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Background: Geriatric patients (≥80 years) are underrepresented in immune checkpoint inhibitor (ICIs) clinical trials. However, their unique biology may affect their response to ICIs. There are currently no established biomarkers of the response to ICIs in adult patients with cancer that can help with patient selection., Methods: We built a multicenter, international retrospective study of 885 patients (<80 years: n = 417, 47.12%; ≥80 years: n = 468, 52.88%) with different tumor types treated with ICIs between 2011 and 2021 from 11 academic centers in the U.S. and Europe. The main outcome measures were objective response rates (ORR), progression-free survival (PFS) and overall survival (OS) stratified by age and circulating inflammatory levels (neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammatory index (SII))., Results: Patients ≥80 years with low NLR (NLR-L) and SII (SII-L) had significantly higher ORR (vs. high NLR [NLR-H], p < 0.01 and SII-H, p < 0.05, respectively). At median follow-ups (13.03 months), and compared to SII-H, patients with SII-L had significantly longer median PFS and OS in patients <80 ( p < 0.001), and ≥80 years ( p < 0.001). SII-L was independently associated with longer PFS and OS (HR: 0.61 and 0.62, respectively, p < 0.01)., Conclusion: Lower inflammation pre-ICI initiation may predict an improved response and survival in geriatric patients with cancer.

Many new treatment modalities for non-small-cell carcinoma (NSCLC) have been described in the last two decades. Surgical resections remain the gold standard for early stages and may be considered for locally advanced tumors. Medical treatment has changed drastically in recent years, especially for advanced stages, for which the development of immunotherapy and molecular targeted therapy significantly increased survival and quality of life. The addition of radical surgical resection following immunotherapy or immuno-chemotherapy is feasible and safe with low surgical-related mortality and morbidity in selected patients with initially unresectable NSCLC. However, data from multiple ongoing trials with overall survival as the primary endpoint should be awaited before this strategy is introduced into the standard of care.

(1) Objective: the purpose of this study was to evaluate and quantify the stress to which a surgeon is subjected during his/her surgical activity; we compared the individual clinical and psychological responses to stress of two surgeons during their surgical activities via robotic and open approaches. (2) Materials and methods: This was a prospective observational study in which we progressively collected data concerning the surgical performances of two different thoracic surgeons (October 2021-June 2022). We evaluated 20 lung resections performed via robot-assisted surgery and 20 lung resections performed via an open approach by each surgeon; in particular, we evaluated a panel of pre-, peri-, and postoperative data concerning the interventions, the patients, and other outcomes concerning the autonomic nervous system (ANS) and psychological responses to stress of the surgeons during their surgical activities. (3) Results: When analyzing data concerning the ANS activity of two surgeons, during robotic activity we found lower maximum, minimum, and mean heart rates; lower mean respiratory frequencies; lower body temperatures; and lower mean desaturations compared to the open approach activity for both surgeons. The psychological monitoring showed that the open approach created more physical fatigue and frustration but higher levels of satisfaction and performance evaluation. The robot-assisted surgeries showed higher levels of anxiety. (4) Conclusions: for different reasons, the robotic approach stimulated the ANS to a lesser degree, causing less stress for surgeons and ensuring greater comfort.

Background: Completion pneumonectomy (CP) is associated with high morbidity and mortality. We reviewed our experience to evaluate whether induction treatment (IT) may affect postoperative outcomes and analyzed factors influencing long-term results., Methods: Between 1998 and 2020, 69 patients with lung cancer underwent CP (50 males, median age 63 years, right CP in 47 patients). A total of 23 patients (33.3%) received IT (chemotherapy in 15, chemoradiotherapy in 7, and radiation in 1). Surgery included 25 (36.2%) extended resections and five (7.2%) tracheal sleeve CP., Results: The 30-day mortality rate was 7.2% (5/69), and overall morbidity was 37.6%. Major complications occurred in five patients (7.2%): one cardiac dislocation, one diaphragmatic hernia, one transient ischemic attack (TIA), and two bronchopleural fistulas. Minor complications occurred in 21 cases (30.4%): pulmonary in 12, cardiac in 7, and neurological in 2. The median hospital stay was 8 days (range, 5-56 days). IT did not influence postoperative morbidity and mortality. Pathological staging included 19 (27.5%) stage I, 36 (52.2%) stage II, and 14 (20.3%) stage III. Overall 5-year survival was 51.7%. Factors influencing survival were IT ( p = 0.01), extension of resection ( p = 0.04), histology ( p = 0.01), pathological stage ( p = 0.03), and T and N factors ( p = 0.2, respectively). Factors affecting survival in multivariate analysis included IT ( p = 0.02) and histology ( p = 0.03)., Conclusions: In our experience, CP had a low mortality, acceptable morbidity, and good long-term survival, which justifies this surgical procedure. Postoperative complications were not influenced by IT. Long-term survival was adversely influenced by the absence of IT, the presence of extended resection, the presence of squamous cell carcinoma, and cancers at advanced stages.

