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Pleural mesothelioma (PM) is an aggressive malignancy with poor prognosis. Although histology and pathologic stage are important prognostic factors, better prognostic biomarkers are needed. The ribosomal protein S6 is a downstream target of the phosphatidylinositol 3-kinase (PI3K) pathway involved in protein synthesis and cell proliferation. In previous studies, low phosphorylated S6 (pS6) immunoreactivity was significantly correlated with longer progression-free survival (PFS) and overall survival (OS) in PM patients. We aimed to correlate pS6 expression to clinical data in a large multi-centre PM cohort as part of the European Thoracic Oncology Platform (ETOP) Mesoscape project. Tissue Micro Arrays (TMAs) of PM were constructed and expression of pS6 was evaluated by a semi-quantitatively aggregate H-score. Expression results were correlated to patient characteristics as well as OS/PFS. pS6 IHC results of 364 patients from 9 centres, diagnosed between 1999 and 2017 were available. The primary histology of included tumours was epithelioid (70.3%), followed by biphasic (24.2%) and sarcomatoid (5.5%). TMAs included both treatment-naïve and tumour tissue taken after induction chemotherapy. High pS6 expression (181 patients with H-score>1.41) was significantly associated with less complete resection. In the overall cohort, OS/PFS were not significantly different between pS6-low and pS6-high patients. In a subgroup analysis non-epithelioid (biphasic and sarcomatoid) patients with high pS6 expression showed a significantly shorter OS (p

Purpose Pulmonary hamartoma is the most common benign tumor of the lung. We analyzed a 20-year historical series of patients with pulmonary hamartoma undergoing surgical resection, aiming to evaluate the characteristics, the outcomes, and the association between hamartoma and lung cancer. Methods It was a retrospective multicenter study including the data of all consecutive patients with pulmonary hamartoma undergoing surgical resection. The end-points were to evaluate: (i) the characteristics of hamartoma, (ii) outcomes, and (iii) whether hamartoma was a predictive factor for lung cancer development Results Our study population included 540 patients. Upfront surgical or endoscopic resection was performed in 385 (71%) cases while in the remaining 155 (29%) cases, the lesions were resected 20 ± 3.5 months later due to increase in size. In most cases, lung sparing resection was carried out including enucleation (n = 259; 48%) and wedge resection (n = 230; 43%) while 5 (1%) patients underwent endoscopic resection. Only two patients (0, 2%) had major complications. One patient (0.23%) had recurrence after endoscopic resection, while no cases of malignant degeneration were seen (mean follow-up:103.3 ± 93 months). Seventy-six patients (14%) had associated lung cancer, synchronous in 9 (12%) and metachronous in 67 (88%). Only age > 70-year-old (p = 0.0059) and smokers > 20 cigarettes/day (p Conclusion PH was a benign tumor, with no evidence of recurrence and/or of malignant degeneration after resection. The association between hamartoma and lung cancer was a spurious phenomenon due to common risk factors.

Objective:To identify histopathological and immunophenotypical features with potential predictive or prognostic value in patients undergoing pulmonary metastasectomy from renal cell carcinoma (RCC).Methods:We retrospectively collected all consecutive patients undergoing pulmonary metastasectomy from RCC after prior nephrectomy. Paired samples of primary tumors and corresponding pulmonary metastases were analyzed, revising histopathological features and testing C-MET, mTOR, and PD-L1 by immunohistochemistry.Results:A total of 25 patients were included. Median overall survival (mOS) from metastasectomy was 5.5 years (95% CI = 1.9–9.1). The laterality of metastases had a significant predictive value, with median relapse-free survival (mRFS) from metastasectomy not reached (NR) at mean follow-up (FU) of 60.8 months for left lung involvement, mRFS of 52.9 months (95% CI = 0–145.5) for the right lung and 6.4 months (95% CI = 1.7–11) for bilateral metastases ( p = 0.028). Primary RCC with positive expression of mTOR had higher mOS after metastasectomy than negative cases ( p < 0.001), NR at mean FU of 4.3 years versus mOS of 2 years (95% CI = 0.7–3.3), respectively. PD-L1 positivity on intra-tumor (TILs) and peri-tumor (RILs) infiltrating lymphocytes of metastases was related to higher OS, NR versus 2 years (95% CI = 1.2–2.7, p = 0.003), and NR versus 1.4 years (95% CI = 0.2–2.6, p = 0.012), respectively. The shorter was the surgical interval, the more probably the metastases had high c-MET expression (>70%) ( p = 0.007) and PD-L1 expression >10% on TILs ( p = 0.024).Conclusions:mTOR positivity on primary RCC could be a favorable prognostic factor to select patients for pulmonary metastasectomy. The positive impact of PD-L1 expression on immune cells is opposite to the well-known negative prognostic value of PD-L1 on tumor cells in RCC.

PURPOSE: This study aimed to evaluate a potential relationship between the diffusing capacity of the lung for carbon monoxide(DLCO) and the aggressiveness of lung adenocarcinoma(ADC).METHODS: Patients who underwent radical surgery for lung ADC between 2001 and 2018 were retrospectively reviewed. DLCO values were dichotomized into DLCOlow(normal(≥80%).Relationships between DLCO and ADC histopathological features, clinical features, as well as with overall survival (OS), were evaluated. RESULTS: Four hundred and sixty patients were enrolled, of which 193(42%) were included in the DLCOlow group. DLCOlow was associated with smoking status, low FEV1, micropapillary and solid ADC, tumour grade 3,high tumour lymphoid infiltrate and presence of tumour desmoplasia. In addition, DLCO values were higher in low-grade ADC and progressively decreased in intermediate and high-grade ADC(p=0.024). After adjusting for clinical variables, at multivariable logistic regression analysis, DLCOlow still showed a significant correlation with high lymphoid infiltrate(p=0.017), presence of desmoplasia(p=0.065), tumour grade 3(p=0.062),micropapillary and solid ADC subtypes(p=0.008).To exclude the association between non-smokers and well-differentiated ADC, the relationship between DLCO and histopathological ADC patterns was confirmed in the subset of 377 former and current smokers(p=0.021).At univariate analysis, gender, DLCO, FEV1, ADC histotype, tumor grade, stage, pleural invasion, tumour necrosis, tumour desmoplasia, lymphatic and blood invasion were significantly related with OS. At multivariate analysis, only gender(pCONCLUSIONS: We found a relationship between DLCO and ADC patterns as well as with tumour grade, tumour lymphoid infiltrate and desmoplasia, suggesting that lung damage may be associated with tumour aggressiveness.

