A prognostic score from a multicentric retrospective analysis of patients affected by sarcoma with metachronous lung metastases undergoing metastasectomy.

BACKGROUND: Despite the lack of evidence-based on prospective randomized studies, surgery has become the cornerstone of the treatment in patients with pulmonary oligometastatic sarcomas. Our study aimed to construct a composite prognostic score for metachronous oligometastatic sarcoma patients. METHODS: A retrospective analysis was performed on data patients who underwent radical surgery for metachronous metastases in six research institutes from January 2010 to December 2018. The log-hazard ratio (HR) obtained from the Cox model was used to derive weighting factors for a continuous prognostic index designed to identify differential outcome risks. RESULTS: A total of 251 patients were enrolled in the study. In the multivariate analysis, a longer disease-free interval (DFI) and a lower neutrophil-to-lymphocytes ratio (NLR) were predictive of a better overall survival (OS) and disease-free survival (DFS). A prognostic score was developed based on DFI and NLR data, identifying 2 risk class groups for DFS (3-years DFS 20.2% for the high-risk group [HRG]and 46.4% for the low-risk group [LRG] [<0.0001]) and 3 risk groups for OS (3 years OS 53.9% for the HRG vs. 76.9% for the intermediate-risk group and 100% of the LRG (p < 0.0001)). CONCLUSION: The proposed prognostic score effectively predicts outcomes for patients with lung metachronous oligo-metastases from the surgically treated sarcoma.

Lymphadenectomy for lung carcinoids: Which factors may predict nodal upstaging? A multi centric, retrospective study.

OBJECTIVE: To investigate risk factors for nodal upstaging in patients with lung carcinoids and to understand which type of lymphadenectomy is most appropriate. METHODS: Data regarding patients with lung carcinoids, who underwent surgical resection and lymphadenectomy in five institutions from January 1, 2005 to December 31, 2019, were collected and retrospectively analyzed. Clinical and pathological tumor characteristics were correlated to analyze lymph node upstaging. RESULTS: The analysis was conducted on 283 patients. Pathology showed 230 typical and 53 atypical carcinoids. Nodal and mediastinal upstaging occurred in 33 (11.6%) and 16 (5.6%) patients, respectively. At the univariable analysis, nodal upstaging was significantly correlated with central location (p = 0.003), atypical histology (p < 0.001), pT dimension (p = 0.004), and advanced age (p = 0.043). The multivariable analysis confirmed atypical histology (odds ratio [OR]: 11.030; 95% confidence interval [CI]: 4.837-25.153, p < 0.001) and central location (OR: 3.295; 95% CI: 1.440-7.540, p = 0.005) as independent prognostic factors for nodal upstaging. Atypical histology (p < 0.001), pT dimension (p = 0.036), number of harvested lymph node stations (p = 0.047), and type of lymphadenectomy (p < 0.001) correlated significantly with mediastinal upstaging. The multivariable analysis confirmed atypical histology (OR: 5.408; 95% CI: 1.391-21.020, p = 0.015) and pT (OR: 1.052; 95% CI: 1.021-1.084, p = 0.001) as independent prognostic factors. CONCLUSION: Atypical histology, dimension, and central location are associated with a high-risk for occult hilo-mediastinal metastases, and mediastinal radical dissection may predict nodal upstaging. Thus, we suggest radical mediastinal lymph node dissection in high-risk tumors, reserving sampling, or lobe-specific dissection in peripheral, small typical carcinoids.

Immunological and Inflammatory Impact of Non-Intubated Lung Metastasectomy.

BACKGROUND: We hypothesized that video-assisted thoracic surgery (VATS) lung metastasectomy under non-intubated anesthesia may have a lesser immunological and inflammatory impact than the same procedure under general anesthesia. METHODS: Between December 2005 and October 2015, 55 patients with pulmonary oligometastases (at the first episode) successfully underwent VATS metastasectomy under non-intubated anesthesia. Lymphocytes subpopulation and interleukins 6 and 10 were measured at different intervals and matched with a control group composed of 13 patients with similar clinical features who refused non-intubated surgery. RESULTS: The non-intubated group demonstrated a lesser reduction of natural killer lymphocytes at 7 days from the procedure (p = 0.04) compared to control. Furthermore, the group revealed a lesser spillage of interleukin 6 after 1 (p = 0.03), 7 (p = 0.04), and 14 (p = 0.05) days. There was no mortality in any groups. Major morbidity rate was significantly higher in the general anesthesia group 3 (5%) vs. 3 (23%) (p = 0.04). The median hospital stay was 3.0 vs. 3.7 (p = 0.033) days, the estimated costs with the non-intubated procedure was significantly lower, even excluding the hospital stay. CONCLUSIONS: VATS lung metastasectomy in non-intubated anesthesia had significantly lesser impact on both immunological and inflammatory response compared to traditional procedure in intubated general anesthesia.

