ADA/CD26 axis increases intra-tumor PD-1+CD28+CD8+ T-cell fitness and affects NSCLC prognosis and response to ICB.

Improving cancer immunotherapy efficacy hinges on identifying key T-cell populations critical for tumor control and response to Immune Checkpoint Blockade (ICB). We have recently reported that while the co-expression of PD-1 and CD28 is associated with impaired functionality in peripheral blood, it significantly enhances T-cell fitness in the tumor site of non-small cell lung cancer (NSCLC) patients. To uncover the underlying mechanisms, we explored the role of CD26, a key player in T-cell activation through its interaction with adenosine deaminase (ADA), a crucial intra/extracellular enzyme able to neutralize local adenosine (ADO). We found that an autocrine ADA/CD26 axis enhances CD8+PD-1+CD28+ T-cell function, particularly within an immunosuppressive environment marked by CD39 expression. Then, we interrogated the TCGA and OAK datasets to gain insight into the prognostic/predictive potential of our findings. We identified a signature predicting overall survival (OS) in LUAD patients and response to atezolizumab in advanced LUAD cases. These findings suggest promising avenues for therapeutic intervention targeting the ADA/CD26 axis.

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.

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.

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.

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.

Surgical and survival outcomes with perioperative or neoadjuvant immune-checkpoint inhibitors combined with platinum-based chemotherapy in resectable NSCLC: A systematic review and meta-analysis of randomised clinical trials.

The use of neoadjuvant or perioperative anti-PD(L)1 was recently tested in multiple clinical trials. We performed a systematic review and meta-analysis of randomised trials comparing neoadjuvant or perioperative chemoimmunotherapy to neoadjuvant chemotherapy in resectable NSCLC. Nine reports from 6 studies were included. Receipt of surgery was more frequent in the experimental arm (odds ratio, OR 1.39) as was pCR (OR 7.60). EFS was improved in the experimental arm (hazard ratio, HR 0.55) regardless of stage, histology, PD-L1 expression (PD-L1 negative, HR 0.74) and smoking exposure (never smokers, HR 0.67), as was OS (HR 0.67). Grade > = 3 treatment-related adverse events were more frequent in the experimental arm (OR 1.22). The experimental treatment improved surgical outcomes, pCR rates, EFS and OS in stage II-IIIB, EGFR/ALK negative resectable NSCLC; confirmatory evidence is warranted for stage IIIB tumours and with higher maturity of the OS endpoint.

Adjuvant Transthoracic Negative-Pressure Ventilation in Nonintubated Thoracoscopic Surgery.

BACKGROUND: To minimize the risks of barotrauma during nonintubated thoracoscopic-surgery under spontaneous ventilation, we investigated an adjuvant transthoracic negative-pressure ventilation (NPV) method in patients operated on due to severe emphysema or interstitial lung disease. METHODS: In this retrospective study, NPV was employed for temporary low oxygen saturation and to achieve end-operative lung re-expansion during nonintubated lung volume reduction surgery (LVRS) for severe emphysema (30 patients, LVRS group) and in the nonintubated wedge resection of undetermined interstitial lung disease (30 patients, wedge-group). The results were compared following 1:1 propensity score matching with equivalent control groups undergoing the same procedures under spontaneous ventilation, with adjuvant positive-pressure ventilation (PPV) performed on-demand through the laryngeal mask. The primary outcomes were changes (preoperative-postoperative value) in the arterial oxygen tension/fraction of the inspired oxygen ratio (ΔPO2/FiO2;) and ΔPaCO2, and lung expansion completeness on a 24 h postoperative chest radiograph (CXR-score, 2: full or 1: incomplete). RESULTS: Intergroup comparisons (NPV vs. PPV) showed no differences in demographic and pulmonary function. NPV could be accomplished in all instances with no conversion to general anesthesia with intubation. In the LVRS group, NPV improved ΔPO2/FiO2 (9.3 ± 16 vs. 25.3 ± 30.5, p = 0.027) and ΔPaCO2 (-2.2 ± 3.15 mmHg vs. 0.03 ± 0.18 mmHg, p = 0.008) with no difference in the CXR score, whereas in the wedge group, both ΔPO2/FiO2 (3.1 ± 8.2 vs. 9.9 ± 13.8, p = 0.035) and the CXR score (1.9 ± 0.3 vs. 1.6 ± 0.5, p = 0.04) were better in the NPV subgroup. There was no mortality and no intergroup difference in morbidity. CONCLUSIONS: In this retrospective study, NITS with adjuvant transthoracic NPV resulted in better 24 h oxygenation measures than PPV in both the LVRS and wedge groups, and in better lung expansion according to the CXR score in the wedge group.

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.

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.

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.

Perioperative outcomes of robotic lobectomy for early-stage non-small cell lung cancer in elderly patients.

Introduction: Minimally invasive surgery has become the standard for the early-stage non-small cell lung cancer (NSCLC). The appropriateness of the kind of lung resection for the elderly patients is still debated. Methods: We retrospectively reviewed patients with older than 75 years who underwent robotic lobectomy between May 2016 to June 2022. We selected 103 patients who met the inclusion criteria of the study. The preoperative cardiorespiratory functional evaluations were collected, and the risk of postoperative complications was calculated according to the Charlson Comorbidity Index, the American College of Surgery surgical risk calculator (ACS-NSQIP), EVAD score, and American Society of Anesthesiology (ASA) score. The patients were divided in two groups according to the presence of postoperative complications. Results: Forty-three patients were female, and 72.8% of the total population were former or active smokers. Thirty-five patients reported postoperative complications. The analysis of the two groups showed that the predicted postoperative forced expiratory volumes in the first second (FEV1) and forced vital capacity (FVC) were significantly lower in patients presenting postoperative complications (p=0.04). Moreover, the upstaging rate and the unexpected nodal metastases were higher in the postoperative complication groups. Conclusion: Robotic-assisted lobectomy for early-stage lung cancer is a safe and feasible approach in selected elderly patients. The factors that could predict the complication rate was the predicted postoperative FEV1 and the nodal disease.