Benign metastasizing leiomyoma (BML) is a rare disease characterized by extrauterine benign leiomyomatosis in patients with a previous or concomitant history of uterine leiomyoma. Currently, there are no specific criteria to predict the metastasizing ability of the uterine leiomyoma and the risk of malignant degeneration of pulmonary BML, and these are the aims of this study. We analyzed 10 uterine (three leiomyomas, four leiomyomas that gave rise to lung BML, three healthy tissues) and 11 pulmonary tissue samples (eight lung BML, three healthy tissues). Interestingly, one of the BML lesions exceptionally evolved into a leiomyosarcoma (case 2). Uterine leiomyoma microvascular density (MVD) was higher in the patients with uterine leiomyomas that gave rise to lung BML, reaching a peak in case 2. Strong positivity for the estrogen (ER) and progesterone (PR) receptors and a low proliferation index (Ki67

Objective:To evaluate the prognostic role of maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) measured by FDG–positron emission tomography (PET)/computed tomography (CT) in patients with primary lung adenocarcinoma undergoing surgical resection.Methods:All consecutive patients undergoing curative surgery for primary lung adenocarcinoma at the Thoracic Surgery Unit of the University Hospital of Parma between January 2009 and December 2014 were retrospectively analyzed. The cutoff point of each continuous PET parameter was determined through receiver operating characteristic curve and Youden index, using overall survival (OS) as the classification status. Univariate and multivariate Cox proportional hazards models were applied to evaluate the association between OS and potential prognostic variables, including SUVmax, MTV, and TLG.Results:A total of 193 patients were considered eligible for this study. The mean 5-year OS rate was 70.5 ± 3.5%. Acinar and lepidic patterns were more frequently associated with absent or low (18F]FDG uptake. At univariate analysis, male sex, advanced stage, micropapillary and solid pattern, lymphatic, blood vessels and pleural invasion, high SUVmax, MTV, and TLG were significantly associated with poorer OS. Multivariate analyses revealed that only sex, stage, and TLG were independent factors for OS, with male sex, stage 3+4, and high TLG value ( p = 0.041) significantly associated with poorer OS.Conclusions:In this study, [18F]FDG PET/CT parameters SUVmax, MTV, and TLG were prognostic factors in patients with surgically resected lung adenocarcinoma, able to predict OS and helping to further stratify these patients into prognostic subsets. Elevated TLG was also an independent predictor for shorter OS.

The aim of this study was to assess the impact of BMI on perioperative outcomes in patients undergoing VATS lobectomy or segmentectomy. Data from 5088 patients undergoing VATS lobectomy or segmentectomy, included in the VATS Group Italian Registry, were collected. BMI (kg/m

Objective: To evaluate the influence of lung adenocarcinoma second predominant pattern on the maximal standard uptake value (SUVmax) and its prognostic effect in different histologic groups. Methods: We retrospectively collected surgically resected pathologic stage I and II lung adenocarcinoma from nine European institutions. Only patients who underwent preoperative PET-CT and with available information regarding SUVmax of T (SUVmaxT) and N1 (SUVmaxN1) component were included. Results: We enrolled 344 patients with lung adenocarcinoma. SUVmaxT did not show any significant relation according to the second predominant pattern ( p = 0.139); this relationship remained nonsignificant in patients with similar predominant pattern. SUVmaxT influenced the disease-free survival in the whole cohort ( p = 0.002) and in low- and intermediate-grade predominant pattern groups ( p = 0.040 and p = 0.008, respectively). In the high-grade predominant pattern cohort and in the pathologic N1 cases, SUVmaxT lost its prognostic power. SUVmaxN1 did not show any significant correlation with predominant and second predominant patterns and did not have any prognostic impact on DFS. Conclusions: SUVmaxT is influenced only by the adenocarcinoma predominant pattern, but not by second predominant pattern. Concurrently, in high-grade predominant pattern and pN1 group the prognostic power of SUVmaxT becomes nonsignificant.

Thoracoscopic lobectomy (VATS-L) for non-small-cell lung cancer (NSCLC) is a well-established option for early stage NSCLC, but the evidences are limited for octogenarians.The objectives of this multi-institutional study were to evaluate the post-operative outcomes of VATS-L in octogenarians and to estimate the post-operative quality of life (QoL) using a validated questionnaire (EuroQoL5D).Data from patients underwent VATS-L between 2014 and 2019 were analysed and divided into two groups: Group A (younger patients) and Group B (octogenarians). To define predictors for complications, univariate and multivariable logistic regression analysis were performed.7023 patients underwent VATS-L and 329 (4.6%) were octogenarians. 30-day and 90-day post-operative mortality were similar (0.95% vs 0.91%, p = 0.84 and 1.3% vs 1.2%, p = 0.58), whereas the percentage of patients who suffered from any complication (25.5% vs 31.9%, p = 0.012) and the complication rate (31.6% vs 45.2%, p=0.01) were higher for octogenarians. At discharge, the values of EuroQoL5D were worse in group B, but after one month these levels became similar. Age80 years had a significant influence on morbidity on both univariate and multivariable analyses (p = 0.025).VATS-L for NSCLC can be performed in selected octogenarians without increased risk of post-operative death, acceptable not-life-threatening complications and a moderate impact on QoL.

Objective: Currently, unlike earlier years, patients affected by multiple primary malignancies (MPM) are significantly increased, thus representing a clinical-pathologic category worthy of attention. Their clinical features and prognosis still need to be studied thoroughly, and this is the aim of our study. Methods: Patients with MPM involving lung cancer admitted in our center between January 2006 and December 2016 were considered. Parametric and nonparametric testing was used for statistical comparisons. Univariate and multivariate analysis was used to evaluate the variables associated with a prognostic value. Results: MPM incidence was 19.8%. Among the 222 patients with MPM enrolled, 204 (91.8%) had two malignancies, while 18 (8.2%) had three malignancies, 38 (17.1%) were synchronous, 41 (18.5%) had lung cancer first (LCF) and 181 (81.5%) had other cancer first (OCF). A significant difference between the time of first cancer diagnosis to the second cancer diagnosis in the LCF vs OCF group was found (median 32 vs 51 months; p-value: 0.038). The most frequent anatomical sites of malignancies preceding or following lung cancer were prostate, colorectal, bladder, and larynx. Multivariate analysis revealed that sex, histologic pattern, and time and order of occurrence were independent factors for overall survival, with male sex, squamous cell lung carcinoma, synchronous and LCF MPM significantly associated with poorer overall survival. Conclusions: Prostate, colorectal, bladder, and larynx were the most frequent anatomical sites of malignancies preceding or following lung cancer. Male sex, squamous cell lung carcinoma, synchronous and LCF MPM might be associated with poorer prognosis.