Background: We report the outcomes for unresectable patients with locally advanced or oligometastatic non-small cell lung cancer (NSCLC) treated with tyrosine kinase inhibitor (TKI) or immunotherapy who achieved a clinical downstaging so as to re-enter resectability., Methods: We retrospectively reviewed the clinical, surgical, and pathological data of 42 patients with histologically proven, inoperable NSCLC who received rescue surgery after a good response to TKI or immunotherapy between March 2014 and December 2021., Results: Of 42 patients, 39 underwent pulmonary resection with therapeutic intent (three explorative thoracotomies). There were 26 males, with a median age of 64 years (range, 41-78 years). Twenty-three patients received TKIs and 19 immunotherapies. Anatomic resection was performed in 97.4% of resected patients (38/39) including 30 lobectomies, one right upper sleeve lobectomy, five pneumonectomies, one tracheal sleeve pneumonectomy, and one bilobectomy; a patient underwent wedge resection. Of 10 procedures attempted via a robotic approach, two required conversion to thoracotomy. No intraoperative morbidity/mortality occurred. The median operative time was 190 (range, 80-426) minutes; estimated blood loss was 200 mL (range, 35-780 mL). Morbidity occurred in 13/39 (33.3%). The median length of hospital stay was 6.5 days (range, 4-23 days). Pathologic downstaging was 74.4% (29/39). With a median follow-up of 28.7 months, the 5-year disease-free interval was 46.5%, and the 5-year overall survival was 66.0%; 32/39 patients (82.1%) are alive, 10 with the disease., Conclusions: Lung resection for suspected residual disease after immunotherapy or TKIs is feasible, with encouraging pathological downstaging. Surgical operation may be technically challenging due to the presence of fibrosis, but significant morbidity appears to be rare. Outcomes are encouraging, with reasonable survival during the short-interval follow-up.

After a variable period of activity of the epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment, patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations develop resistance to these TKIs. In some cases, an oligoprogression is diagnosed, and its management is still controversial. The oligoprogression represents an intermediate stage of metastatic NSCLC between localized and widely disseminated disease, and is characterized by a limited number and/or sites of metastases in which a disease progression appears, together with a more indolent tumor biology. Currently, the management of oligoprogressed NSCLC involves local treatment, including radiotherapy and/or surgery, to control the progressive lesions. Systemic therapy should also be a potential approach to boost the activity of EGFR-TKIs. However, considering the lack of large trials addressing this topic, the optimal therapeutic strategies remain undefined and should be evaluated on an individualized basis. In this paper, we review the most relevant scientific evidence of continuing the systemic therapy with the same EGFR-TKI for the management of patients with NSCLC harboring EGFR mutations and oligoprogressed to first-line EGFR-TKIs, also discussing the controversies and potential future directions.

Causing a high mortality rate worldwide, lung cancer remains an incurable malignancy resistant to conventional therapy. Despite the discovery of specific molecular targets and new treatment strategies, there remains a pressing need to develop more efficient therapy to further improve the management of this disease. Cancer stem cells (CSCs) are considered the root of sustained tumor growth. This consensus corroborates the CSC model asserting that a distinct subpopulation of malignant cells within a tumor drives and maintains tumor progression with high heterogeneity. Besides being highly tumorigenic, CSCs are highly refractory to standard drugs; therefore, cancer treatment should be focused on eliminating these cells. Herein, we present the current knowledge of the existence of CSCs, CSC-associated mechanisms of chemoresistance, the ability of CSCs to evade immune surveillance, and potential CSC inhibitors in lung cancer, to provide a wider insight to drive a more efficient elimination of this pro-oncogenic and treatment-resistant cell fraction.

