Comparative Analysis of Comprehensive Genomic Profile in Thymomas and Recurrent Thymomas Reveals Potentially Actionable Mutations for Target Therapies.

Molecular profiles of thymomas and recurrent thymomas are far from being defined. Herein, we report an analysis of a comprehensive genetic profile (CGP) in a highly selected cohort of recurrent thymomas. Among a cohort of 426 thymomas, the tissue was available in 23 recurrent tumors for matching the biomolecular results obtained from primary and relapse samples. A control group composed of non-recurrent thymoma patients was selected through a propensity score match analysis. CGP was performed using the NGS Tru-SightOncology assay to evaluate TMB, MSI, and molecular alterations in 523 genes. CGP does not differ when comparing initial tumor with tumor relapse. A significantly higher frequency of cell cycle control genes alterations (100.0% vs. 57.1%, p = 0.022) is detected in patients with early recurrence (<32 months) compared to late recurrent cases. The CGPs were similar in recurrent thymomas and non-recurrent thymomas. Finally, based on NGS results, an off-label treatment or clinical trial could be potentially proposed in >50% of cases (oncogenic Tier-IIC variants). In conclusion, CGPs do not substantially differ between initial tumor vs. tumor recurrence and recurrent thymomas vs. non-recurrent thymomas. Cell cycle control gene alterations are associated with an early recurrence after thymectomy. Multiple target therapies are potentially available by performing a comprehensive CGP, suggesting that a precision medicine approach on these patients could be further explored.

Study protocol for Near-infrared molecular imaging for lung cancer detection and treatment during mini-invasive surgery (phase II Trial) - (the RECOGNISE study).

INTRODUCTION: To date, radical surgery remains the best curative option in patients with early-stage lung cancer. In patients with small lung lesions, video-assisted thoracic surgery (VATS) should be increasingly chosen as a fundamental alternative to thoracotomy as it is associated with less postoperative pain and better quality of life. This scenario necessarily increases the need for thoracic surgeons to implement new localization techniques. The conventional near-infrared (NIR) indocyanine green (ICG) method demonstrated a significant limitation in deep cancer recognition, principally due to its intrinsic low-depth tissue penetration. Similarly, the lymph-node sentinel approach conducted by the ICG method was demonstrated to be inefficient, mainly due to the non-specificity of the tracker and the irregular pathway of pulmonary lymph node drainage. Our study aims to evaluate the effectiveness of Cetuximab- IRDye800CW in marking lung nodules and mediastinal lymph nodes. METHODS AND ANALYSIS: This study is defined as an open-label, single-arm, single-stage phase II trial evaluating the effectiveness of Cetuximab-IRDye800CW in detecting tumors and lymph-node metastases in patients with lung cancer who are undergoing video-assisted thoracic surgery (VATS). Cetuximab is a monoclonal antibody that binds, inhibits, and degrade the EGFR. The IRDye® 800CW, an indocyanine-type NIR fluorophore, demonstrated enhanced tissue penetration compared to other NIR dyes. The combination with the clinical approved monoclonal antibody anti-epidermal growth factor EGFR Cetuximab (Cetuximab-IRDye800) has shown promising results as a specific tracker in different cancer types (i.e., brain, pancreas, head, and neck). The study's primary outcome is focused on the proportion of patients with lung nodules detected during surgery using an NIR camera. The secondary outcomes include a broad spectrum of items, including the proportion of patients with detection of unexpected cancer localization during surgery by NIR camera and the proportion of patients with negative surgical margins, the evaluation of the time spawns between the insertion of the NIR camera and the visualization of the nodule and the possible morbidity of the drug assessed during and after the drug infusion. ETHICS AND DISSEMINATION: This trial has been approved by the Ethical Committee of Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino (Torino, Italy) and by the Italian Medicines Agency (AIFA). Findings will be written as methodology papers for conference presentations and published in peer-reviewed journals. The Azienda Ospedaliera Universitaria Città della Salute e della Scienza di Torino, the University of Torino, and the AIRC Public Engagement Divisions will help identify how best to publicize the findings.Trial registration EudraCT 202,100,645,430. CLINICALTRIALS: gov NCT06101394 (October 23, 2023).

Ultrasound and Intrapleural Enzymatic Therapy for Complicated Pleural Effusion: A Case Series with a Literature Review.