To evaluate the prognostic role of maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) measured by FDG-positron emission tomography (PET)/computed tomography (CT) in patients with primary lung adenocarcinoma undergoing surgical resection.All consecutive patients undergoing curative surgery for primary lung adenocarcinoma at the Thoracic Surgery Unit of the University Hospital of Parma between January 2009 and December 2014 were retrospectively analyzed. The cutoff point of each continuous PET parameter was determined through receiver operating characteristic curve and Youden index, using overall survival (OS) as the classification status. Univariate and multivariate Cox proportional hazards models were applied to evaluate the association between OS and potential prognostic variables, including SUVmax, MTV, and TLG.A total of 193 patients were considered eligible for this study. The mean 5-year OS rate was 70.5 ± 3.5%. Acinar and lepidic patterns were more frequently associated with absent or low (2.5) SUVmax values [In this study, [

Background: Second cancer is the leading cause of death in lymphoma survivors, with lung cancer representing the most common solid tumor. Limited information exists about the treatment and prognosis of second lung cancer following lymphoma. Herein, we evaluated the outcome and prognostic factors of Lung Cancer in Lymphoma Survivors (the LuCiLyS study) to improve the patient selection for lung cancer treatment. Methods: This is a retrospective multicentre study including consecutive patients treated for lymphoma disease that subsequently developed non-small cell lung cancer (NSCLC). Data regarding lymphoma including age, symptoms, histology, disease stage, treatment received and lymphoma status at the time of lung cancer diagnosis, and data on lung carcinoma as age, smoking history, latency from lymphoma, symptoms, histology, disease stage, treatment received, and survival were evaluated to identify the significant prognostic factors for overall survival. Results: Our study population included 164 patients, 145 of which underwent lung cancer resection. The median overall survival was 63 (range, 58-85) months, and the 5-year survival rate 54%. At univariable analysis no-active lymphoma (HR: 2.19; P=0.0152); early lymphoma stage (HR: 1.95; P=0.01); adenocarcinoma histology (HR: 0.59; P=0.0421); early lung cancer stage (HR: 3.18; P

Validation of predictive risk models for prolonged air leak (PAL) is essential to understand if they can help to reduce its incidence and complications. This study aimed to evaluate both the clinical and statistical performances of 4 existing models. We selected 4 predictive PAL risk models based on their scientific relevance. We referred to these models as Chicago, Bordeaux, Leeds and Pittsburgh model, respectively, according to the affiliation place of the first author. These predicting risk models were retrospectively applied to patients recorded on the second edition of the Italian Video-Assisted Thoracoscopic Surgery Group registry. Predictions for each patient were calculated based on the logistic regression coefficient values provided in the original manuscripts. All models were tested for their overall performance, discrimination, and calibration. We recalibrated the original models with the re-estimation of the model intercept and slope. We used curve decision analysis to describe and compare the clinical effects of the studied risk models. Better statistical metrics characterize the models developed on larger populations (Chicago and Bordeaux models). However, no model has a valid benefit for threshold probability greater than 0.30. The Net benefit of the most performing model (Bordeaux model) at the threshold probability of 0.11 is 23 of 1000 patients, burdened by 333 false positive cases. One of 1000 is the Net benefit at the threshold probability of 0.3. The use of PAL scores based on preoperative predictive factors cannot be currently used in a clinical setting because of a high false positive rate and low positive predictive value.

Purpose: To describe a case of giant intercostal nerve schwannoma successfully resected in a patient with neurofibromatosis type 2. Methods: A 44-year-old woman, with a history of neurofibromatosis type 2, presented with chest discomfort and mild dyspnea. She had undergone a recent resection of a large frontal parasagittal benign meningioma. Radiologic examinations showed a large lesion (9×12×9 cm) of the left hemithorax causing a complete atelectasis of left upper lobe. Bronchoscopy did not show any endobronchial alterations, apart from an ab estriseco compression of the left upper bronchial tree. A transthoracic needle biopsy was then performed and microscopic examination revealed a mesenchymal tumor composed of spindle-like cells. Results: A video-assisted thoracoscopic surgery procedure was proposed. The tumor mass appeared to be tenaciously adherent to the parietal pleura in its anterolateral aspect, confirming the radiologic appearance. No invasion of the lung parenchyma or parietal pleural metastases were visible. Therefore, a left posterolateral thoracotomy at the fifth intercostal space was performed and a macroscopic complete resection was carried out. The recovery was uneventful and the patient was discharged on postoperative day 5. The histologic examination revealed a moderate cellular proliferation of spindle-shaped and oval to polygonal cells with frequent Verocay bodies; mitotic figures were rare. The tumor cells were strongly S-100 positive. The microscopic features were consistent with benign intercostal schwannoma. Eight years later, the patient is disease-free and asymptomatic. Conclusions: An unusual case of giant intercostal nerve schwannoma successfully resected in a patient with neurofibromatosis type 2 is described.

