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Thymic epithelial tumors are presently staged using a consistent TNM classification developed by the International Association for the Study of Lung Cancer (IASLC) and approved by the Union for International Cancer Control and the American Joint Committee on Cancer. The stage classification is incorporated in the eight edition of the TNM classification of thoracic malignancies. The IASLC Staging and Prognostic Factors Committee (SPFC)-Thymic Domain (TD) is in charge for the next (ninth) edition expected in 2024. The present article represents the midterm report of the SPFC-TD: in particular, it describes the unresolved issues identified by the group in the current stage classification which are worth being addressed and discussed for the ninth edition of the TNM classification on the basis of the available data collected in the central thymic database which will be managed and analyzed by Cancer Research And Biostatistics. These issues are grouped into issues of general importance and those specifically related to T, N, and M categories. Each issue is described in reference to the most recent reports on the subject, and the priority assigned by the IASLC SPFC-TD for the discussion of the ninth edition is provided.

The aim of the study is to evaluate clinical applications, safety, and effectiveness of a porcine-derived acellular cross-linked dermal matrix biological mesh in chest wall reconstruction.We retrospectively analyzed a prospective multicenter database of chest wall reconstructions using a biological mesh in adult patients undergoing operation between October 2013 and December 2020. We evaluated preoperative data, type of resection and reconstruction, hospitalization, 30-day morbidity and mortality, and overall survival.A total of 105 patients (36 women [34.2%]; mean age, 57.0 ± 16.1 years; range, 18-90 years) were included, they have admitted for: primary chest wall tumor (n = 52; 49.5%), secondary chest wall tumor (n = 29; 27.6%), lung hernia (n = 12; 11.4%), trauma (n = 10; 9.6%), and infections (n = 2; 1.9%). The surgical sites were preoperatively defined as at high risk of infection in 28 patients (26.7%) or as infected in 16 (15.2%) patients. Thirty-days morbidity was 30.5% (n = 32 patients); 14 patients (13.3%) had postoperative complications directly related to chest wall surgical resection and/or reconstruction. We experienced no 30-day mortality; 1-year and 2-year mortality was 8.4% and 16.8%, respectively.Biological mesh represents a valuable option in chest wall reconstruction even when surgical sites are infected or at high-risk of infections. This mesh shows low early and late postoperative complication rates and excellent long-term stability.

Introduction The International Thymic Malignancy Interest Group (ITMIG) classifies thymoma recurrences on the basis of the topographic location, but its effectiveness in prognosis prediction has not been well investigated yet. Aims of this study are to analyze survival outcome of patients surgically treated for thymoma recurrence according to the ITMIG recurrence classification and to investigate possible alternatives. Methods From January 1, 1990, to January 7, 2017, data on 135 surgically treated patients for thymoma recurrence from three high-volume centers were collected and retrospectively analyzed. Patients were classified according to the ITMIG classification as local, regional, and distant. The ITMIG classification and alternative classifications were correlated to overall survival (OS). Results According to the ITMIG classification, recurrence was local in 17 (12.5%), regional in 97 (71.8%), and distant in 21 (15.7%) patients, with single localization in 38 (28.2%) and multiple localizations in 97 (71.8%). The 5- and 10-year OS were 79.9% and 49.7% in local, 68.3% and 52.6% in regional, and 66.3% and 35.4% in distant recurrences, respectively, but differences were not statistically significant (p = 0.625). A significant difference in survival was present considering single versus multiple localizations: 5- and 10-year OS of 86.2% and 81.2% versus 61.3% and 31.5% (p = 0.005, hazard ratio = 7.22, 95% confidence interval: 0.147–0.740), respectively. Combining the localization number with the recurrence site, ITMIG locoregional single recurrence had a statistically significant better survival compared with patients with ITMIG locoregional multiple recurrence or ITMIG distant recurrence (p = 0.028). Similarly, a significant difference was present considering intrathoracic single versus intrathoracic multiple versus distant recurrence (p = 0.024). Conclusions The ITMIG classification for thymoma recurrence did not have significant survival differences comparing local, regional, and distant recurrences. Integrating this classification with the number of the localizations may improve its effectiveness in prognosis prediction.

