Carolina Sassorossi

Background: For resectable non-small-cell lung cancer, one of the leading causes of cancer-related mortality, surgical resection remains the best treatment. The increased commonality of minimally invasive approaches is due to their equivalence to open surgery in terms of oncological outcomes and results, despite their offer of the benefits of minimally invasive surgery. Methods: A literature search was conducted using PubMed, Web of Science, Google Scholar and Cochrane Library using the following keywords: VATS, uniportal-VATS, multiportal-VATS, minimally invasive surgery, NSCLC, Segmentectomy, Lobectomy, learning curve, perioperative outcomes, Clinical outcome from 1991 to 30 June 2026. Observational studies, multicenter studies, meta-analysis, systematic reviews and randomized controlled trials were included. Results: Compared to thoracotomy, it has been found that postoperative pain, complication rates and the length of hospital stay can be reduced by minimally invasive approaches without compromising surgical efficacy. The shift towards the single-port techniques further enhances these benefits by minimizing surgical trauma while ensuring the safety and feasibility of the procedure for increasingly complex lung resections. Tailoring is organized along three axes: the extent of resection, patient characteristics and team maturity. Conclusions: Current evidence synthesized in this narrative review suggests that minimally invasive surgery combined with ERAS protocols for anatomical lung resections can further optimize short-term outcomes without compromising the radicality or oncological efficacy of the treatment. The choice of technique is not absolute, but rather the result of a decision based on the individual patient, the surgeon’s experience, and the center’s resources.

Objectives: Precision medicine has improved outcomes in advanced lung cancer, but its implementation remains limited. The prospective LANTERN project (NCT05802771) involves comprehensive clinical and multi-omics data collection. Here, we report preliminary genomic findings, focusing on the prognostic impact of gene mutations, pairwise co-mutational patterns, and their stage-specific association with PD-L1 analysis on patients speciments. Methods: This prospective, multicenter observational study enrolled 271 consecutive patients between March 2023 and December 2024, including 137 with stage I–III and 134 with stage IV disease. Comprehensive genomic profiling was performed using the TruSight Oncology 500 High Throughput assay to assess single nucleotide variants, insertions/deletions, copy number alterations, tumor mutational burden and microsatellite instability. The prognostic role of mutations and co-mutations was evaluated, together with associations between genomic alterations and PD-L1 expression. Results: At least one Tier I–II alteration was identified in 84% of patients. TP53 (39%), KRAS (27%), EGFR (15%), and STK11 (11%) were the most frequently altered genes. Several co-mutations were associated with worse overall survival, including TP53/STK11, STK11/LRP1B, STK11/RB1 and RB1/LRP1B, and with reduced disease-free survival, particularly TP53/KRAS, TP53/STK11, KRAS/STK11 and STK11/LRP1B. In advanced disease, STK11 and KEAP1 mutations were associated with low PD-L1 expression, whereas PIK3CA, PTEN and ARID1A mutations correlated with higher PD-L1 expression in early-stage tumors. Conclusions: Comprehensive genomic profiling reveals substantial molecular heterogeneity across lung cancer stages and identifies co-mutational patterns with prognostic and immune-related relevance, supporting broader molecular testing at diagnosis.

Background: Spread through air spaces (STAS) is a prognostic factor for survival in non-small cell lung cancer (NSCLC), but the chance to identify it before surgery remains challenging. In this study, we consider clinical, pathological and metabolic factors, with the aim to identify possible STAS predictors in NSCLC. Methods: Clinical and pathological characteristics of patients who underwent anatomical lung resection from 1 January 2018 to 31 December 2023 were retrospectively reviewed and analyzed. Patients with GGO, AIS, or MIA tumors, metastases, or undergoing neoadjuvant therapy were excluded. The parameters assessed by ¹⁸F-FDG PET/CT were: SUVmax, SUVmean, SUVpeak, TLG and MTV. The primary endpoint was the association between clinical, metabolic, and pathologic characteristics with the presence of STAS. A univariate and multivariate logistic regression model was developed to identify independent predictors of STAS. Results: The final analysis was conducted on 224 patients. Non-lepidic-acinar adenocarcinomas showed a statistically significant higher risk of STAS than the lepidic-acinar histotype: 20.8% vs. 4.3%, p = 0.003, OR 5.87, 95%CI 1.83–18.78. Furthermore, tumor grade was significantly associated with STAS: 4.6% in G1–G2 tumors vs. 23.5% in G3 tumors (p = 0.001, OR 5.79, 95%CI 2.12–15.78); as well as lymph vascular invasion (p = 0.034) and tumor size >2 cm (p = 0.017). Multivariate analysis confirmed high tumor grade as an independent risk factor (OR 4.73, 95%CI 1.16–19.23, p = 0.030). Conclusions: In our study, risk of STAS is not correlated with metabolic parameters, while adenocarcinoma subtypes and tumors grading seem to stratify the risk of STAS occurrence. These results may be consolidated in an external validation analysis to possibly better plan the extent of lung resection.