Background: Pembrolizumab is approved in monotherapy for the first-line (1L) of advanced or metastatic NSCLC patients with high PD-L1 (≥50%). Despite a proportion of patients achieve long-term survival, about one-third of patients experience detrimental survival outcomes, including early death, hyperprogression, and fast progression. The impact of clinical factors on early progression (EP) development has not been widely explored., Methods: We designed a retrospective, multicenter study involving five Italian centers, in patients with metastatic NSCLC with PD-L1 ≥ 50%, treated with Pembrolizumab in a 1L setting. EP was defined as a progressive disease within three months from pembrolizumab initiation. Baseline clinical factors of patients with and without EP were collected and analyzed. Logistic regression was performed to identify clinical factors associated with EP and an EP prognostic score was developed based on the logistic model., Results: Overall, 321 out of 336 NSCLC patients treated with 1L pembrolizumab provided all the data for the analysis. EP occurred in 137 (42.7%) patients; the median PFS was 3.8 months (95% CI: 2.9-4.7), and median OS was not reached in the entire study population. Sex, Eastern Cooperative Oncology Group (ECOG) performance status (PS), steroids, metastatic sites ≥2, and the presence of liver/pleural metastasis were confirmed as independent factors for EP by multivariate analysis. By combining these factors, we developed an EP prognostic score ranging from 0-13, with three-risk group stratification: 0-2 (good prognosis), 3-6 (intermediate prognosis), and 7-13 (poor prognosis). The area under the curve (AUC) of the model was 0.76 (95% CI: 0.70-0.81)., Conclusions: We identified six clinical factors independently associated with EP. We developed a prognostic score model for EP-risk to potentially improve clinical practice and patient selection for 1L pembrolizumab in NSCLC with high PD-L1, in the real-world clinical setting.

Despite tremendous efforts to improve the treatment of lung cancer, prognosis still remains poor; hence, the search for efficacious therapeutic option remains a prime concern in lung cancer research. Cell cycle regulation including mitosis has emerged as an important target for cancer management. Novel pharmacological agents blocking the activities of regulatory molecules that control the functional aspects of mitosis such as Aurora kinases are now being investigated. The Aurora kinases, Aurora-A (AURKA), and Aurora B (AURKB) are overexpressed in many tumor entities such as lung cancer that correlate with poor survival, whereby their inhibition, in most cases, enhances the efficacy of chemo-and radiotherapies, indicating their implication in cancer therapy. The current knowledge on Aurora kinase inhibitors has increasingly shown high potential in ensuing targeted therapies in lung malignancies. In this review, we will briefly describe the biology of Aurora kinases, highlight their oncogenic roles in the pre-clinical and clinical studies in lung cancer and, finally, address the challenges and potentials of Aurora kinases to improve the therapy of this malignancy.

Locally advanced non-small cell lung cancer accounts for one third of non-small cell lung cancer (NSCLC) at the time of initial diagnosis and presents with a wide range of clinical and pathological heterogeneity. To date, the combined multimodality approach involving both local and systemic control is the gold standard for these patients, since occult distant micrometastatic disease should always be suspected. With the rapid increase in treatment options, the need for an interdisciplinary discussion involving oncologists, surgeons, radiation oncologists and radiologists has become essential. Surgery should be recommended to patients with non-bulky, discrete, or single-level N2 involvement and be included in the multimodality treatment. Resectable stage IIIA patients have been the subject of a number of clinical trials and retrospective analysis, discussing the efficiency and survival benefits on patients treated with the available therapeutic approaches. However, most of them have some limitations due to their retrospective nature, lack of exact pretreatment staging, and the involvement of heterogeneous populations leading to the awareness that each patient should undergo a tailored therapy in light of the nature of his tumor, its extension and his performance status., Competing Interests: The authors declare no conflict of interest.

Malignant pleural mesothelioma (MPM) is a rare neoplasm, mainly caused by asbestos exposure, with a high mortality rate. The management of patients with MPM is controversial due to a long latency period between exposure and diagnosis and because of non-specific symptoms generally appearing at advanced stage of the disease. Breath analysis, aimed at the identification of diagnostic Volatile Organic Compounds (VOCs) pattern in exhaled breath, is believed to improve early detection of MPM. Therefore, in this study, breath samples from 14 MPM patients and 20 healthy controls (HC) were collected and analyzed by Thermal Desorption-Gas Chromatography-Mass Spectrometry (TD-GC/MS). Nonparametric test allowed to identify the most weighting variables to discriminate between MPM and HC breath samples and multivariate statistics were applied. Considering that MPM is an aggressive neoplasm leading to a late diagnosis and thus the recruitment of patients is very difficult, a promising data mining approach was developed and validated in order to discriminate between MPM patients and healthy controls, even if no large population data are available. Three different machine learning algorithms were applied to perform the classification task with a leave-one-out cross-validation approach, leading to remarkable results (Area Under Curve AUC = 93%). Ten VOCs, such as ketones, alkanes and methylate derivates, as well as hydrocarbons, were able to discriminate between MPM patients and healthy controls and for each compound which resulted diagnostic for MPM, the metabolic pathway was studied in order to identify the link between VOC and the neoplasm. Moreover, five breath samples from asymptomatic asbestos-exposed persons (AEx) were exploratively analyzed, processed and tested by the validated statistical method as blinded samples in order to evaluate the performance for the early recognition of patients affected by MPM among asbestos-exposed persons. Good agreement was found between the information obtained by gold-standard diagnostic methods such as computed tomography CT and model output., Competing Interests: The authors declare no conflict of interest.

