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PurposeThis prospective study evaluated whether peripheral blood biomarkers and metabolic parameters on F-18 fludeoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) could be associated with clinical outcome in non-small cell lung carcinoma (NSCLC) patients treated with immune checkpoint inhibitors (ICI).MethodsData from 33 patients with NSCLC and treated with ICI were collected. Complete blood cell counts before and at the first restaging were measured. All patients underwent F-18 FDG PET/CT at baseline, while 25 patients at the first restaging. Progression-free survival (PFS) and overall survival (OS) were determined and compared using the Kaplan–Meier and the log-rank test. The median follow-up was 11.3 months (range 1–17 months).ResultsMultivariate analyses demonstrated that low neutrophil-to-lymphocyte ratio (NLR < 4.9) and low total lesion glycolysis (TLG < 541.5 ml) at the first restaging were significantly associated with PFS (both p = 0.019) and OS (p = 0.001 and p = 0.048, respectively). An immune-metabolic-prognostic index (IMPI), based on post-NLR and post-TLG was developed, categorizing 3 groups: high risk, 2 factors; intermediate risk, 1 factor; low risk, 0 factors. Median PFS for low, intermediate and high risk was 7.8 months (95% CI 4.6–11.0), 5.6 months (95% CI 3.8–7.4), and 1.8 months (95% CI 1.6–2.0) (p < 0.001) respectively. Likewise, median OS was 15.2 months (95% CI 10.9–19.6), 13.2 months (95% CI 5.9–20.3), and 2.8 months (95% CI 1.4–4.2) (p < 0.001), respectively.ConclusionIMPI at the first restaging, combining both inflammatory and metabolic biomarkers, was correlated with PFS and OS. IMPI can be a potentially valuable tool for identifying NSCLC patients who are likely to benefit from ICI.

Introduction: In the current study, we aimed to assess the impact of antibiotics (ATB) and metabolic parameters on clinical outcome of non-small cell lung carcinoma (NSCLC) patients treated with immune checkpoint inhibitors (ICI). Methods: Data from fifty NSCLC patients referred for ICI between December 2015 and May 2019 were analyzed. All patients underwent 18F-fluorodeoxyglucose positron emission tomography computed tomography (18F-FDG PET/CT) and contrast-enhanced CT at baseline and for response assessment after 6–8 weeks. Patients who received ATB within 1 month before or after the first dose of ICI were compared with those who did not. Response assessment according to iRECIST and EORTC was evaluated, as well as progression-free survival (PFS) and overall survival (OS). For semi-quantitative parameters, we computed metabolic tumor volume (MTV), total lesion glycolysis (TLG) and their variations (∆). Results: Twenty NSCLC cases of 50 (40%) had received ATB. Patients receiving ATB had a higher number of metastases (p = 0.046), and were associated with an elevated tumor burden, expressed by TLG (687 vs. 235.3, p = 0.007) and MTV (125.6 vs. 40.6, p = 0.002), compared to no-ATB patients. According to iRECIST, progressive disease rate was significantly higher for ATB group (64.7% vs. 27.6%, p = 0.029). Likewise, PFS was shorter for ATB compared to no-ATB (median 4.1 vs. 12.4 months, p = 0.004), while no difference for OS was detected. On multivariate analysis, the effect of ATB remained significant for poor PFS along with performance status (ECOG ≥ 1), and ∆SUVmax. Conclusions: ATB therapy seems to be associated with a worse treatment response, PFS, and higher metabolic tumor burden in NSCLC patients treated with ICI.

BackgroundBone metastases (BoM) are a negative prognostic factor in non-small-cell lung cancer (NSCLC). Beyond its supportive role, bone is a hematopoietic organ actively regulating immune system. We hypothesized that BoM may influence sensitivity to immunotherapy.MethodsPretreated non-squamous (cohort A) and squamous (cohort B) NSCLCs included in the Italian Expanded Access Program were evaluated for nivolumab efficacy according to BoM.ResultsCohort A accounted for 1588 patients with non-squamous NSCLC, including 626 (39%) with (BoM+) and 962 (61%) without BoM (BoM-). Cohort B accounted for 371 patients with squamous histology including 120 BoM+ (32%) and 251 (68%) BoM- cases. BoM+ had lower overall response rate (ORR; Cohort A: 12% versus 23%, p <  0.0001; Cohort B: 13% versus 22%, p = 0.04), shorter progression free survival (PFS; Cohort A: 3.0 versus 4.0 months, p <  0.0001; Cohort B: 2.7 versus 5.2 months, p <  0.0001) and overall survival (OS; Cohort A: 7.4 versus 15.3 months, p <  0.0001; Cohort B: 5.0 versus 10.9 months, p < 0.0001). Moreover, BoM negatively affected outcome irrespective of performance status (PS; OS in both cohorts: p < 0.0001) and liver metastases (OS cohort A: p < 0.0001; OS Cohort B: p = 0.48). At multivariate analysis, BoM independently associated with higher risk of death (cohort A: HR 1.50; cohort B: HR 1.78).ConclusionsBoM impairs immunotherapy efficacy. Accurate bone staging should be included in clinical trials with immunotherapy.