The modified Lyon's position: an alternative approach to robotic thymectomy.

The conventional supine position for robotic thymectomy may present challenges in accessing the lower thymic horns, particularly in cases requiring extensive resection of mediastinal fat. To address this issue, the authors advocate for a lateral patient position during the procedure, emphasizing optimized access to the thymic horns and improved procedural efficacy. The lateral approach involves specific trocar placements and port arrangements to minimize conflicts between instruments. This report proposes an innovative approach to robotic thymectomy for patients diagnosed with thymoma or thymic hyperplasia associated with myasthenia gravis.

Ergonomic Assessment of Robotic versus Thoracoscopic Thymectomy.

Introduction: Robotic and thoracoscopic surgery are being increasingly adopted as minimally invasive alternatives to open sternotomy for complete thymectomy. The superior maneuverability range and three-dimensional magnified vision are potential ergonomical advantages of robotic surgery. To compare the ergonomic characteristics of robotic versus thoracoscopic thymectomy, a previously developed scoring system based on impartial findings was employed. The relationship between ergonomic scores and perioperative endpoints was also analyzed. Methods: Perioperative data of patients undergoing robotic or thoracoscopic complete thymectomy between January 2014 and December 2022 at three institutions were retrospectively retrieved. Surgical procedures were divided into four standardized surgical steps: lower-horns, upper-horns, thymic veins and peri-thymic fat dissection. Three ergonomic domains including maneuverability, exposure and instrumentation were scored as excellent(score-3), satisfactory(score-2) and unsatisfactory(score-1) by three independent reviewers. Propensity score matching (2:1) was performed, including anterior mediastinal tumors only. The primary endpoint was the total maneuverability score. Secondary endpoints included the other ergonomic domain scores, intraoperative adverse events, conversion to sternotomy, operative time, post-operative complications and residual disease. Results: A total of 68 robotic and 34 thoracoscopic thymectomies were included after propensity score matching. The robotic group had a higher total maneuverability score (p = 0.039), particularly in the peri-thymic fat dissection (p = 0.003) and peri-thymic fat exposure score (p = 0.027). Moreover, the robotic group had lower intraoperative adverse events (p = 0.02). No differences were found in residual disease. Conclusions: Robotic thymectomy has shown better ergonomic maneuverability compared to thoracoscopy, leading to fewer intraoperative adverse events and comparable early oncological results.

Pathological T3 Non-Small Cell Lung Cancer with satellite nodules: Number or size, what does matter?

BACKGROUND: Non-small Cell Lung Cancer (NSCLC) with intralobar satellite nodule are defined as T3 (T3SN). We investigated the main features of these tumors and analyzed their impact on Overall Survival (OS). METHODS: This was a retrospective multicentric study including all pT3SN NSCLC operated on between 2005 and 2020, excluding patients with multifocal ground-glass opacities; who received induction therapies; N3 or stage IV. The diameter of largest (LgN) and smallest nodule (SmN), the total diameter (sum of diameter of all nodules, TS), and the number of SN were measured. RESULTS: Among 102 patients, 64.7 % were male. 84.3 % of patients had one SN (84.3 %), 9.8 % two SN while 5.9 % more than 2 SN. 63 patients were pN0. LgN (p = 0.001), SN (p = 0.005) and TS (p = 0.014) were significantly related to lymph-node metastasis; the LgN and TS were related to visceral pleural invasion (p < 0.001). Five-year OS was 65.1 %; at univariable analysis more than 2 satellite nodules, LgN and TS were significantly related to worse OS; at multivariable analysis, TS (Hazard Ratio [HR] 1.116 95 % Confidence Interval [CI] 1.008-1.235, p = 0.034) was an independent prognostic factors for OS. No significant prognostic factors were found for DFS at multivariable analysis. In pN0 patients, LgN (HR 1.051, 95 % CI 1.066-1.099, p = 0.027) and non-adenocarcinoma (HR 5.315 CI 95 % 1.494-18.910, p = 0.010) influenced OS. CONCLUSIONS: Tumor size is related to tumor's local invasiveness. TS is an independent prognostic factor for OS. Patients with more than 2 SN seem to be at higher risk for death and recurrence.