Backgrounds Oligometastatic Non-Small Cell Lung Cancer (NSCLC) patients represent a category without a standard therapeutic approach. However, in selected oligometastatic NSCLC, radical surgery seems to offer a good prognosis. This retrospective study aimed to analyse the long-term outcomes of synchronous oligometastatic patients treated with curative intent and identify the factors associated with better results and the proposal of a risk stratification system for classifying the synchronous oligometastatic NSCLC. Methods The medical records of patients from 18 centres with pathologically diagnosed synchronous oligometastatic NSCLC were retrospectively reviewed. The inclusion criteria were synchronous oligometastatic NSCLC, radical surgical treatment of the primary tumour with or without neoadjuvant/adjuvant therapy and radical treatment of all metastatic sites. The Kaplan – Meier method estimated survivals. A stratified backward stepwise Cox regression model was assessed for multivariable survival analyses. Results 281 patients were included. The most common site of metastasis was the brain, in 50.89 % patients. Median overall survival was 40 months (95 % CI: 29–53). Age ≤65 years (HR = 1.02, 95 % CI: 1.00–1.05; p = 0.019), single metastasis (HR = 0.71, 95 % CI: 0.45–1.13; p = 0.15) and presence of contralateral lung metastases (HR = 0.30, 95 % CI: 0.15 – 0.62; p = 0.001) were associated with a good prognosis. The presence of pathological N2 metastases negatively affected survival (HR = 2.00, 95 % CI: 1.21–3.32; p = 0.0065). These prognostic factors were used to build a simple risk classification scheme. Conclusions Treatment of selected synchronous oligometastatic NSCLC with curative purpose could be conducted safely and at acceptable 5-year survival levels, especially in younger patients with pN0 disease.

The current COVID-19 pandemic has shown a relevant rate of patients developing an acute respiratory distress syndrome that requires hospitalization. Approximately 3-17% of hospitalized patients require Intensive Care Unit (ICU) and invasive mechanical ventilation. Initial recommendations advocated for early intubation, while early tracheotomy should not be routinely performed in COVID-19 patients. We report the case of a COVID-19 patient developing laryngo-tracheal stenosis secondary to an open surgical tracheotomy in the ICU. A conservative endoscopic management was not successful and we performed a laryngo-tracheal resection. The specimen was negative for COVID-19 but the pathological examination revealed how the virus damaged the trachea. This case is, as far as we are aware, the first case of laryngo-tracheal surgery in a COVID-19 patient and provides an insight to justify the higher rate of tracheal injuries occurring in intubated COVID-19 patients.

Objective: Our aim was to validate the prognostic relevance in NSCLC of potential residual tumor (R) descriptors, including the proposed International Association for the Study of Lung Cancer definition for uncertain resection, referred to as R(un). Methods: A total of 14,712 patients undergoing resection with full R status and survival were analyzed. The following were also evaluated: whether fewer than three N2 stations were explored, lobe-specific nodal dissection, extracapsular extension, highest lymph node station status, carcinoma in situ at the bronchial resection margin, and pleural lavage cytologic examination result. Revised categories of R0, R(un), R1, and R2 were tested for survival impact. Results: In all, 14,293 cases were R0, 263 were R1, and 156 were R2 (median survivals not reached, 33 months, and 29 months, respectively). R status correlated with T and N categories. A total of 9290 cases (63%) had three or more N2 stations explored and 6641 cases (45%) had lobespecific nodal dissection, correlated with increasing pN2. Extracapsular extension was present in 62 of 364 cases with available data (17%). The highest station was positive in 942 cases (6.4%). The pleural lavage cytologic examination result was positive in 59 of 1705 cases (3.5%): 13 had carcinoma in situ at the bronchial resection margin. After reassignment because of inadequate nodal staging in 56% of cases, 6070 cases were R0, 8185 were R(un), 301 were R1, and 156 were R2. In node-positive cases, the median survival times were 70, 50, and 30 months for RO, R(un) (p < 0.0001), and R1 (p < 0.001), respectively, with no significant difference between RO and R(un) in pN0 cases. Conclusions: R descriptors have prognostic relevance, with R(un) survival stratifying between R0 and R1. Therefore, a detailed evaluation of R factor is of particular importance in the design and analyses of clinical trials of adjuvant therapies. (C) 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

