышение уровня простатического специфического антигена (ПСА), выживаемость без прогрессирования, а также общую выживаемость, были рассчитаны отношения рисков (ОР) и 95 % доверительные интервалы (ДИ). Для оценки конечных точек по безопасности (частота нежелательных явлений и серьезных нежелательных явлений) рассчитывали отношения шансов.Результаты. Перед уравновешиванием данных в исследованиях SPARTAN и ARAMIS наблюдались значимые различия по уровню ПСА (медиана 7,8 нг/мл против 9,2 нг/мл), числу пациентов со статусом 1 по шкале Eastern Cooperative Oncology Group (23 % против 31 %), частоте использования препаратов для модификации костной ткани (10 % против 4 %), медиане времени с момента установления первичного диагноза (94,9 мес против 85,4 мес) и числу пациентов из США (35 % против 12 %) и Европы (50 % против 64 %). После уравновешивания данных (n = 455) мы установили, что режим, включающий апалутамид + АДТ, с высокой долей вероятности более эффективен, чем даролутамид + АДТ, по выживаемости без метастазирования (98,3 %; ОР 0,70; 95 % ДИ 0,51–0,98), повышениюуровня ПСА (~100 %; ОР 0,46; 95 % ДИ 0,33–0,64) и выживаемости без прогрессирования (93,2 %; ОР 0,79; 95 % ДИ 0,59–1,08). Показатели общей выживаемости и переносимости не различались значительно при сравнении групп апалутамид + АДТ и даролутамид + АДТ.Заключение. Результаты анализа данных 2 важнейших исследований III фазы по неметастатическому кастрационно-резистентному раку предстательной железы с помощью метода MAIC указывают на то, что апалутамид + АДТ является более эффективной схемой лечения, чем даролутамид + АДТ, по показателям выживаемости без прогрессирования и повышению уровня ПСА, в то время как общая выживаемость и профиль безопасности этих 2 режимов не различаются.

ПОБОЧНЫЕ ЭФФЕКТЫ СОРАФЕНИБА, СУНИТИНИБА И ТЕМСИРОЛИМУСА И ИХ ЛЕЧЕНИЕ У БОЛЬНЫХ МЕТАСТАТИЧЕСКИМ ПОЧЕЧНО-КЛЕТОЧНЫМ РАКОМ

Objective: to provide a systematic review of the adverse reactions of sorafenib, sunitinib, and temsirolimus and to outline actions for their prevention and correction.Materials and methods. To provide a description of the main methods to decrease the toxicity of these drugs, the authors made a systemat- ic review of their adverse reactions, by using the publications available in the PubMed database, monographs on the medicines, and instruc- tions for their medical use. Results. The frequency of their adverse reactions varied from < 1 to 72%. Grades III—IV side effects are noted more rarely; their incidence is < 1 to 13% for sorafenib, < 1 to 16% for sunitinib, and 1 to 20% for temsirolimus. Sinitinib causes most grades III—IV adverse reactions and sofafenib does the least. However, close comparative studies of the safety of these kinase inhibitors are still lacking. Virtually all side effects can be effectively prevented and treated.  Conclusion. The prevention, timely recognition, and treatment of the adverse reactions of these agents are of great importance, which allows avoidance of the unneeded dosage reduction that may result in worse therapeutic efficiency.   Цель исследования — представить систематический обзор побочных эффектов сорафениба, сунитиниба и темсиролимуса, а также в общих чертах описать меры по их предупреждению и коррекции. Материалы и методы. Для того чтобы представить описание основных методов, направленных на снижение токсичности этих препаратов, нами проведен систематический обзор побочных эффектов на основе публикаций в базе данных PubMed, монографий по лекарственным препаратам и инструкций по их медицинскому применению.Результаты. Частота развития побочных эффектов варьирует от < 1 до 72%. Побочные эффекты III—IV степени отмечаются реже, частота их возникновения от < 1 до 13% для сорафениба, от < 1 до 16% — для сунитиниба и от 1 до 20% — для темсиролимуса. Сунитиниб вызывает наибольшее количество побочных эффектов III—IV степени, а сорафениб — наименьшее. Однако все еще отсутствуют тщательные сравнительные клинические исследования безопасности этих ингибиторов киназ. Практически все побочные эффекты можно эффективно предупреждать и лечить.Заключение. Большое значение имеют профилактика, своевременное распознавание и лечение побочных эффектов этих препаратов, что позволяет избежать ненужного снижения дозы, грозящего ослаблением эффективности лечения.