National Multicenter Study on the Comparison of Robotic and Open Thymectomy for Thymic Neoplasms in Myasthenic Patients: Surgical, Neurological and Oncological Outcomes.

Thymectomy is the gold standard in the treatment of thymic neoplasm and plays a key role in the therapeutic path of myasthenia gravis. For years, sternotomy has been the traditional approach for removing anterior mediastinal lesions, although the robotic thymectomy is now widely performed. The literature is still lacking in papers comparing the two approaches and evaluating long-term oncological and neurological outcomes. This study aims to analyze the postoperative results of open and robotic thymectomy for thymic neoplasms in myasthenic patients. Surgical, oncological and neurological data of myasthenic patients affected by thymic neoplasms and surgically treated with extended thymectomy, both with the open and the robotic approach, in six Italian Thoracic Centers between 2011 and 2021 were evaluated. A total of 213 patients were enrolled in the study: 110 (51.6%) were treated with the open approach, and 103 (48.4%) were treated with robotic surgery. The open surgery, compared with the robotic, presented a shorter operating time (p < 0.001), a higher number of postoperative complications (p = 0.038) and longer postoperative hospitalization (p = 0.006). No other differences were observed in terms of surgical, oncological or neurological outcomes. The robotic approach can be considered safe and feasible, comparable to the open technique, in terms of surgical, oncological and neurological outcomes.

Tumoral and stromal hMENA isoforms impact tertiary lymphoid structure localization in lung cancer and predict immune checkpoint blockade response in patients with cancer.

BACKGROUND: Tertiary Lymphoid Structures (TLS) correlate with positive outcomes in patients with NSCLC and the efficacy of immune checkpoint blockade (ICB) in cancer. The actin regulatory protein hMENA undergoes tissue-specific splicing, producing the epithelial hMENA11a linked to favorable prognosis in early NSCLC, and the mesenchymal hMENAΔv6 found in invasive cancer cells and pro-tumoral cancer-associated fibroblasts (CAFs). This study investigates how hMENA isoforms in tumor cells and CAFs relate to TLS presence, localization and impact on patient outcomes and ICB response. METHODS: Methods involved RNA-SEQ on NSCLC cells with depleted hMENA isoforms. A retrospective observational study assessed tissues from surgically treated N0 patients with NSCLC, using immunohistochemistry for tumoral and stromal hMENA isoforms, fibronectin, and TLS presence. ICB-treated patient tumors were analyzed using Nanostring nCounter and GeoMx spatial transcriptomics. Multiparametric flow cytometry characterized B cells and tissue-resident memory T cells (TRM). Survival and ICB response were estimated in the cohort and validated using bioinformatics pipelines in different datasets. FINDINGS: Findings indicate that hMENA11a in NSCLC cells upregulates the TLS regulator LTßR, decreases fibronectin, and favors CXCL13 production by TRM. Conversely, hMENAΔv6 in CAFs inhibits LTßR-related NF-kB pathway, reduces CXCL13 secretion, and promotes fibronectin production. These patterns are validated in N0 NSCLC tumors, where hMENA11ahigh expression, CAF hMENAΔv6low, and stromal fibronectinlow are associated with intratumoral TLS, linked to memory B cells and predictive of longer survival. The hMENA isoform pattern, fibronectin, and LTßR expression broadly predict ICB response in tumors where TLS indicates an anti-tumor immune response. INTERPRETATION: This study uncovers hMENA alternative splicing as an unexplored contributor to TLS-related Tumor Immune Microenvironment (TIME) and a promising biomarker for clinical outcomes and likely ICB responsiveness in N0 patients with NSCLC. FUNDING: This work is supported by AIRC (IG 19822), ACC (RCR-2019-23669120), CAL.HUB.RIA Ministero Salute PNRR-POS T4, "Ricerca Corrente" granted by the Italian Ministry of Health.