© Journal of Thoracic Disease. Background: Malignant mesothelioma is an invasive neoplasm arising from mesothelial surfaces of the pleural and peritoneal cavities. Mesothelioma treatment is unsatisfactory and recurrence is common. Here an innovative locoregional treatment for malignant pleural mesothelioma is presented. Methods: Chitosan- and hyaluronate-based films were loaded with 0.5% and 4% w/w cisplatin and were studied for their physicochemical, mechanical and drug release characteristics. The performance of the drug delivery systems was assessed in vitro on A549 cells and on an orthotopic model of MPM recurrence in rats. Results: Polysaccharide films produced were thin, flexible and resistant. Cisplatin was completely released from hyaluronic acid films within 96 hours, while drug release was found to be much more prolonged with chitosan films. The drug released from hyaluronate films was effective against A549 cell line, while for chitosan films the release was too slow to produce cytotoxicity. Similarly, cisplatin-loaded chitosan films in vivo released minimal quantities of cisplatin and induced inflammation and foreign body reaction. Cisplatinloaded hyaluronate acid films on the contrary were able to prevent tumor recurrence. The cisplatinloaded hyaluronate films provided higher Cmax and AUC compared to a solution of cisplatin administered intrapleurally, but did not show any sign of treatment related toxicity. Conclusions: Hyaluronate-based films appear as an optimal platform for the development of drug delivery systems suitable for the loco-regional post-surgical treatment of lung malignancies.

Solid-phase microextraction and gas chromatography-mass spectrometry followed by multivariate data analysis were used to analyze lung tissues from both healthy and carcinogenic patients. A total of 78 volatile compounds belonging to different chemical classes were identified, seven of which were able to discriminate between the two groups. Discriminant analysis allowed to correctly classify 98.3% of the cases. By using the leave-one-method, 100% of the cross-validated samples belonging to the "tumor" group was correctly classified, whereas 2 cross-validated healthy samples out of 48 were erroneously allocated in the "tumor" group. Achieved results suggest the need of further investigation to assess the role of the seven identified compounds as lung cancer biomarkers in breath analysis, thus allowing the development of low-cost diagnostic devices.

The COVID-19 pandemic has now affected around 190 million people worldwide, accounting for more than 4 million confirmed deaths. Besides ongoing global vaccination, finding protective and therapeutic strategies is an urgent clinical need. SARS-CoV-2 mostly infects the host organism via the respiratory system, requiring angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2) to enter target cells. Therefore, these surface proteins are considered potential druggable targets. Hydrogen sulfide (H2S) is a gasotransmitter produced by several cell types and is also part of natural compounds, such as sulfurous waters that are often inhaled as low-intensity therapy and prevention in different respiratory conditions. H2S is a potent biological mediator, with anti-oxidant, anti-inflammatory, and, as more recently shown, also anti-viral activities. Considering that respiratory epithelial cells can be directly exposed to H2S by inhalation, here we tested the in vitro effects of H2S-donors on TMPRSS2 and ACE2 expression in human upper and lower airway epithelial cells. We showed that H2S significantly reduces the expression of TMPRSS2 without modifying ACE2 expression both in respiratory cell lines and primary human upper and lower airway epithelial cells. Results suggest that inhalational exposure of respiratory epithelial cells to natural H2S sources may hinder SARS-CoV-2 entry into airway epithelial cells and, consequently, potentially prevent the virus from spreading into the lower respiratory tract and the lung.

Background: Pulmonary metastasectomy is considered a standard procedure in the treatment of metastatic colorectal cancer (CRC). Different prognostic factors including multiple metastatic nodules, the presence of extra-pulmonary metastases and BRAF mutation status have been associated with poor survival. The aim of this study was to evaluate which factors influenced survival in CRC patients undergoing pulmonary metastasectomy by studying primary tumors and pulmonary metastases. Methods: All patients treated for primary CRC who presented pulmonary metastases in a 10-year period were considered (group A). A control group treated for primary CRC who did not develop any pulmonary or extra-pulmonary metastases was taken for comparison (group B). Different prognostic factors including gender, age, tumor location, histological type, inflammatory infiltrate, BRAF, CDX2 and extra-pulmonary metastases were analyzed. Overall survival (OS) and patients’ survival after pulmonary metastasectomy were also considered. Results: Fifty-four patients were evaluated in group A and twenty-three in group B. In group A, BRAF immunohistochemistry did not significantly differ between primary tumors and pulmonary metastases; no difference of BRAF expression was found between group A and B. Even the expression of CDX2 was not significantly different in primary tumors and metastases. Similarly, in group B CDX2 did not significantly differ from primary CRC of group A. The most significant prognostic factor was the presence of extra-pulmonary metastases. Patients with extra-pulmonary metastases experienced a significant shorter survival compared to patients with pulmonary metastases alone (P=0.001 with log-rank test vs. P=0.003 with univariate Cox regression). Interestingly, patients with right pulmonary metastases presented a significant longer survival than those with left pulmonary metastases (P=0.027 with log-rank test vs. 0.04 with univariate Cox regression). Conclusions: The main prognostic factor associated with poor survival after lung resection of CRC metastases is a history of extra-pulmonary metastases. BRAF and CDX2 did not have a significant role in this small series of patients.

Malignant pleural mesothelioma (MPM) is a progressive malignancy associated to the exposure of asbestos fibers. The most frequently inactivated tumor suppressor gene in MPM is CDKN2A/ARF , encoding for the cell cycle inhibitors p16 INK4a and p14 ARF , deleted in about 70% of MPM cases. Considering the high frequency of alterations of this gene, we tested in MPM cells the efficacy of palbociclib (PD-0332991), a highly selective inhibitor of cyclin-dependent kinase (CDK) 4/6. The analyses were performed on a panel of MPM cell lines and on two primary culture cells from pleural effusion of patients with MPM. All the MPM cell lines, as well as the primary cultures, were sensitive to palbociclib with a significant blockade in G0/G1 phase of the cell cycle and with the acquisition of a senescent phenotype. Palbociclib reduced the phosphorylation levels of CDK6 and Rb, the expression of myc with a concomitant increased phosphorylation of AKT. Based on these results, we tested the efficacy of the combination of palbociclib with the PI3K inhibitors NVP-BEZ235 or NVP-BYL719. After palbociclib treatment, the sequential association with PI3K inhibitors synergistically hampered cell proliferation and strongly increased the percentage of senescent cells. In addition, AKT activation was repressed while p53 and p21 were up-regulated. Interestingly, two cycles of sequential drug administration produced irreversible growth arrest and senescent phenotype that were maintained even after drug withdrawal. These findings suggest that the sequential association of palbociclib with PI3K inhibitors may represent a valuable therapeutic option for the treatment of MPM.