Pleural effusion is the most common manifestation of pleural disease, and chest ultrasound is crucial for diagnostic workup and post-treatment monitoring. Ultrasound helps distinguish the various types of pleural effusion and enables the detection of typical manifestations of empyema, which presents as a complicated, septated effusion. This may benefit from drainage and the use of intrapleural enzyme therapy or may require more invasive approaches, such as medical or surgical thoracoscopy. The mechanism of action of intrapleural enzymatic therapy (IPET) is the activation of plasminogen to plasmin, which breaks down fibrin clots that form septa or the loculation of effusions and promotes their removal. In addition, IPET has anti-inflammatory properties and can modulate the immune response in the pleural space, resulting in reduced pleural inflammation and improved fluid reabsorption. In this article, we briefly review the literature on the efficacy of IPET and describe a case series in which most practical applications of IPET are demonstrated, i.e., as a curative treatment but also as an alternative, propaedeutic, or subsequent treatment to surgery.

Lazarus Response to Selpercatinib for Bleeding Colic Metastasis in a Patient With RET Fusion-Positive Pulmonary Sarcomatoid Carcinoma: A Case Report.

In recent years, the widespread use of next-generation sequencing (NGS) allowed clinicians to identify and treat non-small cell lung cancer (NSCLC) efficiently with target therapy. RET inhibitors, like selpercatinib and pralsetinib, for RET rearrangements in lung cancer showed high efficacy and clinical benefit. Nevertheless, to date, the use of molecular-targeted agents has not been tested in all lung cancer subtypes. Indeed, pulmonary sarcomatoid carcinoma (PSC) remains a rare form of NSCLC, unresponsive to standard chemotherapy, and associated with extremely poor prognosis. We report the first case of a patient affected by RET fusion-positive PSC with a bleeding colic metastasis and a consequent poor performance status who achieved a dramatic response to selpercatinib and a remarkable clinico-radiological benefit.

Artificial Intelligence Applications for Thoracic Surgeons: "The Phenomenal Cosmic Powers of the Magic Lamp".

In the digital age, artificial intelligence (AI) is emerging as a transformative force in various sectors, including medicine. This article explores the potential of AI, which is akin to the magical genie of Aladdin's lamp, particularly within thoracic surgery and lung cancer management. It examines AI applications like machine learning and deep learning in achieving more precise diagnoses, preoperative risk assessment, and improved surgical outcomes. The challenges and advancements in AI integration, especially in computer vision and multi-modal models, are discussed alongside their impact on robotic surgery and operating room management. Despite its transformative potential, implementing AI in medicine faces challenges regarding data scarcity, interpretability issues, and ethical concerns. Collaboration between AI and medical communities is essential to address these challenges and unlock the full potential of AI in revolutionizing clinical practice. This article underscores the importance of further research and interdisciplinary collaboration to ensure the safe and effective deployment of AI in real-world clinical settings.

Thymoma resection and myasthenia gravis: what is the neurological outcome in patients older than 65 years?

To increase the neurological results in patients older than 65 years with myasthenia gravis after thymectomy, we retrospectively analysed this outcome in a large bicentric cohort of patients with myasthenia gravis (MG)years, for which surgery was indicated for a concurrent thymoma. From 1/2000 to 2/2022, 502 patients underwent thymectomy for thymic epithelial tumours (TETs) in two high-volume Institutions (167aged more than 65 years). Among them, 66 patients were affected by TET and MG, representing our final study group. The mean age for MG onset was 68.3 ± 6 years.At surgery, the Osserman score 2 was the most diffuse in our cohort (43, 65.1%), followed by 1 (20, 30.3%). In 11 cases, the MG diagnosis coincided with thymoma diagnosis. In the other cases, the interval between MG diagnosis and surgery was 1.7 years ± 1.9. The most common surgical approach was sternotomy (41,62.1%), followed by RATS (14,21.2%). The most frequent TNM stage was T1N0 (75.7%) and most patients had WHO type-B tumour. After radical thymectomy, 58 patients (88%) reported a significant neurological improvement. According to MGFA-PIS, after surgery we had 4 (6%) complete stable remission, 11 (16.7%) pharmacological remission, 43 (65.2%) minimal manifestation, 2 (3%) worsening/death for MG, and 5 (7.6%) unchanged. No association was found between neurological outcome and age of MG onset, kind of pharmacological therapy before surgery, surgical approach (sternotomy vs others), tumour dimension, the ITMIG stage and the preoperative Osserman score. For MG and thymoma-afftected patients over 65 years, thymectomy seems to be an effective treatment to improve neurological symptoms. We suggest to set up clinical trials to explore the neurological efficacy of mini-invasive thymectomy in clinically selected MG patients aged over 65 years.

Pneumomediastinum in COVID-19: Risk factors and outcomes from a multicentre case-control study.

