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Solitary bees provide essential pollination services. Concerns for the decline of these wild bee species have led to calls for their inclusion in pesticide risk assessment. Solitary bees differ from honey bees in their physiology and ecology and this may affect how they respond to pesticide exposure. Here we investigate the life-time toxicity of two insecticides, the organophosphate dimethoate and neonicotinoid clothianidin, for two mason bee species, Osmia bicornis and O. cornuta using a toxicokinetic/toxicodynamic stochastic death model taken from Dynamic Energy Budget (DEBtox) theory. Both species showed concentration and exposure duration dependent effects for each chemical. LC 50 values estimated from the model parameters at 48 h were ≥ 14 fold and 6 fold those at 480 h for dimethoate and clothianidin respectively. Survival modelling indicated greater sensitivity in O. bicornis than for O. cornuta to dimethoate, whilst for clothianidin, O. cornuta females but not males, were more sensitive than both sexes of O. bicornis. These sensitivity differences were not related to body size. Toxicokinetic and toxicodynamic traits derived from modelling indicated lower elimination rates in O. bicornis and higher killing rates for O. cornuta females for dimethoate and lower elimination rates for clothianidin in O. cornuta females that were related to sensitivity. This study shows the near life-time testing is possible for solitary bees and that combining adult life-time toxicity tests with toxicokinetic/toxicodynamic modelling provides a more mechanistic understanding of pesticide effects in solitary bee species. [Display omitted] • Life-span toxicity of dimethoate and clothianidin compared in two mason bee species. • Species and sex differences in sensitivity modelled using DEBtox. • Osmia bicornis have greater sensitivity to dimethoate compared to O. cornuta. • Bee species show sex-related differences in sensitivity to clothianidin. • Life-span toxicity tests provide improved understanding of pesticide effects in bees. [ABSTRACT FROM AUTHOR]

In recent years, the thoracic malignancies treatment landscape has become more complex with the emergence of novel targeted and immunotherapy-based treatments. Although beneficial to patients and physicians, this fast-paced therapeutic evolution has increased the complexity of clinical decision-making and amplified the importance of real-world evidence to support data from randomized controlled trials. The international I-O Optimise initiative was established in 2016 to provide real-world insights into the thoracic malignancies treatment landscape, and has since collaborated with 14 data sources across Europe and Canada, allowing access to data from ~ 500,000 patients with non-small-cell lung cancer, small-cell lung cancer, and malignant pleural mesothelioma. This article reviews pertinent I-O Optimise research, with discussion of the methodological/data-related learnings and expectations for future insights.

Purpose: CD276 (B7-H3) is an immunoregulatory protein that plays an important role in the inhibition of T-cell function. CD276 is overexpressed on a variety of human solid cancer cells with limited expression in normal tissues, making it an appealing target for innovative cancer immunotherapy approaches. Pleural mesothelioma (PM) is a highly aggressive disease with a need for new treatment options. Our objective was to investigate the expression of CD276 in the multicenter PM cohort of the European Thoracic Oncology Platform Mesoscape project and correlate the results with annotated clinical data., Materials and Methods: Using tissue microarrays (TMAs), the expression of CD276, assessed using a semiquantitative aggregate H -score method on the membrane (and secondarily in the cytoplasm), was correlated with clinicopathologic characteristics and survival outcome., Results: CD276 immunohistochemistry results were available for 353 patients, with mostly epithelioid histology (71%). Membranous CD276 expression was present in 86%. High membranous CD276 expression ( H -score ≥the median H -score of 120) was significantly more common in females ( P = .0029; 71% v 47%) and in epithelioid histology ( P < .001; 59% v 29%), whereas no significant association in clinical outcome (overall survival [OS]/progression-free survival) was found. Cross-validation of the TMA method using whole sections revealed a moderate agreement for membranous assessment (Cohen's kappa = 0.47) and a lower agreement for cytoplasm assessment (Cohen's kappa = 0.37). In an exploratory analysis, high cytoplasmic CD276 expression was associated with worse prognosis (OS, log-rank P = .043), but was not significant when adjusting for other clinical variables., Conclusion: Although no prognostic value of CD276 expression was found, its high membranous expression (86%) in the PM samples of the study supports further research of its potential as a therapeutic target for this disease.

Purpose: Datopotamab deruxtecan (Dato-DXd) is a trophoblast cell-surface antigen-2-directed antibody-drug conjugate with a highly potent topoisomerase I inhibitor payload. The TROPION-Lung05 phase II trial (ClinicalTrials.gov identifier: NCT04484142) evaluated the safety and clinical activity of Dato-DXd in patients with advanced/metastatic non-small cell lung cancer (NSCLC) with actionable genomic alterations progressing on or after targeted therapy and platinum-based chemotherapy., Patients and Methods: Patients received Dato-DXd 6 mg/kg once every 3 weeks. The primary end point was objective response rate (ORR) by blinded independent central review. Secondary end points included duration of response (DOR), safety, tolerability, and survival., Results: Among 137 patients who received at least 1 dose of Dato-DXd, 71.5% received at least three lines of prior therapies for advanced/metastatic disease. Overall, 56.9% had EGFR mutations and 24.8% had ALK rearrangements. Median treatment duration was 4.4 months (range, 0.7-20.6). The confirmed ORR was 35.8% (95% CI, 27.8 to 44.4) overall, and 43.6% (95% CI, 32.4 to 55.3) and 23.5% (95% CI, 10.7 to 41.2) in those with EGFR mutations and ALK rearrangements, respectively. The median DOR was 7.0 months (95% CI, 4.2 to 9.8), and the overall disease control rate was 78.8% (95% CI, 71.0 to 85.3). Grade ≥3 treatment-related adverse events (TRAEs) occurred in 28.5% of patients. The most common TRAE was stomatitis (preferred term; any grade: 56.2%; grade ≥3: 9.5%). Five (3.6%) patients experienced adjudicated treatment-related interstitial lung disease/pneumonitis, with 1 (0.7%) grade 5 event., Conclusion: Encouraging and durable antitumor activity was observed with Dato-DXd in this heavily pretreated advanced/metastatic NSCLC population with actionable genomic alterations. The rate of treatment-related grade ≥3 toxicities was comparable with previous observations, and no new safety signals were observed.