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Lung cancer remains one the most common cancers in Europe and ranks first in terms of cancer mortality in both sexes. Incidence rates vary by region and depend above all on the prevalence of tobacco consumption. In this study we describe recent trends in lung cancer incidence by sex, age and histological type in Catalonia and project changes according to histology by 2025. Bayesian age-period-cohort models were used to predict trends in lung cancer incidence according to histological type from 2012 to 2025, using data from the population-based Catalan cancer registries. Data suggest a decrease in the absolute number of new cases in men under the age of 70 years and an increase in women aged 60 years or older. Adenocarcinoma was the most common type in both sexes, while squamous cell carcinoma and small cell carcinoma were decreasing significantly among men. In both sexes, the incident cases increased by 16% for patients over 70 years. Increases in adenocarcinoma and rising incidence in elderly patients suggest the need to prioritize strategies based on multidisciplinary teams, which should include geriatric specialists.

Aim: Few published studies comprehensively describe the characteristics of patients with pancreatic cancer and their treatment in clinical practice. This study aimed to describe the current clinical practice for treating pancreatic cancer in Catalonia, along with the associated survival and treatment costs. Methods: A retrospective observational cohort study in patients diagnosed with pancreatic cancer from 2014 to 2018, using data from the healthcare records of the Public Health System of Catalonia, was conducted. Treatment patterns and costs were described by age groups from 2014 to 2018, with survival reported until December 2021. Results: The proportion of patients receiving surgery with curative intent was low, especially in older patients (23% of patients <60 years and 9% of patients ≥80 years). The percentage of patients treated with drugs for unresectable disease also decreased with age (45% of patients <60 years and 8% of patients ≥80 years). Although age was associated with significant differences in survival after curative surgery, no differences attributable to age were observed in patients who received pharmacological treatment for unresectable disease. In patients under 60 years of age, the mean cost of the first year of treatment was EUR 17,730 (standard deviation [SD] 5754) in those receiving surgery and EUR 5398 (SD 9581) in those on pharmacological treatment for unresectable disease. In patients over 80, the mean costs were EUR 15,339 (SD 2634) and EUR 1845 (SD 3413), respectively. Conclusions: Half of the patients diagnosed with pancreatic cancer did not receive specific treatment. Surgery with curative intent was associated with longer survival, but only 18% of (mostly younger) patients received this treatment. Chemotherapy was also used less frequently in patients of advanced age, though survival in treated patients was comparable across all age groups, so careful oncogeriatric assessment is advisable to ensure the most appropriate indication for eligibility in older patients. In general, earlier diagnosis and more effective pharmacological treatments are necessary to treat frail patients with high comorbidity, a common profile in older patients.

Objective: Few published studies have described multidisciplinary therapeutic strategies for lung cancer. This study aims to describe the different approaches used for treating lung cancer in Catalonia in 2014 and 2018 and to assess the associated cost and impact on patient survival. Methods: A retrospective observational cohort study using data of patients with lung cancer from health care registries in Catalonia was carried out. We analyzed change in treatment patterns, costs and survival according to the year of treatment initiation (2014 vs. 2018). The Kaplan–Meier method was used to estimate survival, with the follow-up until 2021. Results: From 2014 to 2018, the proportion of patients undergoing surgery increased and treatments for unresectable tumors decreased, mainly in younger patients. Immunotherapy increased by up to 9% by 2018. No differences in patient survival were observed within treatment patterns. The mean cost per patient in the first year of treatment increased from EUR 14,123 (standard deviation [SD] 4327) to EUR 14,550 (SD 3880) in surgical patients, from EUR 4655 (SD 3540) to EUR 5873 (SD 6455) in patients receiving curative radiotherapy and from EUR 4723 (SD 7003) to EUR 6458 (SD 10,116) in those treated for unresectable disease. Conclusions: From 2014 to 2018, surgical approaches increased in younger patients. The mean cost of treating patients increased, especially in pharmaceutical expenditure, mainly related to the use of several biomarker-targeted treatments. While no differences in overall patient survival were observed, it seems reasonable to expect improvements in this outcome in upcoming years as more patients receive innovative treatments.

VN2222 (1-(benzo[b]thiophen-3-yl)-3-[4-(2-methoxiphenyl piperazin-1-yl]propan-1-ol) is a potential antidepressant with high affinity for the serotonin transporter and 5-HT(1A) receptors. Locally applied, VN2222 enhanced the extracellular 5-hydroxytryptamine (5-HT) concentration (5-HT(ext)) in rat striatum to 780% of baseline whereas its systemic administration (1-10 mg/kg s.c.) reduced 5-HT(ext). In the presence of citalopram, 8-OH-DPAT or VN2222 applied in medial prefrontal cortex reduced 5-HT(ext). Fluoxetine, VN2222, and 8-OH-DPAT suppressed the firing rate of dorsal raphe 5-HT neurons (ED(50): 790, 14.9, and 0.8 microg/kg i.v., respectively). These effects were antagonized by WAY 100635. Administration of VN2222 for 2 weeks desensitized 5-HT(1A) receptors as assessed by microdialysis and single-unit recordings (ED(50) values for 8-OH-DPAT were 0.45 and 2.34 microg/kg i.v. for controls and rats treated with 6 mg/kg day VN2222). These results show that VN2222 is a mixed 5-HT reuptake inhibitor/5-HT(1A) agonist that markedly desensitizes 5-HT(1A) autoreceptors. These properties suggest that it may be a clinically effective dual action antidepressant drug.

