Nivolumab plus cabozantinib (NIVO + CABO) was approved for first-line treatment of advanced renal cell carcinoma (aRCC) based on superiority versus sunitinib (SUN) in the phase III CheckMate 9ER ...trial (18.1 months median survival follow-up per database lock date); efficacy benefit was maintained with an extended 32.9 months of median survival follow-up. We report updated efficacy and safety after 44.0 months of median survival follow-up in intent-to-treat (ITT) patients and additional subgroup analyses, including outcomes by International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic risk score.
Patients with treatment-naïve aRCC received NIVO 240 mg every 2 weeks plus CABO 40 mg once daily or SUN 50 mg for 4 weeks (6-week cycles), until disease progression/unacceptable toxicity (maximum NIVO treatment, 2 years). Primary endpoint was progression-free survival (PFS) per blinded independent central review (BICR). Secondary endpoints were overall survival (OS), objective response rate (ORR) per BICR, and safety and tolerability.
Overall, 323 patients were randomised to NIVO + CABO and 328 to SUN. Median PFS was improved with NIVO + CABO versus SUN 16.6 versus 8.4 months; hazard ratio (HR) 0.59; 95% confidence interval (CI) 0.49-0.71; median OS favoured NIVO + CABO versus SUN (49.5 versus 35.5 months; HR 0.70; 95% CI 0.56-0.87). ORR (95% CI) was higher with NIVO + CABO versus SUN 56% (50% to 62%) versus 28% (23% to 33%); 13% versus 5% of patients achieved complete response, and median duration of response was 22.1 months versus 16.1 months, respectively. PFS and OS favoured NIVO + CABO over SUN across intermediate, poor and intermediate/poor IMDC risk subgroups; higher ORR and complete response rates were seen with NIVO + CABO versus SUN regardless of IMDC risk subgroup. Any-grade (grade ≥3) treatment-related adverse events occurred in 97% (67%) versus 93% (55%) of patients treated with NIVO + CABO versus SUN.
After extended follow-up, NIVO + CABO maintained survival and response benefits; safety remained consistent with previous follow-ups. These results continue to support NIVO + CABO as a first-line treatment for aRCC.
ClinicalTrials.gov, NCT03141177.
•With 44.0 months of median follow-up for OS, long-term efficacy outcomes with NIVO + CABO over SUN were maintained.•Median OS (95% CI) in ITT patients: 49.5 months (40.3 months-NE) with NIVO + CABO vs 35.5 months (29.2-42.3 months) with SUN.•Survival outcomes favoured NIVO + CABO over SUN across intermediate, poor and combined intermediate/poor IMDC risk subgroups.•Objective responses were durable with NIVO + CABO; response rates were higher versus SUN regardless of IMDC risk group.•No new safety signals emerged with additional follow-up in either treatment arm.
In this paper, an optimisation algorithm is used to simulate the management of distributed energy resources in an academic building. This optimisation algorithm, called DEROP, consists of an ...iterative procedure reach a supply schedule with the minimum energy cost. The inputs to the algorithm are the demand forecast, the availability of each resource, the level of storage in energy storage systems and prices and efficiencies of each resource. With these data, the algorithm proposes the optimal schedule to minimise costs of energy supply. The main advantages of this algorithm are that it is fast, easy to be implemented in real buildings and flexible. The algorithm is simulated with real data to optimise management of distributed energy resources and energy storage systems in an academic building. The management of these resources is optimised for a tariff with hourly discrimination and for a tariff with no time restrictions. One of the main conclusions drawn from these simulations are that significant savings are obtained with this algorithm. Also, DEROP allows taking advantage of tariffs with hourly discrimination, even in an academic building with low night-time consumption in which, a priori, these tariffs are not profitable.