Primary neuroendocrine tumors (NETs) of the mediastinum are very rare. Prognosis is usually poor despite treatment options. We present the case of a primary atypical carcinoid tumor of the mediastinum successfully treated by multimodal approach. A 50-year-old man presented for asthenia, dyspnea, and substernal sense of weight for two weeks. A chest-CT scan revealed a tumor mass of 107×55×95 mm3 localized in the anterosuperior mediastinum compressing both brachiocephalic veins, the superior vena cava, the pericardium, and lungs. A FDG-PET demonstrated high FDG uptake only in the mediastinal mass; no metastases were seen. CT-guided needle biopsy revealed a NET; cells were immunoreactive for synaptophysin; Ki67 was 20%. After neoadjuvant chemotherapy, the chest CT-scan showed a significant reduction of the tumor. A surgical excision was proposed. The tumor was radically removed along with a partial resection of the vena cava and reconstruction with a bovine pericardium patch. The patient underwent 25 sessions of adjuvant radiotherapy. Microscopically the tumor showed clusters of medium-sized cells, eosinophilic cytoplasm with nuclear pleomorphism and small nucleoli, arranged in trabeculae, nests and lobules. No thymic tissue was found. Immunohistochemically the tumor cells were positive for CD117, synaptophysin, chromogranin, CD56, cytokeratin pool, epithelial membrane antigen (EMA), and negative for thyroid transcription factor-1 (TTF1), leukocyte common antigen (LCA), fibroblast-activation protein (FAP), prostate-specific antigen (PSA), P63, CD5 and CD99. Mitoses were found to be 8/10 HPF. The Ki67 was 10%. A diagnosis of primary NET of the mediastinum, intermediate grade (G2), atypical carcinoid according to WHO 2015, was formulated. Even in case of primary NE mediastinal tumor, a multimodal approach could lead to long-term survival.

Black hairy tongue (BHT) is a self-limiting disorder characterized by abnormal hypertrophy and elongation of filiform papillae on the surface of the tongue. The exact mechanism of drug-induced BHT is unknown. Several factors have been implicated and included smoking or chewing tobacco, drinking alcohol, poor oral hygiene and antibiotics such as tetracyclines and penicillins. We report a quite uncommon case of Linezolid-induced BHT in a patient with a long-lasting history of chest wall infection (www.actabiomedica.it)

OBJECTIVES Tumour-infiltrating lymphocytes (TILs) are critically implicated in the clinical outcome and response to immunotherapy in non-small-cell lung cancer (NSCLC) patients. The functional competence of lymphocyte subpopulations is strongly conditioned by their spatial arrangement within the tumour immune microenvironment. The aim of this study was to determine whether the tissue localization of specific TIL subpopulations might have an impact on the risk of recurrence in surgically resected NSCLC. METHODS High-speed scanning of whole slide images was performed on immunohistochemically stained tissue sections from 97 NSCLC patients to assess the number and ratio of CD3+, CD8+ and PD-1+ T-lymphocytes. TIL distribution was computed considering the intratumoural (proximal or distal) and peripheral (invasive margin) localization as well as their location within the fibrotic tissue (immune excluded). The tumour proliferative index was assessed by Ki67 labelling. The impact of TILs number and distribution on clinical-pathological characteristics and outcomes were statistically analysed. RESULTS High density and percentage of proximal CD8+ TILs and low PD-1-to-CD8 ratio had a positive impact on disease-free-survival (P = 0.03) and overall survival (P = 0.003). An inverse correlation was observed between the abundance of intratumoural CD8+ TILs carrying PD-1 inhibitory receptor and cancer cell proliferation. Cases with high compared to low fraction of immune excluded CD8+ TILs had significantly reduced 5-year overall survival (n events: 22 vs 12; P = 0.04) and disease-free survival (n events: 24 vs 16; P = 0.03) rates while the amount of CD3+ and CD8+ TILs located at the invasive margin had a favourable effect on the clinical course. CONCLUSIONS Mapping TIL subpopulations may implement the definition of prognostic parameters in surgically resected NSCLC.

Aim: The knowledge of the immune context of renal cell carcinoma (RCC) is useful to predict benefit from immunotherapy. We retrospectively characterized the immune context of RCC patients underwent primary nephrectomy and pulmonary metastasectomy. Materials & methods: Intratumoral infiltrating lymphocytes and peritumoral renal infiltrating lymphocytes, lymphocyte subpopulations (CD4+, CD8+), PD-1, PD-L1 were explored in paired samples of primary RCC (T) and respective pulmonary metastases (M). Results: The immune variables demonstrated intralesional and intratumoral heterogeneity. Intralesional lymphocyte heterogeneity reached 76% of cases in T, 28% in M. The heterogeneity rate for PD-L1 expression was from 44% (T) to 56% (M); it correlated with better survival. Conclusion: The immune context of RCC is highly variable both within a given tumor and among primary and metastases.

Objectives Vascular injuries are among the most severe causes of unplanned conversion during VATS lobectomies. The study aimed to analyse the incidence of vascular injuries and their risk factors during VATS lobectomy. Methods The Italian VATS lobectomy Registry was used to collect data from 66 Thoracic Surgery Units. From 2013 to October 2016 (out of more than 3,700 patients enrolled) only information from Units with an enrollment >100 VATS lobectomies were retrospectively analysed. Logistic regression analysis was performed on selected variables of the univariate analysis. Results Ten institutions contributed a total of 1,679 patients. Vascular injuries leading to conversion occurred in 44 (2.6%) patients. Years of experiences were inversely related to the risk of vascular injuries. Univariate analysis showed age, gender, surgical activity, Charlson Index Score and number of resected lymph nodes like significantly associated variables. Multivariate analysis revealed that number of resected lymph nodes, VATS experience ratio (number of VATS lobectomies/total lobectomies performed in the same year at same centre), and surgical activity of the centre were significantly associated with the risk of conversion. Unplanned thoracotomy was correlated with postoperative morbidity. Conclusion Vascular injuries in VATS lobectomies represented a rare complication which could directly affect the postoperative outcomes. The predictive factors for conversion were multifactorial and depended on characteristics of centres and surgeons’ seniority. Minimally invasive VATS lobectomy approaches did not influence the risk of vascular damages.