Robotic thymectomy in thymic tumours: a multicentre, nation-wide study.

OBJECTIVES: Robotic thymectomy has been suggested and considered technically feasible for thymic tumours. However, because of small-sample series and the lack of data on long-term results, controversies still exist on surgical and oncological results with this approach. We performed a large national multicentre study sought to evaluate the early and long-term outcomes after robot-assisted thoracoscopic thymectomy in thymic epithelial tumours. METHODS: All patients with thymic epithelial tumours operated through a robotic thoracoscopic approach between 2002 and 2022 from 15 Italian centres were enrolled. Demographic characteristics, clinical, intraoperative, postoperative, pathological and follow-up data were retrospectively collected and reviewed. RESULTS: There were 669 patients (307 men and 362 women), 312 (46.6%) of whom had associated myasthenia gravis. Complete thymectomy was performed in 657 (98%) cases and in 57 (8.5%) patients resection of other structures was necessary, with a R0 resection in all but 9 patients (98.6%). Twenty-three patients (3.4%) needed open conversion, but no perioperative mortality occurred. Fifty-one patients (7.7%) had postoperative complications. The median diameter of tumour resected was 4 cm (interquartile range 3-5.5 cm), and Masaoka stage was stage I in 39.8% of patients, stage II in 56.1%, stage III in 3.5% and stage IV in 0.6%. Thymoma was observed in 90.2% of patients while thymic carcinoma occurred in 2.8% of cases. At the end of the follow-up, only 2 patients died for tumour-related causes. Five- and ten-year recurrence rates were 7.4% and 8.3%, respectively. CONCLUSIONS: Through the largest collection of robotic thymectomy for thymic epithelial tumours we demonstrated that robot-enhanced thoracoscopic thymectomy is a technically sound and safe procedure with a low complication rate and optimal oncological outcomes.

Robotic Lobectomy without Complete Fissure for Non-Small Cell Lung Cancer: Technical Aspects and Perioperative Outcomes of the Tunnel Technique.

Even though the use of the "fissure-last" technique in mini-invasive lobectomy with the fissureless condition is well accepted, in terms of perioperative outcomes, controversies still surround the hilar lymph node dissection. In this article, we reported a description of the robotic "tunnel technique" approach in the right upper lobectomy in the absence of a defined fissure. We then compared the short terms outcomes of 30 consecutive cases treated using this technique, with 30 patients treated using the "fissure last" VATS approach in the same institution, before the start of the robotic surgery program.

Should EUS-FNA be considered also for the diagnosis of peripheral small pulmonary lesions?

Given the high rate of small lung nodules detected during the oncological follow up for various cancers, in the era of personalize medicine, the histological diagnosis is of paramount importance. Usually, the small peripheral lung nodules are historically reached using a CT guided biopsy but this technique is characterized by an high rate of pneumothorax. Endoscopic procedures were referred only for central tumor that occluded the mains bronchi. In the last few years, the spreading of EBUS-TBNA, EUS-FNA and the navigational bronchoscopy systems has increase the use of these technique also for the diagnosis of small lung nodules.

Non-Small Cell Lung Cancer With N1 Involvement or Skip Metastases Presents the Same Survival Outcome: Results From a Multicentric Study.

BACKGROUND: The prognostic difference among patients affected by NSCLC with hilar metastases only or mediastinal nodes metastases without hilar involvement (skip metastases) is still unclear. Aim of this study is to analyse if prognostic difference are present or if the two groups present the same survival outcome. MATERIALS AND METHODS: Data on NSCLC patients from 7 high volume centres (2004-2014) were collected and retrospectively reviewed. Histology different from adenocarcinoma(ADC) or squamous cell carcinoma(SCC), patients without data on lymphadenectomy, who underwent neoadjuvant treatment, with distant metastases or incomplete resection were excluded, selecting patients with hilar involvement or with skip metastases. Different prognostic factors such as Tstage, histology, pathological stage, nodal characteristics and adjuvant therapy administration were correlated to overall survival (OS) by the Kaplan-Meier product-limit method. The log-rank test was used to assess differences between subgroups. A multivariable Cox proportional hazard model was developed using stepwise regression to compare the prognostic power of different factors. RESULTS: The final analysis was conducted on 480 adenocarcinoma/squamous cell carcinoma patients. Five-year OS (5YOS) resulted 53.9%. No significant differences in OS were detected comparing pN1 vs. pN2 patients or stage IIB vs. stage IIIA-B patients. Univariable confirmed as favourable prognostic factors young age (P<.001), T1-2 tumors (P=.030), number of resected nodes≥10 (P=.040), lymph node ratio (P=.026). Multivariable analysis confirmed as independent negative prognostic factors T≥3 (HR:1.385, 95%CI:1.037-1.851, P=.027) and age≥68 years (HR1.637, 95%CI:1.245-2.152). CONCLUSION: Patients with N1 involvement or skip metastases present a similar prognosis, suggesting that N2 involvement in these cases may be related to a direct lymphatic drainage to the mediastinal stations.