We retrospectively evaluated the role of neutrophil-to-lymphocyte ratio (NLR) and lymphocyte-to-monocyte ratio (LMR) as prognostic factors in metastatic non-small-cell lung cancer patients treated with nivolumab. Medical records of 65 patients were reviewed. NLR and LMR were calculated at baseline (t0) and at first radiological tumor assessment (t1). At univariate analysis, low NLR or high LMR values at t0 were associated with longer overall survival (p = 0.0001). At multivariate analysis including NLR and LMR at t0 and t1 and their trend, only NLR at t1 (p < 0.0001) and NLR trend (p < 0.0001) were significantly associated with overall survival outcomes. Our study suggests that NLR value at first tumor assessment or NLR trend could be used as prognostic indicators during nivolumab treatment in metastatic non-small-cell lung cancer.

Physical Restraint (PR) is a coercive procedure used in emergency psychiatric care to ensure safety in life-threatening situations. Because of its traumatic nature, studies emphasize the importance of considering the patient’s subjective experience. We pursued this aim by overcoming classic qualitative approaches and innovatively applying a multilayered semiautomated language analysis to a corpus of narratives about PR collected from 99 individuals across seven mental health services in Italy. Compared to a reference corpus, PR narratives were characterized by reduced fluency and lexical density, yet a greater use of emotional and cognitive terms, verbs, and first-person singular pronouns. Sadness was the most represented emotion, followed by anger and fear. One-third of the PR narratives contained at least one metaphor, with Animals and War/Prison as the most distinctive source domains. The quality and length of the PR experience impacted both the structure and the sentiment of the narratives. Findings confirm the distressful nature of PR but also point to the use of various linguistic mechanisms which might serve as an early adaptive response toward healing from the traumatic experience. Overall, the study highlights the importance of Natural Language Processing as an unobtrusive window into subjective experience, offering insights for therapeutic choices.

Diagnostic and treatment algorithms in non-small cell lung cancer (NSCLC) are evolving at a never-before-seen pace. Histological subtyping to maximise treatment efficacy and avoid toxicity has marked the beginning of the revolution, opening the way to molecular characterisation to guide genomically driven treatments with targeted agents, led by Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK) inhibitors. More recently, agents against the Program Death 1 receptor (PD-1) and ligand 1 (PD-L1) have entered the clinical arena, offering new hope to NSCLC patients, although several uncertainties remain to be elucidated. Here, we review the most clinically relevant advances in the diagnosis and treatment of NSCLC in the past decade.

BackgroundImmune checkpoint inhibitors (ICI) improved survival of patients with non-small cell lung cancer (NSCLC), yet many patients do not respond to treatment. The identification of markers for ICI response remains an unmet clinical need. This study hypothesizes that host genetics influences the response to ICI, contributing to the variability in efficacy among individuals.MethodsWe conducted a genome-wide association study (GWAS) in patients with NSCLC on ICI monotherapy with nivolumab, pembrolizumab, or atezolizumab, to identify germline variants associated with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) at 24 months after the start of ICI therapy. Genomic DNA was genotyped using Axiom Precision Medicine Research Arrays. Raw data were processed with Axiom Analysis Suite, and quality checked with PLINK software. Imputation to the whole genome was done on the Michigan Imputation Server. Association analyses were performed for ORR (logistic regression with PLINK2 software) and survival (Cox proportional hazards model, with GenAbel package in R environment), with appropriate covariates. Variants were annotated for functional significance using SNPnexus and FUMA. Post-GWAS analyses, including colocalization, were performed to explore the function of the identified variants. Their possible role as expression quantitative trait loci was investigated in different databases (GTEx, eQTLGen, TCGA).ResultsNo genome-wide significant associations were found for ORR or PFS, while a locus on chromosome 2 (lead variant: rs111648355) showed near genome-wide significance (p value=6.3×10⁻⁸) for OS. Patients with minor alleles of these variants exhibited significantly worse OS (HR=5.1, 95% CI: 2.9 to 9.2). Functional annotation linked these variants to regulatory effects on genes including MSH2, MSH6, PPP1R21, FBXO11, and STON1. These genes play a role in mismatch repair, endosomal trafficking, or major histocompatibility complex class II regulation, and might influence the response to immunotherapy.ConclusionsThis study identifies an association between a genomic locus on chromosome 2 and OS in patients with NSCLC treated with ICI. Although these results need validation in larger cohorts and functional studies to elucidate the underlying mechanisms, they highlight the potential of germline variants as predictive biomarkers of response to ICI.