VN2222 (1-(benzo[ b ]thiophen-3-yl)-3-[4-(2-methoxiphenyl piperazin-1-yl]propan-1-ol) is a potential antidepressant with high affinity for the serotonin transporter and 5-HT 1A receptors. Locally applied, VN2222 enhanced the extracellular 5-hydroxytryptamine (5-HT) concentration (5-HT ext ) in rat striatum to 780% of baseline whereas its systemic administration (1–10 mg/kg s.c.) reduced 5-HT ext . In the presence of citalopram, 8-OH-DPAT or VN2222 applied in medial prefrontal cortex reduced 5-HT ext . Fluoxetine, VN2222, and 8-OH-DPAT suppressed the firing rate of dorsal raphe 5-HT neurons (ED 50 : 790, 14.9, and 0.8 μg/kg i.v., respectively). These effects were antagonized by WAY 100635. Administration of VN2222 for 2 weeks desensitized 5-HT 1A receptors as assessed by microdialysis and single-unit recordings (ED 50 values for 8-OH-DPAT were 0.45 and 2.34 μg/kg i.v. for controls and rats treated with 6 mg/kg day VN2222). These results show that VN2222 is a mixed 5-HT reuptake inhibitor/5-HT 1A agonist that markedly desensitizes 5-HT 1A autoreceptors. These properties suggest that it may be a clinically effective dual action antidepressant drug.

The present double-blind clinical trial compared two therapeutic strategies, combined therapy and dose-titration, as second-line treatment options after a first failure in patients not controlled with monotherapy, to assess potential advantages of each option. Three hundred and twenty-eight patients went into a placebo run-in for 2 weeks and then received amlodipine 5mg for 4 weeks. Within non-controlled patients, 245 were randomly assigned to either a fixed-dose combination of enalapril 10 mg / nitrendipine 20 mg (E/N) (N=126) or to dose titration with amlodipine 10 mg (A) (N=119) for 6 weeks. The main efficacy variable was DBP. During the double-blind period of the study E/N allowed control of BP in 2.8 patients per each patient that experienced related adverse events (55%/19.8%), while amlodipine allowed control of BP in 1.6 patients per each patient that experienced related adverse events (60.2%/37%). The risk/benefit assessment was better for enalapril/nitrendipine fixed-dose combination than for dose titration with amlodipine. (See Table 1)Main Study Results Efficacy E/N (N=100) A (N=98) Diff. 95% CI Chi2 P DBP and SBP <90/140 mmHg 55 (55%) 59 (60.2%) −5.2 8.5 to −18.9 0.458 SBP <140 mmHg 60 (60%) 69 (70.4%) −10.4 2.8 to −23.6 0.124 DBP <90 mmHg 75 (75%) 78 (79.6%) −4.6 7.1 to −16.2 0.441 Tolerability E/N (N=126) A (N=119) Diff. 95% CI Chi2 P Incidence of related AEs 25 (19.8%) 44 (37%) −17.1 −6.0 to −28.3 0.003 Incidence of leg oedema 14 (11.1%) 40 (33.6%) −22.5 −12.5 to −32.6 <0.0001

Canine transmissible venereal tumor is one of the few cancer lineages that is transferred among individuals through contact. It arose millennia ago and has been evolving independently from its hosts ever since. Baez-Ortega et al. looked at the phylogenetic history of the cancer and describe several distinctive mutational patterns (see the Perspective by Maley and Shibata). Most notably, both positive and negative selection show only weak or distant signals. This suggests that the main driver of the lineage's evolution is neutral genetic drift. Understanding the influence of drift may reshape how we think about long-term cancer evolution. Science , this issue p. eaau9923 ; see also p. 440 Canine venereal tumor evolution was largely driven by genetic drift. The canine transmissible venereal tumor (CTVT) is a cancer lineage that arose several millennia ago and survives by “metastasizing” between hosts through cell transfer. The somatic mutations in this cancer record its phylogeography and evolutionary history. We constructed a time-resolved phylogeny from 546 CTVT exomes and describe the lineage’s worldwide expansion. Examining variation in mutational exposure, we identify a highly context-specific mutational process that operated early in the cancer’s evolution but subsequently vanished, correlate ultraviolet-light mutagenesis with tumor latitude, and describe tumors with heritable hyperactivity of an endogenous mutational process. CTVT displays little evidence of ongoing positive selection, and negative selection is detectable only in essential genes. We illustrate how long-lived clonal organisms capture changing mutagenic environments, and reveal that neutral genetic drift is the dominant feature of long-term cancer evolution.

Autonomous replication and segregation of mitochondrial DNA (mtDNA) creates the potential for evolutionary conflict driven by emergence of haplotypes under positive selection for ‘selfish’ traits, such as replicative advantage. However, few cases of this phenomenon arising within natural populations have been described. Here, we survey the frequency of mtDNA horizontal transfer within the canine transmissible venereal tumour (CTVT), a contagious cancer clone that occasionally acquires mtDNA from its hosts. Remarkably, one canine mtDNA haplotype, A1d1a, has repeatedly and recently colonised CTVT cells, recurrently replacing incumbent CTVT haplotypes. An A1d1a control region polymorphism predicted to influence transcription is fixed in the products of an A1d1a recombination event and occurs somatically on other CTVT mtDNA backgrounds. We present a model whereby ‘selfish’ positive selection acting on a regulatory variant drives repeated fixation of A1d1a within CTVT cells. The competitive dynamics of mitochondrial haplotypes juxtaposed within the same cell are poorly studied. Here the authors show, in the context of a transmissible cancer, that one haplotype has recurrently entered cancer cells by horizontal transfer and appears to have a ‘selfish’ selective advantage.