Multimodal evaluation of locoregional anaesthesia efficacy on postoperative pain after robotic pulmonary lobectomy for NSCLC: a pilot study.

The primary objectives of the study were to analyse the robotic approach and ultrasound-guided paravertebral block compared to thoracoscopic intercostal nerve block after robotic pulmonary lobectomy on postoperative pain and opioids use. The secondary objectives were to analyse and compare patients' necessity of additional antalgic drugs and patients' performance during respiratory therapy, following robotic surgery and in the two groups. Consecutively, 52 patients undergoing robotic pulmonary lobectomies were treated either with ropivacaine-based intercostal nerve block or paravertebral block from February 2022 to October 2022. When necessary, morphine was administered at day 1. Acetaminophen was administered as an additional antalgic drug on demand up to 3 g per day. Pain was measured 1 h after the end of the surgical procedure and daily through the pain numeric rating scale (NRS). Morphine administration rate and per day and total additional administrations of acetaminophen were recorded. Pain and opioids administration was measured 1 month after the procedure. Data were analysed in the overall population and in the intercostal nerve block group VS paravertebral block group. Overall, 34.6% of the patients required morphine administration and 51.7% of the patients required at least daily acetaminophen administration up to discharge. At 1 month postoperatively, four patients presented with chronic pain and one still was under opioid medication. At intergroup analysis, the paravertebral block group demonstrated lower NRS at fixed time points (p < 0.0001) and lower morphine consumption (45.7%VS11.8%; p = 0.02). Acetaminophen rescue administration at fixed time points was lower in the paravertebral block group (p < 0.0001) and mobility and dynamic pain resulted in better results (p = 0.03; p = 0.04). At 1 month, no differences were found between study groups. Similarly to other minimally invasive techniques, postoperative pain may arise after robotic pulmonary lobectomy. Paravertebral bloc can help to reduce postoperative pain as well as morphine and antalgic drugs administration and improve early mobilization.

ALK rearrangement is an independent predictive factor of unexpected nodal metastasis after surgery in early stage, clinical node negative lung adenocarcinoma.

OBJECTIVES: Despite notable advances made in preoperative staging, unexpected nodal metastases after surgery are still significantly detected. Given the promising role of neoadjuvant targeted treatments, the definition of novel predictive factors of nodal metastases is an extremely important issue. In this study we aim to analyze the upstaging rate in patients with early stage NSCLC without evidence of nodal disease in the preoperative staging who underwent lobectomy and radical lymphadenectomy. MATERIAL AND METHODS: Patients who underwent lobectomy and systematic lymphadenectomy for early stage LUAD without evidence of nodal disease at the preoperative staging using NGS analysis for actionable molecular targets evaluation after surgery were evaluated. Exclusion criteria included the neoadjuvant treatment, incomplete resection and no adherence to preoperative guidelines. RESULTS: A total of 359 patients were included in the study. 172 patients were female, and the median age was 68 (61-72). The variables that showed a significant correlation with the upstaging rate at the univariate analysis were the ALK rearrangement, the number of resected lymph nodes and the diameter of the tumor. This result was confirmed in the multivariate analysis, with an OR of 8.052 (CI95% 3.123-20.763, p = 0.00001) for ALK rearrangement, 1.087 (CI95% 1.048-1.127, p = 0.00001) for the number of resected nodes and 1.817 (CI95% 1.214-2.719, p = 0.004) for cT status. CONCLUSION: Our results showed that in a homogeneous cohort of patients with clinical node early stage LUAD the ALK rearrangement, the number of resected lymph nodes and the tumor diameter can significantly predict nodal metastasis.

