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Ewing's sarcoma of the bone is a rare, highly aggressive tumor that typically affects children and young adults. Progress in the treatment of Ewing's sarcoma has improved survival from about 10%, before the introduction of chemotherapy, to about 75% today for patients with localized tumors. On the contrary, metastatic disease still has a poor prognosis, and a multidisciplinary approach is essential to improve the outcome. Molecular techniques and new imaging modalities are affecting the diagnosis and classification of patients with Ewing's sarcoma. The most frequent sites of metastases in Ewing's sarcoma include lungs, bones and bone marrow. Lymph nodes are a rare site of metastatic spread, particularly in the mediastinum. In this report, we present two consecutive cases of patients with Ewing's Sarcoma, diagnosed, and treated at our institute. We focused particularly on the rarity of the atypical presentation of the disease and on the synergistic strategy to adopt as a model of networking in treating patients with rare diseases.

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.

Next-generation sequencing has become a cornerstone in clinical oncology practice and is recommended for the appropriate use of tailored therapies in NSCLC. While NGS has already been standardised in advanced-stage NSCLC, its use is still uncommon in the early stages. The recent approval of Osimertinib for resected EGFR-mutated NSCLC in an adjuvant setting has launched the hypothesis that other targeted therapies used in metastatic patients can also lead to improved early-stage outcomes of NSCLC. The impact of molecular biomarkers on the prognosis of patients undergoing radical surgery for NSCLC is still unclear. Notably, the heterogeneous populations included in the studies that analysed surgical patients could be the main reason for these results. In this review, we report the most important studies that analysed the impact of principal molecular biomarkers on the survival outcomes of patients who underwent radical surgery for NSCLC.

Lipoma is a benign mesenchymal tumor. It is a very common tumor and in 13% of cases occurs in head and neck. Giant lipomas are extraordinary and cervical involvement with mediastinal extension is an exceedingly rare presentation. Only a few cases of thoracic extension are reported in literature.We describe the case of a 62-years-old man with a giant cervico-mediastinic lipoma which required a combined approach through cervicotomy and sternotomy to ensure surgical radicality. Differential diagnoses could be thymolipoma, liposarcoma or familiar lipomatosis.The mass was removed en-bloc with thymus and locoregional lymph nodes. The patient recovered uneventfully.The aim of this report is to discuss potential pitfalls of differential diagnosis and implementation of the therapeutic treatment. Focus on the relevance of performing fluorescence in situ hybridization (FISH) for MDM2 amplification is reported, a necessary technique for the differential diagnosis. (www.actabiomedica.it).

Background Thymic epithelial tumors (TETs) are rare neoplasms, originating from epithelial thymic cells. The oncogenic potential of these rare neoplasms is still largely undefined, and a deeper molecular characterization could result in a relevant advance in their management, greatly improving diagnosis, prognosis and treatment choice. Deregulation of N6-methyladenosine (m6A) RNA modification, catalyzed by the METTL3/METTL14 methyltransferase complex, is emerging as a relevant event in cell differentiation and carcinogenesis. Various studies have reported that altered expression of METTL3 is associated with an aggressive malignant phenotype and favors migration and invasiveness, but its role in Thymic Tumors remains unknown. Results In this study, we characterized that METTL3 contributes to Thymic Epithelial Tumor phenotype. We evidenced that METTL3 is overexpressed in tumor tissue compared to normal counterpart. Silencing of METTL3 expression in thymic carcinoma cells results in reduced cell proliferation and overall translation rate. Of note, METTL3 is responsible for the induction of c-MYC expression in TET cells. Specifically, high expression of c-MYC protein is enabled by lncRNA MALAT1, which is methylated and delocalized by METTL3. Interestingly, blocking of c-MYC by using JQ1 inhibitor cooperates with METTL3 depletion in the inhibition of proliferation and induction of cell death. Conclusion This study highlighted METTL3 as a tumor promoter in Thymic tumors and c-MYC as a promising target to be exploited for the treatment of TET.

Introduction: The standard surgical procedures for patients with early-stage NSCLC is lobectomy-associated radical lymphadenectomy performed by using the thoracotomy approach. In the last few years, minimally invasive techniques have increasingly strengthened their role in lung cancer treatment, especially in the early stage of the disease. Although the lobectomy technique has been accepted, controversy still surrounds lymph node dissection. In our study, we analyze the rate of upstaging early non-small cell lung cancer patients who underwent radical surgical treatment using the robotic and the VATS techniques compared to the standard thoracotomy approach.Methods and Materials: We retrospectively reviewed patients who underwent a lobectomy and radical lymphadenectomy at our Institute between 2010 and 2019. We selected 505 patients who met the inclusion criteria of the study: 237 patients underwent robotic surgery, 158 patients had thoracotomy, and 110 patients were treated with VATS. We analyzed the demographic features between the groups as well as the nodal upstaging rate after pathological examination, the number of dissected lymph nodes and the ratio of dissected lymph nodes to metastatic lymph nodes of the three groups.Results: The patients of the three groups were homogenous with respect to age, sex, and histology. The postoperative major morbidity rate was significantly higher in the thoracotomy group, and hospital stay was significantly longer. The percentage of the mediastinal nodal upstaging rate and the number of dissected lymph nodes was significantly higher in the robotic group compared with the VATS group. The ratio of dissected lymph nodes to metastatic lymph nodes was significantly lower compared with the VATS group and the thoracotomy group.Discussion: The prognostic impact of the R(un) status is still highly debated. A surgical approach that allows better results in terms of resection has still not been defined. Our results show that robotic surgery is a safe and feasible approach especially regarding the accuracy of mediastinal lymphadenectomy. These findings can lead to defining a more precise pathological stage of the disease and, if necessary, to more accurate postoperative treatment.