Currently the dominant limiting factor to maize production in Spain is caused by Maize rough dwarf virus (MRDV). This study aimed to evaluate the epidemiology factors involved in the increased ...incidence of MRD disease in Spain. We examined the maize planthopper dynamics and MRDV incidence throughout two maize growing seasons in six locations using a set of eight maize varieties: four Bt‐varieties (BT‐var) and their isogenic counterparts (NBT‐var). Our results indicate that MRDV incidence is greatly influenced by the first colonisation of maize by Laodelphax striatellus but not by Metadelphax propinqua and by the susceptibility of the maize varieties. No significant differences were observed between the BT‐var and NBT‐var, although BT‐var exhibited 1% less MRDV infection than NBT‐var. Cultivated wheat and Lolium perenne were found for the first time to be natural hosts of MRDV. However, wheat does not seem to be a preferred host for the development of L. striatellus. Partial sequencing of genome segments S1–S9 and full sequencing of segment S10 revealed that the Spanish MRDV isolate shares nucleotide identities ranging from 93% to 97% with the available sequences of segments S7–S10 of the Italian MRDV isolate. The highest nucleotide identities with other fijiviruses were observed with Rice black‐streaked dwarf virus. Molecular variability analysis of MRDV isolates collected over a ten years period showed high nucleotide (>97%) and amino sequence identities (>99%) on segment S10, suggesting a low temporal variability.
The Patient Reported Outcome for Fighting FInancial Toxicity (PROFFIT) questionnaire was developed to measure financial toxicity (FT) and identify its determinants. The aim of the present study was ...to confirm its validity in a prospective cohort of patients receiving anticancer treatment.
From March 2021 to July 2022, 221 patients were enrolled at 10 Italian centres. Selected items of the EORTC-QLQ-C30 questionnaire represented the anchors, specifically, question 28 (Q-28) on financial difficulties, and questions 29-30 measuring global health status/quality of life (HR-QOL). The study had 80% power to detect a 0.20 correlation coefficient (r) between anchors and PROFFIT-score (items 1-7, range 0-100, 100 indicating maximum FT) with bilateral alpha 0.05 and 80% power. Confirmatory factor analysis was conducted. FT determinants (items 8-16) were described.
Median age of patients was 65 years, 116 (52.5%) were females, 96 (43.4%) had low education level. Confirmatory factor analysis confirmed goodness of fit of the PROFFIT-score. Significant partial correlation of PROFFIT-score was found with Q-28 (r = 0.51) and HR-QOL (r = -0.23). Mean (SD) PROFFIT-score at baseline was 36.5 (24.9); it was statistically significantly higher for patients living in South Italy, those with lower education level, those who were freelancer/unemployed at diagnosis and those who reported significant economic impact from the COVID-19 pandemic. Mean (SD) scores of determinants ranged from 17.6 (27.1) for item 14 (support from medical staff) to 49.0 (36.3) for item 10 (expenses for medicines or supplements). PROFFIT-score significantly increased with worsening response to determinants.
External validation of PROFFIT-score in an independent sample of patients was successful. The instrument is now being used in clinical studies.
One of the crucial and unsolved problems of the airborne carbon nanoparticles is the role played by the adsorbed environmental pollutants on their toxicological effect. Indeed, in the urban areas, ...the carbon nanoparticles usually adsorb some atmospheric contaminants, whose one of the leading representatives is the benzo(α)pyrene. Herein, we used the proteomics to investigate the alteration of toxicological pathways due to the carbon nanopowder-benzo(α)pyrene complex in comparison with the two contaminants administered alone on human skin-derived fibroblasts (hSDFs) exposed for 8 days in semi-static conditions. The preliminary confocal microscopy observations highlighted that carbon-nanopowder was able to pass through the cell membranes and accumulate into the cytoplasm both when administered alone and with the adsorbed benzo(α)pyrene. Proteomics revealed that the effect of carbon nanopowder-benzo(α)pyrene complex seems to be related to a new toxicological behavior instead of simple additive or synergistic effects. In detail, the cellular pathways modulated by the complex were mainly related to energy shift (glycolysis and pentose phosphate pathway), apoptosis, stress response and cellular trafficking.
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•Skin represents an alternative route of exposure for carbon nanoparticles.•Carbon nanoparticles act as carrier for benzo(α)pyrene.•Proteomics is a useful tool for the eco-nanotoxicological studies.
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