CD28/PD1 co-expression: dual impact on CD8+ T cells in peripheral blood and tumor tissue, and its significance in NSCLC patients' survival and ICB response.

BACKGROUND: Immune checkpoint blockade (ICB) has significantly prolonged survival of non-small cell lung cancer (NSCLC) patients, although most patients develop mechanisms of resistance. Recently single-cell RNA-sequencing (scRNA-Seq) revealed a huge T-cell phenotypic and (dys)functional state variability. Accordingly, T-cell exhaustion is recognized as a functional adaptation, with a dynamic progression from a long-lived "pre-exhausted stem-like progenitor" to a "terminally exhausted" state. In this scenario it is crucial to understand the complex interplay between co-stimulatory and inhibitory molecules in CD8+ T-cell functionality. METHODS: To gain a baseline landscape of the composition, functional states, and transcriptomic signatures predictive of prognosis, we analyzed CD8+ T-cell subsets characterized by the presence/absence of PD1 and CD28 from periphery, adjacent non-tumor tissue and tumor site of a cohort of treatment-naïve NSCLC patients, by integrated multiparametric flow cytometry, targeted multi-omic scRNA-seq analyses, and computational pipelines. RESULTS: Despite the increased PD1 levels, an improved PD1+CD28+ T-cell polyfunctionality was observed with the transition from periphery to tumor site, associated with lack of TIGIT, TIM-3 and LAG-3, but not with Ag-experienced-marker CD11a. Differently from CD28+ T cells, the increased PD1 levels in the tumor were associated with reduced functionality in PD1+CD28- T cells. CD11ahigh, although expressed only in a small fraction of this subset, still sustained its functionality. Absence of TIGIT, TIM-3 and CTLA-4, alone or combined, was beneficial to CD28- T cells. Notably, we observed distinct TRM phenotypes in the different districts, with CD28+ T cells more capable of producing TGFß in the periphery, potentially contributing to elevated CD103 levels. In contrast CD28- TRM mainly produced CXCL13 within the tumor. ScRNA-seq revealed 5 different clusters for each of the two subsets, with distinctive transcriptional profiles in the three districts. By interrogating the TCGA dataset of patients with lung adenocarcinoma (LUAD) and metastatic NSCLC treated with atezolizumab, we found signatures of heterogeneous TRM and "pre-exhausted" long-lived effector memory CD8+ T cells associated with improved response to ICB only in the presence of CD28. CONCLUSIONS: Our findings identify signatures able to stratify survival of LUAD patients and predict ICB response in advanced NSCLC. CD28 is advocated as a key determinant in the signatures identified, in both periphery and tumor site, thus likely providing feasible biomarkers of ICB response.

Analysis of predictive factors of unforeseen nodal metastases in resected clinical stage I NSCLC.

Background: Despite notable advances made in preoperative staging, unexpected nodal metastases after surgery are still significantly detected. In this study we aim to analyze the upstaging rate in patients with clinical stage I NSCLC without evidence of nodal disease in the preoperative staging who underwent lobectomy and radical lymphadenectomy. Methods: Patients who underwent lobectomy and systematic lymphadenectomy for clinical stage I NSCLC were evaluated. Exclusion criteria included the neoadjuvant treatment, incomplete resection and no adherence to preoperative guidelines. Results: A total of 297 patients were included in the study. 159 patients were female, and the median age was 68 (61 - 73). The variables that showed a significant correlation with the upstaging rate at the univariate analysis were the number of resected lymph nodes and micropapillar/solid adenocar-cinoma subtype. This result was confirmed in the multivariate analysis with a OR= 2.545 (95%CI 1.136-5.701; p=0.02) for the number of resected lymph nodes and a OR=2.717 (95%CI 1.256-5.875; p=0.01) for the high-grade pattern of adenocarcinoma. Conclusion: Our results showed that in a homogeneous cohort of patients with clinical stage I NSCLC, the number of resected lymph nodes and the histological subtype of adenocarcinoma can significantly be associated with nodal metastasis.