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The ever-growing knowledge regarding NSCLC molecular biology has brought innovative therapies into clinical practice; however, the treatment situation in the non-metastatic setting is rapidly evolving. Indeed, immunotherapy-based perioperative treatments are currently considered the standard of care for patients with resectable NSCLC in the absence of EGFR mutations or ALK gene rearrangements. Recently, data have been presented on the use of tyrosine kinase inhibitors (TKIs) in the adjuvant and locally advanced setting for patients with NSCLC harboring such driver gene alterations. The aim of the current work is to review the available evidence on the use of targeted treatments in the non-metastatic setting, together with a summary of the ongoing trials designed for actionable gene alterations other than EGFR and ALK . To date, 3-year adjuvant osimertinib treatment has been demonstrated to improve DFS and OS and to reduce CNS recurrence in resected EGFR -mutated NSCLC in stage IB-IIIA (TNM 7th edition). The use of osimertinib after chemo-radiation in stage III unresectable EGFR -mutated NSCLC showed the relevant PFS improvement. In the ALK -positive setting, 2-year alectinib treatment was shown to clearly improve DFS compared to adjuvant standard chemotherapy in resected NSCLC with stage IB (≥4 cm)-IIIA (TNM 7th edition). Several trials are ongoing to establish the optimal adjuvant TKI treatment duration, as well as neoadjuvant TKI strategies in EGFR- and ALK -positive disease, and (neo)adjuvant targeted treatments in patients with actionable gene alterations other than EGFR or ALK . In conclusion, our review depicts how the current treatment scenario is expected to rapidly change in the context of non-metastatic NSCLC with actionable gene alterations, hence appropriate molecular testing from the early stages has become crucial to establish the most adequate approaches both in the perioperative and the locally advanced disease.

Introduction: Although both aging and menopause influence cardiovascular autonomic control, the effect of menopause per se remains unclear. The current study was undertaken to test the hypothesis that post-menopausal women (PMW) have a blunted cardiovascular autonomic adjustment to active standing compared to pre-menopausal women. Thus, we compared the heart rate variability (HRV) indexes from supine (SUP) to orthostatic (ORT) positions among young women (YW), young men (YM), older men (OM), and PMW., Methods: The participants rested for 10 min in SUP and then stood up and remained for 5 min in ORT. ECG was continuously recorded, and R-R time series of about 300 beats were analyzed using linear (spectral analysis) and non-linear (symbolic analysis) methods. The variation from SUP to ORT was calculated ( Δ  = ORT-SUP) for each HRV index., Results: In SUP, no difference was found for any HRV index among groups. However, Δ 0V% and Δ LFn (cardiac sympathetic modulation) were reduced in PWM compared to all groups (OM, YW, and YM), while Δ 2UV% and Δ HFn (cardiac vagal modulation) were reduced in PMW than the younger group (YW and YM). No differences were found among the male groups (OM and YM)., Discussion: In light of our results, the cardiac autonomic dynamic response to orthostatic stress is blunted in post-menopausal women compared to younger women and older men, a finding that might be influenced not only by aging., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Scatà, Ferreira, Padilha, Carandina, Asnaghi, Bellocchi, Tobaldini, Montano, Soares and Rodrigues.)

Background: Actionable driver mutations account for 40-50% of NSCLC cases, and their identification clearly affects treatment choices and outcomes. Conversely, non-actionable mutations are genetic alterations that do not currently have established treatment implications. Among co-occurring alterations, the identification of concurrent actionable genomic alterations is a rare event, potentially impacting prognosis and treatment outcomes. Methods: We retrospectively evaluated the prevalence and patterns of concurrent driver genomic alterations in a large series of NSCLCs to investigate their association with clinicopathological characteristics, to assess the prognosis of patients whose tumor harbors concurrent alterations in the genes of interest and to explore their potential therapeutic implications. Results: Co-occurring driver alterations were identified in 26 out of 1520 patients with at least one gene alteration (1.7%). Within these cases, the incidence of concurrent actionable gene alterations was 39% (0.7% of the overall cohort). Among compound actionable gene mutations, EGFR was the most frequently involved gene (70%). The most frequent association was EGFR mutations with ROS1 rearrangement. Front-line targeted treatments were the preferred approach in patients with compound actionable mutations, with dismal median PFS observed (6 months). Conclusions: Advances in genomic profiling technologies are facilitating the identification of concurrent mutations. In patients with concurrent actionable gene alterations, integrated molecular and clinical data should be used to guide treatment decisions, always considering rebiopsy at the moment of disease progression.

