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Platinum-based doublet chemotherapy is recommended to treat advanced non-small-cell lung cancer (NSCLC) in fit, non-elderly adults, but monotherapy is recommended for patients older than 70 years. We compared a carboplatin and paclitaxel doublet chemotherapy regimen with monotherapy in elderly patients with advanced NSCLC. In this multicentre, open-label, phase 3, randomised trial we recruited patients aged 70–89 years with locally advanced or metastatic NSCLC and WHO performance status scores of 0–2. Patients received either four cycles (3 weeks on treatment, 1 week off treatment) of carboplatin (on day 1) plus paclitaxel (on days 1, 8, and 15) or five cycles (2 weeks on treatment, 1 week off treatment) of vinorelbine or gemcitabine monotherapy. Randomisation was done centrally with the minimisation method. The primary endpoint was overall survival, and analysis was done by intention to treat. This trial is registered, number NCT00298415. 451 patients were enrolled. 226 were randomly assigned monotherapy and 225 doublet chemotherapy. Median age was 77 years and median follow-up was 30·3 months (range 8·6–45·2). Median overall survival was 10·3 months for doublet chemotherapy and 6·2 months for monotherapy (hazard ratio 0·64, 95% CI 0·52–0·78; p<0·0001); 1-year survival was 44·5% (95% CI 37·9–50·9) and 25·4% (19·9–31·3), respectively. Toxic effects were more frequent in the doublet chemotherapy group than in the monotherapy group (most frequent, decreased neutrophil count (108 [48·4%] vs 28 [12·4%]; asthenia 23 [10·3%] vs 13 [5·8%]). Despite increased toxic effects, platinum-based doublet chemotherapy was associated with survival benefits compared with vinorelbine or gemcitabine monotherapy in elderly patients with NSCLC. We feel that the current treatment paradigm for these patients should be reconsidered. Intergroupe Francophone de Cancérologie Thoracique, Institut National du Cancer.

No standard treatment exists for patients with platinum-refractory advanced type B3 thymoma and thymic carcinoma. In the PECATI trial, we sought to assess the antitumour activity and safety of lenvatinib plus pembrolizumab in this population. In this single-arm phase 2 trial, we recruited participants from 11 hospitals in France, Italy, and Spain. Eligible participants were adults (aged ≥18 years), with an Eastern Cooperative Oncology Group performance status of 0–1, and with relapsed or recurrent histologically confirmed type B3 thymoma or thymic carcinoma, at a metastatic stage of disease, who had received at least one line of platinum-based chemotherapy and had progressed during or after the previous line of chemotherapy, and did not have an autoimmune disorder. Participants received lenvatinib (20 mg orally once a day) combined with pembrolizumab (200 mg intravenously, infused over 30 min on day one of each cycle) in 3-week cycles for a maximum of 35 cycles (2 years), with treatment discontinued for reasons including confirmed clinical or radiological disease progression or unacceptable toxicity. The primary endpoint was 5-month progression-free survival (null hypothesis: 5-month progression-free survival of ≤50%; alternative hypothesis: 5-month progression-free survival of ≥68·6%) assessed by the investigators in the full analysis set. Safety was assessed in all participants who received at least one dose of study treatment. The data cutoff date for the current analyses was July 1, 2024. The trial was registered on ClinicalTrials.gov, NCT04710628, and is ongoing. From May 13, 2022, to Feb 1, 2024, 43 participants were enrolled and started study treatment (18 [42%] female and 25 [58%] male; 27 [63%] White, four [9%] Arabic or North African, one [2%] Albanian, one [2%] Black, and ten [23%] ethnicity missing). Median age was 57 years (IQR 45–66). 36 (84%) participants had thymic carcinoma and seven (16%) had B3 thymoma. Masaoka–Koga stage IVA disease was recorded in 15 (35%) participants and stage IVB in 28 (65%), including 16 (37%) participants with liver metastases. 23 (53%) participants had three or more metastatic sites. 20 (47%) participants had received two or more previous lines of therapy. After a median follow-up of 10·6 months (IQR 7·8–14·7), the study met its primary endpoint, with 5-month progression-free survival of 88·4% (90% CI 79·8–96·7). Treatment-emergent adverse events were reported in 42 (98%) of 43 participants, the most common being hypothyroidism (27 [63%] participants) and fatigue (25 [58%]). Grade 3 or worse treatment-related adverse events were reported in 16 (37%) participants. Serious treatment-emergent adverse events occurred in 17 (40%) participants. Grade 3 or worse immune-related adverse events occurred in six (14%) participants, namely hepatic cytolysis (two [5%] participants), colitis, pneumonitis, and cardiac dysfunction (one [2%] participant each), and myocarditis and encephalitis (one [2%] participant). No treatment-related deaths were reported. Lenvatinib combined with pembrolizumab showed potential as a standard treatment for pretreated advanced B3 thymoma and thymic carcinoma. Although the toxicity profile appeared manageable, close monitoring for toxicity is advised. Investigator-Initiated Studies Program of Merck Sharp & Dohme.