Background/Objectives: Perioperative chemo-immunotherapy (CHT-IO) has emerged as a standard treatment strategy for resectable stage II–IIIB NSCLC. However, data regarding surgical feasibility, mini-invasive surgery rates, perioperative outcomes, and postoperative complications in real-world single-center experiences remain limited. Methods: A retrospective single-center analysis was performed including consecutive patients with locally advanced NSCLC treated with perioperative chemo-immunotherapy between March 2024 and March 2026. Patients received platinum-based chemotherapy combined with pembrolizumab or durvalumab, followed by surgical resection with curative intent. Surgical, pathological, and postoperative outcomes were analyzed. Results: Thirty patients received neoadjuvant CHT-IO, of which 25 (83.3%) underwent surgical resection. Reasons for failure to proceed to surgery included treatment-related toxicity or deterioration in performance status (n = 3), disease progression (n = 1), and patient refusal (n = 1). Lobectomy was the most performed procedure (64%), while a minimally invasive approach (uniportal VATS) was adopted in 44% of cases. Moderate-to-severe pleural adhesions (64%) and hilar fibrosis (60%) were observed intraoperatively. Despite these technical challenges, conversion to thoracotomy was required in only one case (4%), no intraoperative complications occurred, and complete (R0) resection was achieved in 96% of patients. Pathological complete response and major pathological response were observed in 36% and 52% of cases, respectively. Postoperative complications occurred in 56% of patients, although most were Clavien–Dindo grade I–II. The presence of comorbidities was the only factor associated with an increased risk of postoperative complications (OR 10.00, 95% CI 0.99–100.46; p = 0.05). Median length of hospital stay was 5.65 ± 2.04 days. One postoperative death due to septic complications was recorded. Conclusions: In this real-world monocentric experience, the combination of perioperative CH-ICIs and surgical resection (including mini-invasive approach) was safe and feasible in patients with locally advanced NSCLC. High rates of complete (R0) resection and encouraging pathological responses were observed, consistent with outcomes reported in randomized trials. Although surgery was overall frequently technically demanding, these changes did not appear to compromise perioperative safety or oncological radicality, even when minimally invasive approaches were adopted. Larger studies with longer follow-up are needed to better define long-term oncological outcomes.

Introduction: Lung cancer, the leading cause of cancer-related mortality worldwide, is a heterogeneous malignancy comprising distinct histological and molecular subtypes, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases and adenocarcinoma (ADC) representing the most prevalent histotype. An emerging pathological feature of NSCLC, spread through air spaces (STAS)—defined as the extension of tumor cells into the lung parenchyma beyond the main tumor margin—has been associated with worse disease-free and overall survival and has been proposed as a possible predictor of recurrence to guide surgical extent. Concurrently, recent comprehensive genomic profiling of early-stage NSCLC has highlighted the need to interpret multi-omics data and their relationship with pathological variables, including IASLC histological subtypes, to better personalize treatment strategies. In this context, we investigated the overall distribution of STAS and its association with tumor mutational profiles and IASLC histological subtypes in a large real-world cohort of lung adenocarcinoma patients from the LANTERN project. Materials and Methods: In a prospective, multicenter observational study (March 2023–December 2024), 271 NSCLC patients were enrolled, and clinicopathological, immunohistochemical, and genomic data were collected; comprehensive genomic profiling was performed using the TruSight Oncology 500 assay to analyze 523 cancer-related genes, tumor mutational burden (TMB), and microsatellite instability; and STAS was assessed according to IASLC criteria. Adenocarcinoma accounted for roughly 90% of the cases, with a median age of 69 years and a predominance of stage IV disease (49.5%). STAS was evaluable in 162 cases and was detected in 17.9% of tumors. Results: STAS-positive tumors showed a higher trend towards locally advanced and advanced disease; no differences were observed in sex, age, smoking status, tumor mutational burden, or PD-L1 expression. Additionally, STAS-positive tumors showed a higher association with micropapillary, mucinous, and papillary patterns, whereas the acinar pattern was more frequent in STAS-negative tumors. The most frequently mutated genes were TP53, KRAS, EGFR, and STK11, with no significant differences between groups; ROS1 alterations were absent in STAS-negative tumors but detected more frequently in STAS-positive cases. Conclusions: Overall, these findings indicate that STAS positivity is associated with high-risk histological subtypes and advanced disease, suggesting its importance as a marker of tumor aggressiveness and emphasizing the need for its systematic evaluation in lung adenocarcinoma to better guide surgical planning and patient risk assessment.