Various next-generation ALK TKIs are available as first-line options for ALK-positive NSCLC, with alectinib and lorlatinib being commonly preferred. However, no direct comparison between them has been conducted, making it impossible to pick a winner. We performed an analytic, 'non-comparative' assessment of the two phase 3 pivotal clinical trials showing superiority of alectinib (ALEX) and lorlatinib (CROWN) in comparison to crizotinib. Overall, the two studies were very similar in the study design and patient characteristics, with the exception of the selection and evaluation of brain metastases. PFS hazard ratios numerically favored lorlatinib, both according to the investigator and to BICR. Notably, the 3-year PFS rate was numerically higher with lorlatinib (64%) than with alectinib (46.4%). Despite similar response rates and overall intracranial response, the rate of complete intracranial response was higher with lorlatinib, with a cumulative incidence risk of CNS disease progression at 12 months of 9.4% with alectinib and 2.8% with lorlatinib. The peculiar toxicities of lorlatinib were related to lipidic profile alterations, peripheral oedema and cognitive effects, with no impact on cardiovascular risk nor impairment in quality of life versus crizotinib. Furthermore, the rate of permanent treatment discontinuation due to adverse events was numerically higher with alectinib (26%) than with lorlatinib (7%). In conclusion, despite the immature OS data for both drugs, the efficacy of lorlatinib appears higher than alectinib while maintaining a manageable toxicity profile., Competing Interests: I. Attili received consulting fees from Bristol-Myers Squibb outside the submitted work. F. de Marinis received honoraria or consulting fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Pfizer, Novartis, Takeda, Xcovery and Roche outside the submitted work. A. Passaro reports personal fees, as a speaker bureau or advisor, for AstraZeneca, Agilent/Dako, Boehringer Ingelheim, Bristol-Myers Squibb, Eli-Lilly, Merck Sharp & Dohme, Janssen, Novartis, Pfizer and Roche Genentech outside the submitted work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. The funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Small cell lung cancer (SCLC) is an aggressive neuroendocrine carcinoma accounting for 15% of lung cancers with dismal survival outcomes. Minimal changes in therapy and prognosis have occurred in SCLC for the past four decades. Recent progress in the treatment of extensive-stage disease (ES-SCLC) has been marked by incorporating immune checkpoint inhibitors (ICIs) into platinum-based chemotherapy, leading to modest improvements. Moreover, few second-line-and-beyond treatment options are currently available. The main limitation for the molecular study of SCLC has been the scarcity of samples, because only very early diseases are treated with surgery and biopsies are not performed when the disease progresses. Despite all these difficulties, in recent years we have come to understand that SCLC is not a homogeneous disease. At the molecular level, in addition to the universal loss of retinoblastoma (RB) and TP53 genes, a recent large molecular study has identified other mutations that could serve as targets for therapy development or patient selection. In recent years, there has also been the identification of new genetic subtypes which have shown us how intertumor heterogeneity exists. Moreover, SCLC can also develop intratumoral heterogeneity linked mainly to the concept of cellular plasticity, mostly due to the development of resistance to therapies. The aim of this review is to quickly present the current standard of care of ES-SCLC, to focus on the molecular landscapes and subtypes of SCLC, subsequently present the most promising therapeutic strategies under investigation, and finally recap the future directions of ongoing clinical trials for this aggressive disease which still remains a challenge.