The approval of osimertinib for adjuvant treatment of stage I–II–III EGFR-mutated NSCLC (early stage) represents a paradigm shift, raising the question of whether other genotype-matched therapeutics approved for advanced-stage NSCLC can also provide clinical benefit in the adjuvant setting. However, there is a paucity of real-world data on the prevalence of actionable genomic alterations (GAs) in early-stage NSCLC. We used next-generation sequencing, complemented by immunohistochemistry and fluorescence in situ hybridization, to screen our single-institution cohort of 1961 NSCLC consecutive cases for actionable molecular targets. The prevalence of actionable GAs was comparable in early versus advanced-stage NSCLC, the only exception being KRAS mutations (more frequent in early-stage cases). Consistent with advanced-stage tumors being more aggressive, co-occurrence of TP53 and EGFR GAs as well as copy number gains were less frequent in early-stage tumors. EGFR mutations and high expression of PD-L1 were inversely associated, whereas KRAS mutations and high PD-L1 reactivity showed positive association. Recapitulating advanced-stage tumors, early-stage NSCLC had the highest share of EGFR mutations in lepidic and acinar subtypes. Resected lepidic tumors contained the highest proportion of the KRAS G12C actionable variant. These results, obtained with routine diagnostic technologies in an unselected clinical setting, provide a significant addition of real-world data in early-stage NSCLC.

Background: While the thoracotomy approach was considered the gold standard until two decades ago, robotic surgery has increasingly strengthened its role in lung cancer treatment, improving patients’ peri-operative outcomes. In this study, we report our experience in robotic lobectomy for early-stage non-small cell lung cancer, with particular attention to oncological outcomes and nodal upstaging rate. Methods: We retrospectively reviewed patients who underwent lobectomy and radical lymphadenectomy at our Institute between 2016 and 2020. We selected 299 patients who met the inclusion criteria of the study. We analyzed the demographic features of the groups as well as their nodal upstaging rate after pathological examination. Then, we analyzed disease-free and overall survival of the entire enrolled patient population and we compared the same oncological outcomes in the upstaging and the non-upstaging group. Results: A total of 299 patients who underwent robotic lobectomy were enrolled. After surgery, 55 patients reported nodal hilar or mediastinal upstaging. The 3-year overall survival of the entire population was 82.8%. The upstaging group and the non-upstaging group were homogeneous for age, gender, smoking habits, clinical stage, tumor site, tumor histology. The non-upstaging group had better OS (p = 0.004) and DFS (p < 0.0001). Conclusion: Our results show that robotic surgery is a safe and feasible approach for the treatment of early-stage NSCLC, especially for its accuracy in mediastinal lymphadenectomy. The oncological outcomes were encouraging and consistent with previous findings.

Isolated endobronchial tumors of the left main bronchus are quite rare. They are treated by surgical resection, preferably using lung-sparing techniques, when possible. These procedures are technically challenging and are usually performed through a standard thoracotomy. This video tutorial shows a left main bronchus sleeve resection with distal lobar carina reconstruction, performed through a uniportal thoracoscopic approach, for a typical carcinoid tumor of the distal left main bronchus.

Among the group of thymic epithelial tumors (TET), thymomas often show either uncertain or explicit malignant biological behavior, local invasiveness, and intrathoracic relapse and are often difficult to manage. From the initial stages, thymic carcinomas tend to show aggressive behavior and extrathoracic spread. Moreover, the interplay of epithelial cells and thymocytes in thymomas causes complex immune derangement and related systemic autoimmune diseases. Due to their rare occurrence and to the limited funding opportunities available for rare tumors, it is challenging to make advances in clinical and translational research in TET. The authors of this paper are all members of a multidisciplinary clinical and research thoracic tumor team. Strong input was given to the team by long-standing expertise in TET in the Pathology Department. In addition, thanks to the collaboration between research units at our Institute as well as to national collaborations, over the last 10 years we were able to perform several tissue-based research studies. The most recent studies focused on microRNA and on functional studies on the thymic carcinoma cell line 1889c. The recent implementation of our biobank now provides us with a new tool for networking collaborative research activities. Moreover, the participation in a worldwide community such as ITMIG (International Thymic Malignancy Interest Group) has allowed us to significantly contribute toward fundamental projects/research both in tissue-based studies (The Cancer Genome Atlas) and in clinical studies (TNM staging of TET). Our achievements derive from constant commitment and long-standing experience in diagnosis and research in TET. New perspectives opened up due to the establishment of national [the Italian Collaborative Group for ThYmic MalignanciEs (TYME)] and European reference networks such as EURACAN, for an empowered joint clinical action in adult solid rare tumors. The challenge we face still lies in the advancement of clinical and basic science in thymic epithelial malignancies.