For all drugs, effective target engagement requires sufficient intracellular concentrations of drug to be reached, but whether tumour heterogeneity impacts drug distribution and efficacy is poorly studied. Poly (ADP-ribose) polymerase (PARP) inhibitors have transformed treatment opportunities for women with high-grade serous ovarian carcinoma, but resistance remains a clinical hurdle in this highly heterogeneous tumour type. Here, we present a patient-derived explant multi-modal imaging pipeline, which demonstrates that cell-intrinsic PARP inhibitor accumulation is highly variable, both between patients and within tumours. Spatial transcriptomics reveals enrichment of apoptotic and lysosomal signatures in high-drug regions. Rucaparib, an intrinsically fluorescent PARP inhibitor, accumulates heterogeneously at the single-cell level, with rucaparib-high cells demonstrating increased drug response relative to rucaparib-low. Mechanistically, lysosomal sequestration creates a rucaparib reservoir that determines drug levels in the nucleus. Perturbation of lysosomal content alters intracellular levels of weak base PARP inhibitors rucaparib and niraparib, but not olaparib. Together these data suggest that lysosomes act as a reservoir for a subset of PARP inhibitor drugs to improve drug response. Effective target engagement of drugs relies on them achieving sufficient intracellular concentrations. Here, using a multimodal imaging pipeline the authors demonstrate that uneven distribution and uptake of PARP inhibitors in ovarian cancer patient-derived explant models correlates with therapeutic response.

[This corrects the article DOI: 10.1371/journal.pone.0147990.].

This study aimed to optimise techniques for whole transcriptome and small RNA analyses on clinical tissue samples from patients with cardiovascular disease. Clinical samples often represent a particular challenge to extracting RNA of sufficient quality for robust RNA sequencing analysis, and due to availability, it is rarely possible to optimise techniques on the samples themselves. Therefore, we have used equivalent samples from pigs undergoing cardiopulmonary bypass surgery to test different protocols for optimal RNA extraction, and then validated the protocols in human samples. Here we present an assessment of the quality and quantity of RNA obtained using a variety of commercially-available RNA extraction kits on both left ventricular biopsies and blood plasma. RNA extraction from these samples presents different difficulties; left ventricular biopsies are small and fibrous, while blood plasma has a low RNA content. We have validated our optimised extraction techniques on human clinical samples collected as part of the ARCADIA (Association of non-coding RNAs with Coronary Artery Disease and type 2 Diabetes) cohort study, resulting in successful whole transcriptome and small RNA sequencing of human left ventricular tissue.

Spontaneous reports from patients able to report vascular sequelae in real time, and recognition that serum non transferrin bound iron may reach or exceed 10μmol/L in the blood stream after iron tablets or infusions, led us to hypothesize that conventional iron treatments may provoke acute vascular injury. This prompted us to examine whether a phenotype could be observed in normal human endothelial cells treated with low dose iron. Confluent primary human endothelial cells (EC) were treated with filter-sterilized iron (II) citrate or fresh media for RNA sequencing and validation studies. RNA transcript profiles were evaluated using directional RNA sequencing with no pre-specification of target sequences. Alignments were counted for exons and junctions of the gene strand only, blinded to treatment types. Rapid changes in RNA transcript profiles were observed in endothelial cells treated with 10μmol/L iron (II) citrate, compared to media-treated cells. Clustering for Gene Ontology (GO) performed on all differentially expressed genes revealed significant differences in biological process terms between iron and media-treated EC, whereas 10 sets of an equivalent number of randomly selected genes from the respective EC gene datasets showed no significant differences in any GO terms. After 1 hour, differentially expressed genes clustered to vesicle mediated transport, protein catabolism, and cell cycle (Benjamini p = 0.0016, 0.0024 and 0.0032 respectively), and by 6 hours, to cellular response to DNA damage stimulus most significantly through DNA repair genes FANCG, BLM, and H2AFX. Comet assays demonstrated that 10μM iron treatment elicited DNA damage within 1 hour. This was accompanied by a brisk DNA damage response pulse, as ascertained by the development of DNA damage response (DDR) foci, and p53 stabilization. These data suggest that low dose iron treatments are sufficient to modify the vascular endothelium, and induce a DNA damage response.