Objective: The objective of the study is to analyse the causes and impact of conversion from VATS to thoracotomy identifying any possible pre-operative risk factors and related consequences. Methods: Data from patient who underwent VATS lobectomy (VATS-L) for NSCLC at VATS Group participating centres were retrospectively analysed and divided in two groups: patients treated with VATS-L and patients who suffered from conversion. Predictors of conversion were assessed with univariate and multivariable exact logistic regression. Complications were evaluated as dependent variables of conversion in a Cox multivariable logistic regression model. Results: A total of 4629 patients underwent planned VATS-L for NSCLC and of these, 432 (9.3%) required conversion; the most frequent causes were bleeding (30.4%) and fibro-calcified hilar lymph nodes (23.9%). The independent risk factors at multivariable analysis model were sex male (OR 1.458, p < 0.01), age older than 70years (OR 1.248, p = 0.036) and the clinically node-positive disease (OR 2.258, p < 0.01). The mortality rate was similar, but the percentage of patients who suffered from any complication (41.7% vs 24.4%, p < 0.01), the complication rate (65% vs 32.2%, p < 0.01), chest tube duration (p < 0.01) and the hospitalisation rate (p < 0.01) were higher for patients converted. Atrial fibrillation (OR 1.471, p = 0.019), prolonged air leak (OR 1.403, p = 0.043), blood transfusions (OR 4.820, p < 0.01), sputum retention (OR 1.80, p = 0.027) and acute kidney failure (OR 2.758, p = 0.03) were significantly associated with conversion at multivariable analysis. Conclusions: Conversion is associated with increased surgical morbidity, blood loss and hospital stay. Sex male, old age and the clinical involvement of lymph nodes were the strongest predictors of conversion.

Malignant pleural mesothelioma (MPM) is a rare malignancy characterized by a long latency period of 20–50 years after exposure to the main aetiology agent that is asbestos. MPM treatments include surgery, chemotherapy, and radiation therapy, with the combination pemetrexed and cisplatin being the standard chemotherapy approach. Despite this multimodality therapy one of the major issues after surgery is the high rate of local recurrence of the tumor. One possible approach would be the intrapleural application of implants loaded with anticancer drug to be applied during surgery to prevent local tumor recurrence. The implant proposed in the present work is a polymeric film of hyaluronic acid loaded with pemetrexed. The film developed is a hydrophilic, thin and flexible film sufficiently resistant to be applied intrapleurally adhering to the mesothelial surface. The release of pemetrexed from the film was found to be complete within 2 h in phosphate buffered saline. In an orthotopic model of mesothelioma recurrence in rats, pemetrexed loaded films showed the same antitumor efficacy of pemetrexed disodium solutions administered intravenously or intrapleurally, while when administered in combination with cisplatin-loaded hyaluronate film, the implants almost completely prevented tumor recurrence. The local administration of drug-loaded polymer implants appears an ideal chemotherapy strategy especially for patients in which surgery is already selected as a viable therapeutic option.

© Journal of Thoracic Disease. Background: Malignant pleural mesothelioma (MPM) continues to be a distressing tumor due to its aggressive biologic behavior and scanty prognosis. Several therapeutic approaches have been tested both in clinical and preclinical settings, being intrapleural chemotherapy one of the most promising. Some years ago, our interest focused on polymeric films loaded with cisplatin for the adjuvant intrapleural treatment of surgical patients. After in vitro and in vivo studies in a rat recurrence model of MPM, the aim of this study was to evaluate the pharmacokinetics of the polymeric films in a sheep model in view of further studies in a clinical setting. Methods: An ovine model was used. Animals were divided into four groups according to pharmacologic treatment: control group (three animals undergoing left pneumonectomy and saline-NaCl solution); intrapleural hyaluronate cisplatin films (HYALCIS) group (six animals undergoing left pneumonectomy and intrapleural application of polymeric films loaded with cisplatin); intrapleural cisplatin solution (six animals undergoing left pneumonectomy and intrapleural application of cisplatin solution); intravenous cisplatin (five animals undergoing left pneumonectomy and intravenous administration of cisplatin solution). The primary objective was the plasmatic and pleural concentration of cisplatin in the treatment groups. The secondary objective was the treatment-related toxicity evaluated by plasmatic analysis performed at prearranged time intervals and histological examinations of tissue samples collected during animal autopsy. Analysis of variance (ANOVA) was used for statistical analysis. Bonferroni correction was applied for comparison between all groups. Results: Twenty female Sardinian sheep with a mean weight of 45.1 kg were studied. All animals survived the surgical procedures. The whole surgical procedure had a mean duration of 113 minutes. Cisplatin blood levels obtained from polymeric films application were low during the first 24 hours after the application; then, the cisplatin blood level increased gradually and progressively until it reached significantly higher plasmatic concentrations after 120 hours compared to intrapleural cisplatin solution (P=0.004) and intravenous administration (P=0.001), respectively. Considering cisplatin concentration at 168 hours after the application, animals treated with polymeric films had higher plasmatic values than animals treated with intrapleural cisplatin solution and intravenous cisplatin (P=0.001). Despite the high cisplatin plasmatic concentrations, treatment related-toxicity towards kidneys and liver was comparatively lower compared to the intravenous and intrapleural cisplatin administration and closer to the control levels. Conclusions: Polymeric films loaded with cisplatin allowed to reach significantly higher intrapleural and plasmatic cisplatin concentrations compared to intrapleural and intravenous cisplatin solution, providing at the same time, a significant reduction of treatment related toxicity.

OBJECTIVES: Lymphangiogenesis plays a critical role in the immune response, tumour progression and therapy effectiveness. The aim of this study was to determine whether the interplay between the lymphatic and the blood microvasculature, tumour-infiltrating lymphocytes and the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) immune checkpoint constitutes an immune microenvironment affecting the clinical outcome of patients with non-small-cell lung cancer. METHODS: Samples from 50 squamous cell carcinomas and 42 adenocarcinomas were subjected to immunofluorescence to detect blood and lymphatic vessels. CD3pos, CD8pos and PD-1pos tumour-infiltrating lymphocytes and tumour PD-L1 expression were assessed by immunohistochemical analysis. RESULTS: Quantification of vascular structures documented a peak of lymphatics at the invasive margin together with a decreasing gradient of blood and lymphatic vessels from the peritumour area throughout the neoplastic core. Nodal involvement and pathological stage were strongly associated with vascularization, and an increased density of vessels was detected in samples with a higher incidence of tumour-infiltrating lymphocytes and a lower expression of PD-L1. Patients with a high PD-L1 to PD-1 ratio and vascular rarefaction had a gain of 10 months in overall survival compared to those with a low ratio and prominent vascularity. CONCLUSIONS: Microvessels are an essential component of the cancer immune microenvironment. The clinical impact of the PD-1/PD-L1-based immune contexture may be implemented by the assessment of microvascular density to potentially identify patients with non-small-cell lung cancer who could benefit from immunotherapy and antiangiogenic treatment.