BACKGROUND: An increased incidence of pneumomediastinum has been observed among patients hospitalized with coronavirus disease 2019 (COVID-19) pneumonia. The study aimed to identify risk factors for COVID-19-associated pneumomediastinum and investigate the impact of pneumomediastinum on clinical outcomes. METHODS: In this multicentre retrospective case-control study, we included consecutive patients with COVID-19 pneumonia and pneumomediastinum hospitalized from March 2020 to July 2020 at ten centres; then, we identified a similarly sized control group of consecutive patients hospitalized with COVID-19 pneumonia and respiratory failure who did not develop pneumomediastinum during the same period. Clinical, laboratory, and radiological characteristics, as well as respiratory support and outcomes, were collected and compared between the two groups. Risk factors of pneumomediastinum were assessed by multivariable logistic analysis. RESULTS: Overall 139 patients with pneumomediastinum and 153 without pneumomediastinum were analysed. Lung involvement ≥75 %, consolidations, body mass index (BMI) < 22 kg/m2, C-reactive protein (CRP) > 150 mg/L, D-dimer >3000 ng/mL FEUs, and smoking exposure >20 pack-year were all independently correlated with the occurrence of pneumomediastinum. Patients with pneumomediastinum had a longer hospital stay (mean ± SD 31.2 ± 20.2 days vs 19.6 ± 14.2, p < 0.001), higher intubation rate (73/139, 52.5 % vs 27/153, 17.6 %, p < 0.001), and in-hospital mortality (68/139, 48.9 % vs 36/153, 23.5 %, p < 0.001) compared to controls. CONCLUSIONS: Extensive lung parenchyma involvement, consolidations, low BMI, high inflammatory markers, and tobacco exposure are associated with a greater risk of pneumomediastinum in COVID-19 pneumonia. This complication significantly worsens the outcomes.

Implementation of Artificial Intelligence in Personalized Prognostic Assessment of Lung Cancer: A Narrative Review.

Artificial Intelligence (AI) has revolutionized the management of non-small-cell lung cancer (NSCLC) by enhancing different aspects, including staging, prognosis assessment, treatment prediction, response evaluation, recurrence/prognosis prediction, and personalized prognostic assessment. AI algorithms may accurately classify NSCLC stages using machine learning techniques and deep imaging data analysis. This could potentially improve precision and efficiency in staging, facilitating personalized treatment decisions. Furthermore, there are data suggesting the potential application of AI-based models in predicting prognosis in terms of survival rates and disease progression by integrating clinical, imaging and molecular data. In the present narrative review, we will analyze the preliminary studies reporting on how AI algorithms could predict responses to various treatment modalities, such as surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy. There is robust evidence suggesting that AI also plays a crucial role in predicting the likelihood of tumor recurrence after surgery and the pattern of failure, which has significant implications for tailoring adjuvant treatments. The successful implementation of AI in personalized prognostic assessment requires the integration of different data sources, including clinical, molecular, and imaging data. Machine learning (ML) and deep learning (DL) techniques enable AI models to analyze these data and generate personalized prognostic predictions, allowing for a precise and individualized approach to patient care. However, challenges relating to data quality, interpretability, and the ability of AI models to generalize need to be addressed. Collaboration among clinicians, data scientists, and regulators is critical for the responsible implementation of AI and for maximizing its benefits in providing a more personalized prognostic assessment. Continued research, validation, and collaboration are essential to fully exploit the potential of AI in NSCLC management and improve patient outcomes. Herein, we have summarized the state of the art of applications of AI in lung cancer for predicting staging, prognosis, and pattern of recurrence after treatment in order to provide to the readers a large comprehensive overview of this challenging issue.

Linc00941 fuels ribogenesis and protein synthesis by supporting robust cMYC translation in malignant pleural mesothelioma.

Malignant pleural mesothelioma is a rare and lethal cancer caused by exposure to asbestos. The highly inflammatory environment caused by fibers accumulation forces cells to undergo profound adaptation to gain survival advantages. Prioritizing the synthesis of essential transcripts is an efficient mechanism coordinated by multiple molecules, including long non-coding RNAs. Enhancing the knowledge about these mechanisms is an essential weapon in combating mesothelioma. Linc00941 correlates to bad prognosis in various cancers, but it is reported to partake in distinct and apparently irreconcilable processes. In this work, we report that linc00941 supports the survival and aggressiveness of mesothelioma cells by influencing protein synthesis and ribosome biogenesis. Linc00941 binds to the translation initiation factor eIF4G, promoting the selective protein synthesis of cMYC, which, in turn, enhances the expression of key genes involved in translation. We analyzed a retrospective cohort of 97 mesothelioma patients' samples from our institution, revealing that linc00941 expression strongly correlates with reduced survival probability. This discovery clarifies linc00941's role in mesothelioma and proposes a unified mechanism of action for this lncRNA involving the selective translation of essential oncogenes, reconciling the discrepancies about its function.

Survival Outcome After Surgery in Patients With Thymoma Distant Recurrence.