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related mortality globally. While multi-modal artificial intelligence (AI) models offer significant predictive potential, their translation into routine clinical practice is delayed by the “black box” nature of complex algorithms and the fragmentation of heterogeneous data. We present LANTERN-XGB, a hierarchical machine learning workflow designed to bridge this gap by generating interpretable “digital human avatars” for precision oncology. The methodology employs a multi-stage scalable tree boosting system (XGBoost) architecture utilizing shapley additive explanations (SHAP) for rigorous hierarchical feature selection, missing value management, and patient-specific decision support. The workflow was developed and benchmarked using a retrospective cohort of 437 patients with clinical N0 NSCLC, followed by validation on a prospective dataset (n = 100) and an independent external dataset (n = 100). The pipeline integrates diverse data modalities to predict occult lymph node metastasis (OLM). LANTERN-XGB identified a robust consensus signature driven by non-linear interactions among CT textural fragmentation, PET metabolic heterogeneity, tumor density distribution, and systemic clinical modulators. Exploratory transcriptomic pathway analysis (GSVA) revealed that high-risk predictions strongly correlate with systemic molecular dysregulation, such as the enrichment of immune-inflammatory signaling and metabolic stress pathways. The model achieved robust discrimination in external validation (AUC ≈ 0.77), performing comparably to state-of-the-art nomogram benchmarks. Crucially, the LANTERN-XGB framework demonstrated superior utility in handling diagnostic ambiguity; local force plots allowed for the correct reclassification of “borderline” prediction by visualizing feature interactions that standard linear models fail to capture. LANTERN-XGB provides a validated, open-source framework that successfully balances predictive power with clinical transparency. By empowering clinicians to visualize and verify the logic behind AI predictions, this workflow offers a pragmatic path for integrating reliable multi-modal avatars into daily medical decision-making.

Background: The ninth edition of the TNM classification introduced refinements in nodal staging, subdividing mediastinal N2 disease into N2a (single-station) and N2b (multi-station) involvement, alongside several stage group adjustments. The aim of this study is to validate the new TNM in patients with nodal involvement who underwent surgery. Methods: This is a multicentric, retrospective study including NSCLC patients with pathological N1 or N2 involvement who underwent anatomical pulmonary resection between January 2020 and December 2023. Clinical, surgical, and pathological data were collected, including tumor characteristics, lymphadenectomy details, and adjuvant therapy. Patients were reclassified according to the ninth TNM groups: stage IIB, including T1N1, T2N1, and T3N0; IIIA, including T1N2b, T2-3N2a, T3N1, T4N0, and T4N1; and IIIB, including T2-3N2b, T4N2a, and T4N2b. Overall survival (OS) and disease-free survival (DFS) were analyzed using Kaplan–Meier curves. Results: The final analysis involved 291 patients. The three- and five-year OS rates were 82% and 71% for stage IIB, and 75% and 58% for stage IIIA, respectively. At stage IIB, a significant difference was found only for DFS comparing T2N1 and T1N2a, whereas stage IIIA showed no significant differences in either OS or DFS, confirming its prognostic homogeneity. Conversely, stage IIIB exhibited significant heterogeneity in survival (OS p = 0.031; DFS p < 0.0001), with T4N2b subgroups showing the worst outcomes compared to T2-3N2b and T4N2a. Conclusions: Our validation of the ninth edition of lung cancer staging shows improved prognostic granularity: IIB shows non-homogeneous DFS, IIIA is homogeneous, and IIIB shows major OS/DFS substage differences, warranting analyses with larger samples for refined stratification.

Background: The role of thymectomy in ocular myasthenia gravis (OMG) remains controversial, particularly before secondary generalization. Methods: We conducted a multicenter retrospective study on 174 OMG patients who underwent thymectomy (112 OMG, 62 generalized OMG [g-OMG]). The primary endpoint was complete stable remission (CSR; MGFA-PIS criteria). Multivariable analyses identified predictors of CSR and generalization. Results: Mean age at surgery was 42.3 ± 13.0 years; 53.4% were male. Thymoma was present in 29.3%. CSR was achieved in 18.9% overall, significantly higher in OMG (23.2%) compared to g-OMG (11.3%, p = 0.036), with 5-year CSR probabilities of 43% vs. 22% (p = 0.017). In non-thymomatous patients, 5-year CSR remained higher in OMG (41% vs. 17%, p = 0.010). Postoperative myasthenic crisis occurred exclusively in g-OMG (8.1%, p = 0.004). Multivariable analysis identified preoperative cholinesterase inhibitor monotherapy as an independent predictor of CSR (HR = 31.776, 95% CI: 4.188–241.111, p = 0.001; non-thymomatous: HR = 19.746, 95% CI: 2.518–154.849, p = 0.005). Minimally invasive techniques (78.6%) were associated with low morbidity (5.2%). Conclusions: Thymectomy during the purely ocular stage is associated with higher CSR rates and lower perioperative neurological risk than after generalization, particularly in non-thymomatous disease. Use of cholinesterase inhibitors as sole therapy prior to thymectomy independently predicts CSR. These findings support earlier surgical consideration in selected OMG patients and highlight the safety of minimally invasive approaches.