Background. The identification of diagnostic/prognostic biomarkers for asbestos-related diseases is relevant for early diagnosis and patient survival and may contribute to understanding the molecular mechanisms underlying the disease development and progression.Aims. To identify a pattern of miRNAs as possible diagnostic biomarkers for patients with malignant pleural mesothelioma (MPM) and asbestosis (ASB) and as prognostic biomarkers for MPM patients.Methods. miRNA-16, miRNA-17, miRNA-126, and miRNA-486 were quantified in plasma and formalin-fixed paraffin-embedded samples to evaluate their diagnostic and prognostic roles compared to patients with other noncancerous pulmonary diseases (controls). Results. The expression of all the miRNAs was significantly lower in patients with MPM and ASB than that in controls. miRNA-16, miRNA-17, and miRNA-486 in plasma and tissue of MPM patients were significantly correlated. Furthermore, the expression of miRNA-16 in plasma and tissue, and miRNA-486 only in tissue, was positively related with cumulative survival in MPM patients.Conclusions. All the miRNA levels were decreased in patients with MPM or ASB, supporting the role of circulating miRNAs as a potential tool for diseases associated with exposure to asbestos fibers. miRNA-16 was directly related to MPM patient prognosis, suggesting its possible use as a prognostic marker in MPM patients.

Objectives The potential benefit of surgery for malignant pleural mesothelioma (MPM), especially concerning pleurectomy/decortication (P/D), is unclear from the literature. The aim of this study was to evaluate the outcome after multimodality treatment of MPM involving different types of P/D and to analyse the prognostic factors. Methods We reviewed 314 patients affected by MPM who were operated on in 11 Italian centres from 1 January 2007 to 11 October 2014. Results The characteristics of the population were male/female ratio: 3.7/1, and median age at operation was 67.8 years. The epithelioid histotype was observed in 79.9% of patients; neoadjuvant chemotherapy was given to 57% of patients and Stage III disease was found following a pathological analysis in 62.3% of cases. A total of 162 (51.6%) patients underwent extended P/D (EP/D); 115 (36.6%) patients had P/D and 37 (11.8%) received only a partial pleurectomy. Adjuvant radiotherapy was delivered in 39.2% of patients. Median overall survival time after surgery was 23.0 [95% confidence interval (CI): 19.6-29.1] months. On multivariable (Cox) analysis, pathological Stage III-IV [ P = 0.004, hazard ratio (HR):1.34; 95% CI: 1.09-1.64], EP/D and P/D ( P = 0.006, HR for EP/D: 0.46; 95% CI: 0.29-0.74; HR for P/D: 0.52; 95% CI: 0.31-0.87), left-sided disease ( P = 0.01, HR: 1.52; 95% CI: 1.09-2.12) and pathological status T4 ( P = 0.0003, HR: 1.38; 95% CI: 1.14-1.66) were found to be independent significant predictors of overall survival. Conclusions Whether the P/D is extended or not, it shows similarly good outcomes in terms of early results and survival rate. In contrast, a partial pleurectomy, which leaves gross tumour behind, has no impact on survival.

In the article that appeared on page 2061-2070, Vol 9, No 7 (July 2017) Issue of the Journal of Thoracic Disease (1), there are some mistakes in the presented authors information. In the list of collaborators of the Italian VATS Group are not included the following author names: Alessandro Bertani, Alessandro Gonfiotti, Mario Nosotti, Paolo Albino Ferrari, Lavinia De Monte, Emanuele Russo, Gioacchino Di Paola, Piergiorgio Solli, Andrea Droghetti, Luca Bertolaccini, Roberto Crisci. The correct list of collaborators of the Italian VATS Group should have been shown as below. Alessandro Bertani, MD (IRCCS ISMETT, Palermo); Alessandro Gonfiotti, MD (Careggi Hospital, Firenze); Mario Nosotti, MD (Policlinico Ca'Granda, Milano); Paolo Albino Ferrari, MD (IRCCS ISMETT, Palermo); Lavinia De Monte, MD (IRCCS ISMETT, Palermo); Emanuele Russo, MD (IRCCS ISMETT, Palermo); Gioacchino Di Paola, MD (IRCCS ISMETT, Palermo); Piergiorgio Solli, MD PhD (AUSL Romagna Teaching Hospital, Forlì); Andrea Droghetti, MD (ASST Mantova-Cremona, Mantova); Luca Bertolaccini, MD PhD (AUSL Romagna Teaching Hospital, Forlì); Roberto Crisci, MD PhD (Università dell'Aquila, L'Aquila); Carlo Curcio, MD (Monaldi Hospital, Napoli); Dario Amore, MD (Monaldi Hospital, Napoli); Giuseppe Marulli, MD (University of Padova); Samuele Nicotra, MD (University of Padova); Andrea De Negri, MD (San Martino Hospital, Genova); Paola Maineri, MD (San Martino Hospital, Genova); Gaetano di Rienzo (Vito Fazzi Hospital, Lecce); Camillo Lopez, MD (Vito Fazzi Hospital, Lecce); Angelo Morelli, MD (S. Maria delle Misericordia Hospital, Udine); Francesco Londero, MD (S. Maria delle Misericordia Hospital, Udine); Lorenzo Spaggiari, MD (IEO Hospital, Milano); Roberto Gasparri, MD (IEO Hospital, Milano); Guido Baietto, MD (Maggiore della Carità Hospital, Novara); Caterina Casadio, MD (Maggiore della Carità Hospital, Novara); Maurizio Infante, MD (Borgo Trento Hospital, Verona); Cristiano Benato, MD (Borgo Trento Hospital, Verona); Marco Alloisio, MD (IRCCS Humanitas, Milano); Edoardo Bottoni, MD (IRCCS Humanitas, Milano); Giuseppe Cardillo, MD (Forlanini Hospital, Roma); Francesco Carleo, MD (Forlanini Hospital, Roma); Franco Stella, MD (S. Orsola Hospital, Bologna); Giampiero Dolci, MD (S. Orsola Hospital, Bologna); Francesco Puma, MD (University of Perugia); Damiano Vinci, MD (University of Perugia); Giorgio Cavallesco, MD (University of Ferrara); Pio Maniscalco, MD (University of Ferrara); Luca Ampollini, MD (University of Parma); Paolo Carbognani, MD (University of Parma); Alberto Terzi, MD (Negrar Hospital, Verona); Andrea Viti, MD (Negrar Hospital, Verona); Giampiero Negri, MD (S. Raffaele Hospital, Milano); Alessandro Bandiera, MD (S. Raffaele Hospital, Milano); Reinhold Perkmann, MD (Bolzano Hospital, Bolzano); Francesco Zaraca, MD (Bolzano Hospital, Bolzano); Claudio Andretti, MD (S. Andrea Hospital, Roma); Camilla Poggi, MD (S. Andrea Hospital, Roma); Felice Mucilli, MD (S. Maria Annunziata Hospital, Chieti); Pierpaolo Camplese, MD (S. Maria Annunziata Hospital, Chieti); Luca Luzzi, MD (University of Siena); Marco Ghisalberti, MD (University of Siena); Andrea Imperatori, MD (University of Varese); Nicola Rotolo, MD (University of Varese); Luigi Bortolotti, MD (Humanitas Gavazzeni Hospital, Bergamo); Giovanna Rizzardi, MD (Humanitas Gavazzeni Hospital, Bergamo); Massimo Torre, MD (Niguarda Hospital, Milano); Alessandro Rinaldo, MD (Niguarda Hospital, Milano); Armando Sabbatini, MD (Ospedali Riuniti, Ancona); Majed Refai, MD (Ospedali Riuniti, Ancona); Mauro Roberto Benvenuti, MD (Spedali Civili, Brescia); Diego Benetti, MD (Spedali Civili, Brescia); Alessandro Stefani, MD (Ospedale Policlinico, Modena); Pamela Natali, MD (Ospedale Policlinico, Modena); Paolo Lausi, MD (Ospedale Molinette, Torino); Francesco Guerrera, MD (Ospedale Molinette, Torino).