OBJECTIVE: The aim of this study is to describe characteristics and survival outcome of patients who underwent surgical treatment for distant thymoma relapse according to the definition of the International Thymic Malignancy Interest Group. METHODS: Data of patients affected by thymoma recurrence from four different institutions were collected and retrospectively reviewed. Patients with locoregional metastases who underwent nonsurgical therapies and with incomplete data on follow-up were excluded. According to the International Thymic Malignancy Interest Group distant recurrence definition, patients with recurrence due to hematogenic localization were included. Clinical and pathologic characteristics were described using descriptive statistics, whereas survival outcome was calculated using Kaplan-Meier curves and Cox regression analysis. RESULTS: The analysis was conducted on 40 patients. A single localization was present in 13 patients, the relapse was intrathoracic in 28 cases (70%), and lung involvement was found in 26 cases. The liver was operated in seven cases, whereas other kinds of abdominal involvement were detected in eight cases. Adjuvant treatment was administered in 22 cases (55%).Five- and 10-year overall survival (OS) were 67% and 30%, respectively. Univariable analysis identified as significant favorable factor a low-grade histology (A, B1, B2): five-year OS at 92.3% versus 53.3% in high-grade (B3-C) (p = 0.035). Site of recurrence and number of localization did not influence the prognosis, but in patients with adjuvant therapy administration, there was a survival advantage also if not statistically significant: five-year OS 84.8% versus 54.5% in patients without adjuvant therapy (p = 0.101).Multivariable analysis confirmed as independent prognostic factor low-grade histology: hazard ratio = 0.176, 95% confidence interval 0.042-0.744, p = 0.018. CONCLUSIONS: Our study revealed a good survival outcome in patients who underwent surgery for distant thymoma recurrence, independently from the number and site of the relapse localization. Patients with A, B1, or B2 histology presented a significantly better survival than patients with B3-C.

BRCA1-associated protein 1: Tumor predisposition syndrome and Kury-Isidor syndrome, from genotype-phenotype correlation to clinical management.

The BAP1 tumor suppressor gene encodes a deubiquitinase enzyme involved in several cellular activities, including DNA repair and apoptosis. Germline pathogenic variants in BAP1 have been associated with heritable conditions including BAP1 tumor predisposition syndrome 1 (BAP1-TPDS1) and a neurodevelopmental disorder known as Kury-Isidor syndrome (KURIS). Both these conditions are caused by monoallelic, dominant alterations of BAP1 but have never been reported in the same subject or family, suggesting a mutually exclusive genotype-phenotype correlation. This distinction is extremely important considering the early onset and aggressive nature of the types of cancer reported in individuals with TPDS1. Genetic counseling in subjects with germline BAP1 variants is fundamental to predicting the effect of the variant and the expected phenotype, assessing the potential risk of developing cancer for the tested subject and the family members who may carry the same variant and providing the multidisciplinary clinical team with the proper information to establish precise surveillance and management protocols.

Surgeon experience influence lymphadenectomy during VATS lobectomy: National VATS database results.

OBJECTIVES: Aim of this study is to identify the factors that may influence the lymphadenectomy during VATS anatomical lung resection with particular interest on operator experience. MATERIALS AND METHODS: Clinical and pathological data from the prospective VATS Italian nationwide registry were reviewed and analysed. Patients with incomplete data regarding tumor and surgical characteristics, GGO, or with distant metastases were excluded. Patients clinical data, tumor characteristics, operation information and surgeon experience were collected and compared to resected lymph nodes number (#RN), resected N2 nodes number (#N2RN) and resected N2 stations number. A multivariable model was built using logistic regression analysis. Surgeon experience was categorized considering the number of VATS major anatomical resection and years after residency. RESULTS: The final analysis was conducted on 3727 patients. The median #RN and #N2RN were 11 (1-51) and 5 (0-41). Regarding the analysed outcomes, #N2RN > 6 resulted in 1812 (48.8%)cases, #RN > 10 in 2124 (57.0%)cases and more than 3 N2 stations were harvested in 1447 (38.8%)patients. First operator experience with number of VATS lobectomies>50 (p < 0.001), operator seniority after residency5-10years (p < 0.001), cTNM II/III(p = 0.017), lobectomy/bilobectomy vs segmentectomy (p < 0.001), and upper/middle lobe tumor location (p < 0.005)resulted significantly associated to #N2RN > 6 at the multivariable analysis. First operator experience with number of VATS lobectomies>50 (p < 0.001), operator seniority after residency5-10years (p < 0.001) and lobectomy/bilobectomy (p < 0.001) resulted significantly associated to #RN > 10 at the multivariable analysis. CONCLUSIONS: Our study showed that lymphadenectomy during VATS lobectomy is influenced by tumor factors such as cTstage and tumor location but also by operator experience, with a higher number of resected lymph nodes in surgeons with a high number of VATS procedures and years after residency compared to surgeons with less experience.