Background: Aim of this study is to evaluate the prognostic role of nodal parameter in early stage pathologically patients with N0 who underwent lobectomy and lymphadenectomy. Methods: Clinical and pathological characteristics of patients who underwent anatomical lung resection from 1/01/2010 to 31/12/2019 were reviewed and retrospectively analyzed. GGO and part‐solid tumors, MIA, AIS, more than 5 cm in size, with nodal and/or distant metastases, or receiving neoadjuvant treatment were excluded. Operatory and pathological report were reviewed to collect data on lymphadenectomy. The primary end‐point was disease‐free survival (DFS), calculated from surgery to recurrence appearance. Clinical/pathological characteristics and nodal parameters were associate to DFS using Kaplan–Meier curves. The log‐rank test was used to assess differences between subgroups. A multivariable model was built using Cox‐regression analysis, including variable resulting significant ( p value < 0.05), at univariable analysis. Results: The final analysis was conducted on 487 patients. Most patients presented stage I tumor (82.4%). The mean number of resected nodes (#RN), resected N1 (#RN1) nodes, and resected N2 nodes (#RN2) resulted 9.5 ± 8.0, 3.4 ± 4.3, and 5.9 ± 4.4. The mean number of total resected stations (#RS), N1 resected stations (#RSN1), and N2 resected stations (#RSN2) resulted 2.5 ± 1.6, 1 ± 0.8, and 1.5 ± 1.2, respectively. During a mean follow‐up of 43 ± 28 months, a recurrence occurred in 137 (28.1%) patients. At univariable analysis, age < 70 years ( p = 0.025), N1 lymphadenectomy ( p = 0.019), #RSN1 ≥ 3 ( p = 0.001), #RN ≥ 10 ( p = 0.019), #RN1 ≥ 3 ( p < 0.001), node sampling with more than 3 resected nodes ( p = 0.049), at least 3 stations with 3 N1 nodes resected ( p = 0.013), at least 3 stations resected with 10 lymphnodes, and 3N1 lymphnodes ( p = 0.020) significantly correlated with improved DFS. Multivariable analysis confirmed as independent prognostic factor #RN1 ≥ 3 ( p = 0.017; HR 1.782; and 95% CI: 1.107–2.867). Patients with #RN1 ≥ 3 presented a 5‐years DFS of 76.3% versus 57.8% of patients with #RN1 < 3 ( p = 0.001). Conclusions: Hilar lymphadenectomy seems to significantly correlate with disease‐free survival in patients with pN0NSCLC and should be better defined in lymphadenectomy guidelines.

Pulmonary neuroendocrine tumors (PULMONARY NETs) are heterogeneous tumors ranging from well-differentiated to highly aggressive neoplasms. The aim of this study is to prospectively test pre-operative circulating free DNA (cfDNA) in PULMONARY NET patients undergoing surgery and evaluate its relationship to clinicopathological features. From February to December 2024, 136 patients with suspected primary lung cancer underwent pre-operative blood sampling, of whom 21 were diagnosed with PULMONARY NETs. Total cell-free nucleic acid extraction was performed using the Genexus Purification System (Thermofisher). cfDNA was quantified using a fluorometric assay with the Qubit dsDNA HS Assay kit (Thermofisher) and a capillary electrophoresis-based assay (cell-free DNA ScreenTape kit) on the Tape Station 4200 systems (Agilent). A cfDNA quality assessment was also obtained (cfDNA sizing and % cfDNA). Most patients had Stage I (18/21.85.7%) typical carcinoids (16/21.76.2%). Nodal involvement was detected in one patient (0.5%). Six months after surgery, all patients were alive without recurrence. Larger tumors presented higher levels of cfDNA. The mean tumor size in patients with cfDNA > 40 ng was 266 mm (±16.7 mm), compared to 13.2 mm (±7.3 mm) for cfDNA < 40 ng (p-value = 0.018). Higher levels of cfDNA were observed in patients with pStages greater than IA (p-value = 0.007). Although limited by a small sample group and biases of a surgical series, we observed that larger/advanced PULMONARY NETs presented higher cfDNA levels pre-operatively.