OBJECTIVES: The aim of the present study was to characterize the biological properties and in vivo tumourigenic potential of mesenchymal cells (MCs) obtained from non-small-cell lung cancer (NSCLC) samples. METHODS: NSCLC samples (53 adenocarcinomas and 24 squamous-cell carcinomas) surgically removed from 46 males and 31 females were processed to identify mesenchymal cells from human lung cancer (hLc-MCs). hLc-MCs were separated from neoplastic epithelial cells, expanded and extensively characterized in vitro. Subsequently, female BALB/c nude mice were subcutaneously injected with either 10 6 or 2.5 × 10 6 Calu-3 (human adenocarcinoma cell line able to reproducibly induce xenografted tumours) alone or in combination with equal doses of hLc-MCs. Control animals were injected with the two doses of hLc-MCs only. RESULTS: Primary cultures of hLc-MCs were obtained from >80% of NSCLC specimens. The typical MCs immunophenotype was documented by the expression of CD90, CD105, CD73, CD13 and CD44 at fluorescence-activated cell sorting analysis. CD45, CD14, CD34 and epithelial antigens were negative while CD117 (c-kit) and CD133 (prominin) were partially expressed. Interestingly, nuclear transcription factors octamer-binding transcription factor 3/4 and sex determining region Y-box 2 involved in stemness, thyroid transcription factor 1 in bronchoalveolar commitment, and ETS1 in carcinogenesis, were expressed in hLc-MCs isolated from NSCLC. Specific conditioned media and cocultures confirmed the supportive role of hLc-MCs for cancer cells. In vivo experiments showed that at both doses Calu-3 xenografts doubled in size when hLc-MCs were coinjected. Cell tracking in xenografted tumours, by immunofluorescence combined with fluorescence in situ hybridization analysis, documented hX-chromosome-labelled, Calu-3-derived cytokeratin-positive adenocarcinoma structures surrounded by hLc-MCs. CONCLUSIONS: Tumour-propagating cells require the inductive interaction of resident mesenchymal cells to foster lung cancer development.

In the “Results” section of the Abstract, the sentence: “The mortality rate was similar, but the percentage of patients who suffered from any complication (41.7% vs 24.4%, p

Purpose: The aim of this study was to analyse factors predicting the diagnostic accuracy of computed tomography (CT)-guided transthoracic fine-needle aspiration (TTFNA) for solid noncalcified, subsolid and mixed pulmonary nodules, with particular attention to those responsible for false negative results with a view to suggesting a method for their correction. Materials and methods: From January 2007 to March 2010, we retrospectively reviewed the CT images of 198 patients of both sexes (124 males and 74 females; mean age, 70 years; range age, 44-90) used for the guidance of TTFNA of pulmonary nodules. Aspects considered were: lesion size and density, distance from the pleura, and lesion site. Multiplanar reformatted images (MPR) were retrospectively obtained in the sagittal and axial oblique planes relative to needle orientation. Results: The overall diagnostic accuracy of TTFNA CTguided biopsy was 86% for nodules between 0.7 and 3 cm, 83.3% for those between 0.7 and 1.5 cm, and 92% for those between 2 and 3 cm. Accuracy was 95.1% for solid pulmonary nodules, 84.6% for mixed nodules, and 66.6% for subsolid nodules. The diagnostic accuracy of CT-guided TTFNA in relation to the distance between the nodule and the pleural plane was 95.6% for lesions adhering to the pleura and 83.5% for central ones. The diagnostic accuracy was 84.2% for the pulmonary upper lobe nodules, 85.3% for the lower lobe and 90.9% for those in the lingula and middle lobe. In 75% of false negative and inadequate/insufficient cases the needle was found to lie outside the lesion, after reconstruction of the needle path by MPR. Conclusions: The positive predictive factors of CT-guided TTFNA are related to the nodule size, density and distance from the pleural plane. The most common negative predictive factor of CT-guided TTFNA is the wrong position of the needle tip, as observed in the sagittal and axial oblique sections of the MPR reconstructions. The diagnostic accuracy of CT-guided TTFNA can therefore be improved by using the MPR technique to plan the needle path during the FNA procedure. © 2013 Springer-Verlag.