Multifactorial Evaluation following Cytoreductive Surgery for Malignant Pleural Mesothelioma in Patients with High Symptom-Burden.

Mesothelioma has a scant prognosis and a great impact on symptoms and the quality of life. Pleurectomy/decortication and extrapleural pneumonectomy are the two cytoreductive surgical strategies, with different invasiveness, but achieving similar oncological results. Hereafter, the two surgical procedures effects on symptoms and the quality of life are compared in a high symptom-burden population. Between 2003 and 2017, 55 consecutive patients underwent pleurectomy/decortication (n = 26) or extrapleural pneumonectomy (n = 29), both followed by adjuvant chemo-radiotherapy. Cardio-pulmonary function, symptoms and the quality of life (Short-Form-36 and St.George's questionnaires) were evaluated pre- and 3-, 6-, 12- and 24-months postoperatively. Extrapleural pneumonectomy demonstrated lower pain at 12 months but a higher decrement of forced vital capacity at 24 months than pleurectomy/decortication. Both procedures revealed a 3-months improvement of many symptoms and the quality of life determinants. Improvement in physical, social and pain-related measured parameters lasted for a longer time-spawn in the extrapleural pneumonectomy group. No differences were found in chemotherapy compliance and survival between groups. Age-at-presentation (p = 0.02) and non-epitheliod histology (p = 0.10) were the only significant prognosticators. Surgery, despite poor survival results, improved symptoms and the quality of life in patients with mesothelioma with high symptom-burden at diagnosis. Therefore, extrapleural pneumonectomy demonstrated the most durable effects.

An experimental characterization of ventilation motions in healthy subjects.

BACKGROUND: Existing devices detect main breathing data and none is aimed to monitor biomechanics of ventilation motions with small wearable device. METHODS: The used device has been designed for noninvasive wearing to detect main motion parameters of a rib during ventilation in an experimental campaign with 218 subjects. Experimental activity is carried out by testing in vivo with human volunteers for an experimental characterization of ventilation motions as related to normal breathing, maximal breathing and coughing. FINDINGS: Findings can be summarized from a numerical analysis of experimental results in terms of statistical values of ventilation motion parameters in rotation and acceleration as function of age and sex of the tested subjects. The discussed campaign reporting results on healthy patients was carried out with the aim to build a reference database of normal conditions against which the status of patients with both thoracic and ventilation problems can then be judged. Females showed significantly larger lateral-to-lateral movements during basal breathing and lateral-to-lateral Z-axis movements during maximal breathing and cough. Males demonstrated wider antero-posterior Y-axis and cranio-caudal X-axis movements during maximal breathing, while antero-posterior movements prevailed during cough. Older participants demonstrated larger lateral-to-lateral Z-axis and antero-posterior Y-axis movements during basal breathing. Young participants showed more significant increments along antero-posterior Y-axis from basal to maximal breathing and basal to cough, demonstrating a more efficient muscular activity. INTERPRETATION: The ventilation motion during ventilation act is useful to detect the status of ventilation and can give indications for diagnostics and medical solutions even in thoracic surgery.

Transesophageal Endoscopic Ultrasound Fine Needle Biopsy for the Diagnosis of Mediastinal Masses: A Retrospective Real-World Analysis.

Background: Endoscopic ultrasound (EUS) plays an important role in the diagnosis and staging of thoracic disease. Our report studies the diagnostic performance and clinical impact of EUS fine needle aspiration (FNA) in a homogenous cohort of patients according to the distribution of the enlarged MLNs or pulmonary masses. Methods: We retrospectively reviewed the diagnostic performance of 211 EUS-FNA in 200 consecutive patients with enlarged or PET-positive MLNs and para-mediastinal masses who were referred to our oncological center between January 2019 and May 2020. Results: The overall sensitivity of EUS-FNA was 85% with a corresponding negative predictive value (NPV) of 56% and an accuracy of 87.5%. The sensitivity and accuracy in patients with abnormal MLNs were 81.1% and 84.4%, respectively. In those with para-mediastinal masses, sensitivity and accuracy were 96.4% and 96.8%. The accuracy for both masses and lymph nodes was 100%, and in the LAG (left adrenal gland), it was 66.6%. Conclusions: Our results show that, in patients with suspected mediastinal masses, EUS-FNA is an accurate technique to evaluate all reachable mediastinal nodal stations, including station 5.

Fluorescence-guided lung nodule identification during minimally invasive lung resections.

In the last few years, minimally invasive surgery has become the standard routine practice to manage lung nodules. Particularly in the case of robotic thoracic surgery, the identification of the lung nodules that do not surface on the visceral pleura could be challenging. Therefore, together with the evolution of surgical instruments to provide the best option in terms of invasiveness, lung nodule localization techniques should be improved to achieve the best outcomes in terms of safety and sensibility. In this review, we aim to overview all principal techniques used to detect the lung nodules that do not present the visceral pleura retraction. We investigate the accuracy of fluorescence guided thoracic surgery in nodule detection and the differences among the most common tracers used.