Background Regarding the staging of mediastinal lymph nodes before lung cancer surgery, Endobronchial Ultrasound Transbronchial Needle Aspirations (EBUS-TBNA) have proven to be highly sensitive and specific as well as safe. Endoscopic Ultrasound Fine Needle Aspirations (EUS-FNA) plays an important role in the diagnosis and staging of thoracic diseases, including lung cancer. In this study we analysed all patients underwent endoscopic procedures in our endoscopic mediastinal ultrasound unit. Methods Between January 2013 and February 2018, we performed a total of 929 endoscopic procedures, 432 EBUS-TBNA and 497 EUS-FNA. Biopsy was performed at the following mediastinal sites: station 7 in 642 cases, at stations 8 and 9 in 211 cases; at station 3P and 4L in 27 and 114 cases respectively; with EUS we were able to perform biopsy at station 5 in 52 cases. Results A total of 841 patients showed a diagnosis of cancer: non-small cell lung cancer (NSCLC) in 645 patients, SCLC in 190 patients, neuroendocrine tumour in 5 patients and one patient with mesothelioma. 88 patients were negative for cancer. In terms of sensitivity, specificity and accuracy, the association between EUS-FNAb and EBUS-TBNAb showed a better quality on diagnosis compared to single procedures. EUS-FNA and EBUS-TBNA are safe, feasible, and highly sensitive techniques. Conclusions An endoscopic mediastinal ultrasound unit allows to perform a higher number of endoscopic procedures and improved the sensitivity and the accuracy of the minimally invasive hilar-mediastinal staging.

Background: We report the feasibility and safety of chest surgery through the subxiphoid single port approach based on our preliminary experience. Methods: From December 2013 till January 2016, 39 patients underwent 40 thoracoscopic surgeries via a 3- to 4-cm subxiphoid single incision. A sternal lifter was applied for better entrance and working angle. A zero-degree deflectable scope was preferred. The technique for anatomic resection was similar to that in the traditional single-port approach. Patient characteristics and demographic data were analyzed. Results: There were 29 females and 10 males, with a median age of 56 years. Indication for surgery included 24 patients with primary lung cancer, eight with lung metastases, two with benign lung lesions, one with bilateral pneumothorax, and five with mediastinal tumors. Surgeries included lobectomy in 21, segmentectomy in five, wedge resection in nine, and mediastinal surgery in five patients. There was no surgical mortality. Complications (10%, 4 in 40) included postoperative bleeding in one patient, chylothorax in one patient, and transient arrhythmia in the early learning curve in two patients. Conclusions: Our results indicated that subxiphoid single-incision thoracoscopic pulmonary resection could be performed safely but under careful patient selection with modification of instruments. Moreover, having a previous single-port incision experience was crucial. Major limitations of this approach included more frequently encountered instrument fighting; interference of left-side procedure related to heartbeat and radical mediastinal lymph node (LN) dissection; and the ability to handle complex conditions, such as anthracotic LNs, diffuse adhesion, and major bleeding.

Objectives Transplantation of a human trachea has been reported only twice in the literature with limited documentation of the functional and structural properties of the allograft. Patients and methods A 57-year-old patient with chronic obstructive pulmonary disease with low segment tracheal stenosis was accepted for lung transplantation and 2-stage tracheal allotransplantation. Standard bilateral sequential lung transplantation was performed with the transfer of the donor trachea into the recipient's abdomen, which was wrapped in the greater omentum and sutured into the abdominal wall, similar to a stoma. The patient received immunosuppression consisting of cyclosporine A, mycophenolate mofetil, and cortisone. Sixty days later, the tracheal allograft presented with macroscopically normal appearance with maintained elasticity and rigidity. The patient underwent a cricotracheal resection 6 months after lung transplantation. However, reconstruction with direct end-to-end anastomosis was achievable. The tracheal allograft, therefore not needed for reconstruction, was harvested and underwent complete investigations. Results Cross-section of the graft revealed a mechanically stable and macroscopically intact trachea. Hematoxylin-eosin staining demonstrated vital cartilage covered by respiratory epithelium. Angiography, followed by corrosion studies and electromicroscopy, demonstrated excellent vascularization of the tracheal wall. Conclusion The patient is alive 31 months posttransplantation and remains in bronchiolitis obliterans syndrome stage 0. Human trachea wrapped in omentum maintains its functional and structural integrity and may be used for 2-stage allotransplantation.