Understanding development and genetic regulation in the Anopheles gambiae germline is essential to engineer effective genetic control strategies targeting this malaria mosquito vector. These include targeting the germline to induce sterility or using regulatory sequences to drive transgene expression for applications such as gene drive. However, only very few germline-specific regulatory elements have been characterised with the majority showing leaky expression. This has been shown to considerably reduce the efficiency of current genetic control strategies, which rely on regulatory elements with more tightly restricted spatial and/or temporal expression. Meiotic silencing of the sex chromosomes limits the flexibility of transgene expression to develop effective sex-linked genetic control strategies. Here, we build on our previous study, dissecting gametogenesis into four distinct cell populations, using single-cell RNA sequencing to define eight distinct cell clusters and associated germline cell–types using available marker genes. We reveal overexpression of X-linked genes in a distinct cluster of pre-meiotic cells and document the onset of meiotic silencing of the X chromosome in a subcluster of cells in the latter stages of spermatogenesis. This study provides a comprehensive dataset, characterising the expression of distinct cell types through spermatogenesis and widening the toolkit for genetic control of malaria mosquitoes. A scRNA-seq dataset reveals the transcriptomic profile of individual cell types in the male germline of the mosquito and malaria vector, Anopheles gambiae .

Integration of genome-wide expression profiling with linkage analysis is a new approach to identifying genes underlying complex traits. We applied this approach to the regulation of gene expression in the BXH/HXB panel of rat recombinant inbred strains, one of the largest available rodent recombinant inbred panels and a leading resource for genetic analysis of the highly prevalent metabolic syndrome. In two tissues important to the pathogenesis of the metabolic syndrome, we mapped cis - and trans -regulatory control elements for expression of thousands of genes across the genome. Many of the most highly linked expression quantitative trait loci are regulated in cis , are inherited essentially as monogenic traits and are good candidate genes for previously mapped physiological quantitative trait loci in the rat. By comparative mapping we generated a data set of 73 candidate genes for hypertension that merit testing in human populations. Mining of this publicly available data set is expected to lead to new insights into the genes and regulatory pathways underlying the extensive range of metabolic and cardiovascular disease phenotypes that segregate in these recombinant inbred strains.

Purpose: Few data have been published on the management of patients with synchronous head-and-neck cancer (HNC) and lung cancer (LC). This observational study was undertaken to describe the management of these patients in multiple centers. Materials and Methods: All patients consecutively diagnosed with synchronous HNC and LC in 26 French centers were included. Information was collected on patients' clinical characteristics, management, and outcomes. Those characteristics and treatments were analyzed descriptively. Kaplan-Meier progression-free and overall survival probabilities were estimated. Results: The study included 132 patients: 83% male; median age: 63.7 (range: 62.1-65.4) years; all current or former smokers; Eastern Cooperative Oncology Group performance status: 0 or 1 for 21.9% or 65.9% of the patients, respectively; cardiovascular comorbidities: 63%; chronic obstructive pulmonary disease: 33%; and previous cancer: 11%. HNC histology was 98% squamous: 23.5% oral cavity, 26.5% oropharyngeal, 22.0% hypopharyngeal, and 28.0% laryngeal. LCs were mainly localized (47.7% Stage I and 9.9% Stage II): 38% squamous, 49% adenocarcinomas, and 13% others. LC diagnosis impacted HNC management for 38% of the patients, with a median time from HNC diagnosis to first HNC treatment of 40 days. HNC impacted LC management for 48% of the patients, with a median time from LC diagnosis-to-LC treatment interval of 41 days. Conclusions: Synchronous LC at HNC diagnosis impacted management and outcomes of both cancers. Specific recommendations should be elaborated to improve the management of these patients.

Molecular genetic testing is recommended for diagnosis of inherited cardiac disease, to guide prognosis and treatment, but access is often limited by cost and availability. Recently introduced high-throughput bench-top DNA sequencing platforms have the potential to overcome these limitations. We evaluated two next-generation sequencing (NGS) platforms for molecular diagnostics. The protein-coding regions of six genes associated with inherited arrhythmia syndromes were amplified from 15 human samples using parallelised multiplex PCR (Access Array, Fluidigm), and sequenced on the MiSeq (Illumina) and Ion Torrent PGM (Life Technologies). Overall, 97.9% of the target was sequenced adequately for variant calling on the MiSeq, and 96.8% on the Ion Torrent PGM. Regions missed tended to be of high GC-content, and most were problematic for both platforms. Variant calling was assessed using 107 variants detected using Sanger sequencing: within adequately sequenced regions, variant calling on both platforms was highly accurate (Sensitivity: MiSeq 100%, PGM 99.1%. Positive predictive value: MiSeq 95.9%, PGM 95.5%). At the time of the study the Ion Torrent PGM had a lower capital cost and individual runs were cheaper and faster. The MiSeq had a higher capacity (requiring fewer runs), with reduced hands-on time and simpler laboratory workflows. Both provide significant cost and time savings over conventional methods, even allowing for adjunct Sanger sequencing to validate findings and sequence exons missed by NGS. MiSeq and Ion Torrent PGM both provide accurate variant detection as part of a PCR-based molecular diagnostic workflow, and provide alternative platforms for molecular diagnosis of inherited cardiac conditions. Though there were performance differences at this throughput, platforms differed primarily in terms of cost, scalability, protocol stability and ease of use. Compared with current molecular genetic diagnostic tests for inherited cardiac arrhythmias, these NGS approaches are faster, less expensive, and yet more comprehensive.