Malignant pleural mesothelioma (MPM) is a rare neoplasm related to asbestos exposure and with high mortality rate. The management of patients with MPM is complex and controversial, particularly with regard to early diagnosis. In the last few years, breath analysis has been greatly implemented with this aim. In this review the strengths of breath analysis and preliminary results in searching breath biomarkers of MPM are highlighted and discussed, respectively. Through a systematic electronic literature search, collecting papers published from 2000 until December 2018, fifteen relevant scientific papers were selected. All papers considered were prospective, comparative, observational case-control studies although every single one pilot and based on a relatively small number of samples. The identification of diagnostic VOCs pattern, through breath sample characterization and the statistical data treatment, allows to obtain a strategic information for clinical diagnostics. To date the collected data provide just preliminary information and, despite the promising results and diagnostic accuracy, conclusions cannot be generalized due to the limited number of individuals included in each cohort study. Furthermore none of studies was externally validated, although validation process is a necessary step towards clinical implementation. Breathomics-based biomarker approach should be further explored to confirm and validate preliminary findings and to evaluate its potential role in monitoring the therapeutic response.

Despite that the impact of immune checkpoint inhibitors on malignancies treatment is unprecedented, a lack of response to these molecules is observed in several cases. Differently from melanoma and non-small cell lung cancer, where the use of immune checkpoint inhibitors results in a high efficacy, the response rate in other tumors, such as gastrointestinal cancers, breast cancer, sarcomas, and part of genitourinary cancers remains low. The first strategy evaluated to improve the response rate to immune checkpoint inhibitors is the use of predictive factors for the response such as PD-L1 expression, tumor mutational burden, and clinical features. In addition to the identification of the patients with a higher expression of immune checkpoint molecules, another approach currently under intensive investigation is the use of therapeutics in a combinatory manner with immune checkpoint inhibitors in order to obtain an enhancement of efficacy through the modification of the tumor immune microenvironment. In addition to the abscopal effect induced by radiotherapy, a lot of studies are evaluating several drugs able to improve the response rate to immune checkpoint inhibitors, including microbiota modifiers, drugs targeting co-inhibitory receptors, anti-angiogenic therapeutics, small molecules, and oncolytic viruses. In view of the rapid and extensive development of this research field, we conducted a systematic review of the literature identifying which of these drugs are closer to achieving validation in the clinical practice.

Recent findings suggest that a fraction of EGFR-mutant non-small-cell lung cancers (NSCLC) carry additional driver mutations that could potentially affect the activity of EGFR tyrosine kinase inhibitors (TKIs). We investigated the role of concomitant KRAS, NRAS, BRAF, PIK3CA, MET and ERBB2 mutations (other mutations) on the outcome of 133 EGFR mutant patients, who received first-line therapy with EGFR TKIs between June 2008 and December 2014. Analysis of genomic DNA by Next Generation Sequencing (NGS) revealed the presence of hotspot mutations in genes other than the EGFR, including KRAS, NRAS, BRAF, ERBB2, PIK3CA, or MET, in 29/133 cases (21.8%). A p.T790M mutation was found in 9/133 tumour samples (6.8%). The progression free survival (PFS) of patients without other mutations was 11.3 months vs. 7 months in patients with other mutations (log-rank test univariate: p = 0.047). In a multivariate Cox regression model including the presence of other mutations, age, performance status, smoking status, and the presence of p.T790M mutations, the presence of other mutations was the only factor significantly associated with PFS (Hazard Ratio 1.63, 95% CI 1.04⁻2.58; p = 0.035). In contrast, no correlation was found between TP53 mutations and patients' outcome. These data suggest that a subgroup of EGFR mutant tumours have concomitant driver mutations that might affect the activity of first-line EGFR TKIs.