Background/Objectives: Lung cancer (LC) remains one of the most lethal malignancies worldwide, with both environmental and occupational exposures contributing to its incidence. While oncogene-addicted tumors—defined by single driver mutations—have garnered attention due to their therapeutic implications, less is known about the mutational landscape of tumors potentially arising from occupational exposure to carcinogens. This real-life observational study aimed to assess whether previous occupational exposure to lung carcinogens correlates with distinct LC phenotypes, particularly non-oncogene-addicted (nOA) profiles. Methods: A total of 199 LC patients were enrolled across two specialized oncology centers in Northern Italy between 2021 and 2023. Each participant underwent detailed occupational history taking and molecular characterization using next-generation sequencing. Patients were stratified into nonexposed (NE), low exposed (LE), and high exposed (HE) to carcinogens for lung based on standardized questionnaires and sector-specific assessments. Results: No significant differences were found in histological subtypes across exposure groups. However, people with adenocarcinoma and high occupational exposure to lung carcinogens were more frequently characterized by a nOA phenotype compared to those with low occupational exposure. Logistic regression models—adjusted for age, sex, and smoking habits—confirmed that HE patients had a significantly higher likelihood of developing nOA tumors (OR = 3.07; 95% CI: 1.16–8.11; p = 0.023). This association persisted after adjusting for smoking habits Exposures occurring 5–10 years before diagnosis seemed to be associated with an increased nOA profile. Conclusions: These findings suggest that high levels of exposure to occupational carcinogens impact LC phenotypes. Indeed, these phenotypes are more complex to treat and show the worst prognosis. Assessing the occupational exposure to lung carcinogens during work may offer prognostic insights and support the request for more adequate compensation for the patients. Further studies are warranted to validate these results and to explain the mechanisms that produce the differences observed in LC phenotypes in people with high exposure to occupational carcinogens.

Background/Objectives: Alterations of the phosphatidylinositol 3-kinase catalytic subunit alpha gene (PIK3CA) are identified in approximately 2–4% of non-small cell lung cancer (NSCLC) cases; however, their biological and clinical relevance in NSCLC remains incompletely understood. This study aimed to comprehensively characterize the clinical and molecular features, as well as outcomes, of patients with PIK3CA-altered NSCLC across different disease stages. Methods: We conducted a retrospective multicenter analysis of 62 patients with histologically confirmed early-stage or advanced NSCLC-harboring PIK3CA alterations (mutations and/or gene amplifications) treated between 2015 and 2022 at three Italian institutions. Demographic, clinical, pathological, and molecular variables were systematically collected and analyzed. Results: PIK3CA mutations accounted for the majority of alterations (90.3%), while amplifications represented 9.7%. The most frequent mutations involved exon 9 (66.1%), predominantly E545K and E542K, followed by exon 20 (16.1%). Most patients were current or former smokers, and concomitant oncogenic alterations were detected in 59.7% of cases, most commonly KRAS mutations. A history of prior malignancy was reported in 24.6% of cases. In the metastatic setting, adenocarcinoma histology was associated with significantly longer overall survival (OS) compared with non-adenocarcinoma histologies (18.4 vs. 5.5 months; p = 0.02). Patients with PD-L1–negative tumors demonstrated a numerically longer OS than those with PD-L1–positive tumors; however, this difference did not reach statistical significance (19.1 vs. 5.4 months; p = 0.05). No statistically significant survival differences were observed according to specific PIK3CA mutation subtypes or treatment strategies. Conclusions: PIK3CA-altered NSCLC represents a molecularly heterogeneous and clinically understudied subgroup, frequently characterized by co-occurring oncogenic alterations. In this study, no definitive prognostic or predictive role for PIK3CA alterations could be established. Nevertheless, these findings provide a descriptive real-world characterization of this molecular subset and support the need for validation in larger, prospectively designed, molecularly stratified studies.

Background Although many well-known factors affect the maximum standardized uptake value (SUVmax), it remains the most requested and used parameter, especially among clinicians, despite other parameters, such as the standardized uptake value corrected for lean body mass and the metabolic tumor volume, being proven to be less sensitive to the same factors, more robust, and eventually more informative. This study intends to provide robust evidence regarding the diagnostic and prognostic value of SUVmax in a large cohort of subjects with suspected malignant lung nodules imaged by [ 18 F]FDG PET/CT. Materials and methods We performed a retrospective analysis of patients with suspected/confirmed primary lung tumours undergoing [18F]FDG PET/CT. The sample size was 567 patients. Demographics, imaging, surgical, histological, and follow-up data were collected. SUVmax was analysed according to histology, stage, scanner, and outcome. The impact on measured values of different reconstruction protocols was assessed. All potential predictors of patients’ outcome were assessed. Results 91% cases were primary lung tumours. Lung benign nodules or metastases accounted for 5% and 4% of cases. Most patients presented with adenocarcinoma (70%) and stage I disease (51%); 144 patients relapsed and 55 died. SUVmax failed to effectively differentiate benign lesions from primary tumours or metastases. Stage I patients presented lower SUVmax. SUVmax significantly correlated with patient weight, injected [ 18 F]FDG activity, and lesion size and differed between reconstructions’ protocols. Survival analyses revealed no independent prognostic significance for SUVmax in progression-free after adjusting for other variables. SUVmax correlated with overall survival, disease stage and tumour histotype. Conclusion Our study confirms that SUVmax, though widely employed, present relevant limitations in discriminating between benign lesion and lung cancer, in classifying cancer histotypes, and in predicting patient outcomes independently. Known influencing factors significantly impact on numerical values, thus SUV values should be regarded with caution in clinical practice.