Decrease of pro-angiogenic monocytes predicts clinical response to anti-angiogenic treatment in patients with metastatic renal cell carcinoma

The modulation of subpopulations of pro-angiogenic monocytes (VEGFR-1+ CD14 and Tie2+ CD14) was analyzed in an ancillary study from the prospective PazopanIb versus Sunitinib patient preferenCE Study (PISCES) (NCT01064310), where metastatic renal cell carcinoma (mRCC) patients were treated with two anti-angiogenic drugs, either sunitinib or pazopanib. Blood samples from 86 patients were collected prospectively at baseline (T1), and at 10 weeks (T2) and 20 weeks (T3) after starting anti-angiogenic therapy. Various subpopulations of myeloid cells (monocytes, VEGFR-1+ CD14 and Tie2+ CD14 cells) decreased during treatment. When patients were divided into two subgroups with a decrease (defined as a >20% reduction from baseline value) (group 1) or not (group 2) at T3 for VEGFR-1+ CD14 cells, group 1 patients presented a median PFS and OS of 24 months and 37 months, respectively, compared with a median PFS of 9 months (p = 0.032) and a median OS of 16 months (p = 0.033) in group 2 patients. The reduction in Tie2+ CD14 at T3 predicted a benefit in OS at 18 months after therapy (p = 0.04). In conclusion, in this prospective clinical trial, a significant decrease in subpopulations of pro-angiogenic monocytes was associated with clinical response to anti-angiogenic drugs in patients with mRCC

Cloud thermodynamic phase inferred from merged POLDER and MODIS data

The global spatial and diurnal distribution of cloud properties is a key issue for understanding the hydrological cycle, and critical for advancing efforts to improve numerical weather models and general circulation models. Satellite data provides the best way of gaining insight into global cloud properties. In particular, the determination of cloud thermodynamic phase is a critical first step in the process of inferring cloud optical and microphysical properties from satellite measurements. It is important that cloud phase be derived together with an estimate of the confidence of this determination, so that this information can be included with subsequent retrievals (optical thickness, effective particle radius, and ice/liquid water content). In this study, we combine three different and well documented approaches for inferring cloud phase into a single algorithm. The algorithm is applied to data obtained by the MODIS (MODerate resolution Imaging Spectroradiometer) and POLDER3 (Polarization and Directionality of the Earth Reflectance) instruments. It is shown that this synergistic algorithm can be used routinely to derive cloud phase along with an index that helps to discriminate ambiguous phase from confident phase cases. The resulting product provides a semi-continuous index ranging from confident liquid to confident ice instead of the usual discrete classification of liquid phase, ice phase, mixed phase (potential combination of ice and liquid particles), or simply unknown phase clouds. The index value provides simultaneously information on the phase and the associated confidence. This approach is expected to be useful for cloud assimilation and modeling efforts while providing more insight into the global cloud properties derived from satellite data

Predictive biomarker discovery through the parallel integration of clinical trial and functional genomics datasets

The European Union multi-disciplinary Personalised RNA interference to Enhance the Delivery of Individualised Cytotoxic and Targeted therapeutics (PREDICT) consortium has recently initiated a framework to accelerate the development of predictive biomarkers of individual patient response to anti-cancer agents. The consortium focuses on the identification of reliable predictive biomarkers to approved agents with anti-angiogenic activity for which no reliable predictive biomarkers exist: sunitinib, a multi-targeted tyrosine kinase inhibitor and everolimus, a mammalian target of rapamycin (mTOR) pathway inhibitor. Through the analysis of tumor tissue derived from pre-operative renal cell carcinoma (RCC) clinical trials, the PREDICT consortium will use established and novel methods to integrate comprehensive tumor-derived genomic data with personalized tumor-derived small hairpin RNA and high-throughput small interfering RNA screens to identify and validate functionally important genomic or transcriptomic predictive biomarkers of individual drug response in patients. PREDICT's approach to predictive biomarker discovery differs from conventional associative learning approaches, which can be susceptible to the detection of chance associations that lead to overestimation of true clinical accuracy. These methods will identify molecular pathways important for survival and growth of RCC cells and particular targets suitable for therapeutic development. Importantly, our results may enable individualized treatment of RCC, reducing ineffective therapy in drug-resistant disease, leading to improved quality of life and higher cost efficiency, which in turn should broaden patient access to beneficial therapeutics, thereby enhancing clinical outcome and cancer survival. The consortium will also establish and consolidate a European network providing the technological and clinical platform for large-scale functional genomic biomarker discovery. Here we review our current understanding of molecular mechanisms driving resistance to anti-angiogenesis agents, the current limitations of laboratory and clinical trial strategies and how the PREDICT consortium will endeavor to identify a new generation of predictive biomarkers