Background: In previous multicentre studies, the longest survival was observed in synchronous lung oligometastatic patients without pN2 disease. This paper aimed to identify preoperative favourable prognostic factors and propose a preoperative classification for categorising the synchronous oligometastatic non-small cell lung cancer (NSCLC). Methods: A retrospective review of prospectively collected patients was performed. The inclusion criteria were: synchronous oligometastatic NSCLC (≤5 extrapulmonary metastases), radical surgical treatment of the primary tumour and all metastatic sites (2005–2018). Exclusion criteria were: palliative surgery, recurrent lung cancer, low-performance status, follow-up information unavailable. The reverse Kaplan – Meier method estimated median overall survival (OS) and progression-free survival. A stratified backward stepwise Cox regression model was employed for multivariable survival analyses. A prognostic grouping considering all the relevant prognostic factors simultaneously was constructed, and a Receiver Operating Characteristic (ROC) curve was generated. Hosmer-Lemeshow χ statistics was used for measuring OS calibration within groups. Findings: 281 patients were included. Data from the Cox regression model were used to construct a prognostic risk classification. Four parameters (age ≤65 years, site of metastasis, clinical nodal status, and induction treatment) were used to build a risk classification. Group A: no risk factors (age ≤65 years, lung/brain metastasis, cN0, induction treatment); Group B: one risk factor (age >65 years or no lung/brain metastasis or cN1–2 or no induction treatment); Group C: two risk factors; Group D: ≥3 risk factors. The Area Under the Curve (AUC) was 0.56 (95% CI: 0.49–0.62), Hosmer-Lemeshow χ statistics was 21.3 (3 degrees of freedom, p=0.0042). Interpretations: Patient selection is critical in identifying the proper subsets of oligometastatic NSCLC. After clinical validation, this preoperative risk classification might support decision-making during the multidisciplinary team assessment and patient selection for enrolment in future randomised trials. Funding: This work was partially supported by the Italian Ministry of Health with Ricerca Corrente and 5 x 1000 funds. Declaration of Interest: All authors have no conflict of interest to declare. Ethical Approval: This research was carried out following the Helsinki Declaration 10. The Ethical Committee authorised the study (785/19).

Lungs are pharmacologically active organs and the pulmonary drug metabolism is of interest for inhaled drugs design. Carboxylesterases (CESs) are enzymes catalyzing the hydrolysis of many structurally different ester, amide and carbamate chemicals, including prodrugs. For the first time, the presence, kinetics, inhibition and inter-individual variations of the major liver CES isozymes (CES1 and CES2) were investigated in cytosol and microsomes of human lungs from 20 individuals using 4-nitrophenyl acetate (pNPA), 4-methylumbelliferyl acetate (4-MUA), and fluorescein diacetate (FD) as substrates the rates of hydrolysis (V-max) for pNPA and 4-MUA, unlike FD, were double in microsomes than in cytosol. In these cellular fractions, the V-max of pNPA, as CES1 marker, were much greater (30-50-fold) than those of FD, as a specific CES2 marker. Conversely, the K-m values were comparable suggesting the involvement of the same enzymes. Inhibition studies revealed that the FD hydrolysis was inhibited by bis-p-nitrophenylphosphate, phenylmethanesulfonyl fluoride, and loperamide (specific for CES2), whereas the pNPA and 4-MUA hydrolysis inhibition was limited. Inhibitors selective for other esterases missed having any effect on above-mentioned activities. In cytosol and microsomes of 20 lung samples, inter-individual variations were found for the hydrolysis of pNPA (2.5-5-fold), FD or 4-MUA (8-15-fold). Similar variations were also observed in CES1 and CES2 gene expression, although determined in a small number (n = 9) of lung samples. The identification of CES1 and CES2 and their variability in human lungs are important for drug metabolism and design of prodrugs which need to be activated in this organ.

Introduction Patients with lung cancer who harbor multiple pulmonary sites of disease have been challenging to classify; a subcommittee of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee was charged with developing proposals for the eighth edition of the tumor, node, and metastasis (TNM) classification to address this issue. Methods A systematic literature review and analysis of the International Association for the Study of Lung Cancer database was performed to develop proposals for revision in an iterative process involving multispecialty international input and review. Results Details of the evidence base are summarized in other articles. Four patterns of disease are recognized; the clinical presentation, pathologic correlates, and biologic behavior of these suggest specific applications of the TNM classification rules. First, it is proposed that second primary lung cancers be designated with a T, N, and M category for each tumor. Second, tumors with a separate tumor nodule of the same histologic type (either suspected or proved) should be classified according to the location of the separate nodule relative to the index tumor—T3 for a same-lobe, T4 for a same-side (different lobe), and M1a for an other-side location—with a single N and M category. Third, multiple tumors with prominent ground glass (imaging) or lepidic (histologic) features should be designated by the T category of the highest T lesion, the number or m in parentheses (#/m) to indicate the multiplicity, and a collective N and M category for all. Finally, it is proposed that diffuse pneumonic-type lung cancers be designated by size (or T3) if in one lobe, T4 if involving multiple same-side lobes, and M1a if involving both lungs with a single N and M category for all areas of involvement. Conclusion We propose to tailor TNM classification of multiple pulmonary sites of lung cancer to reflect the unique aspects of four different patterns of presentation. We hope that this will lead to more consistent classification and clarity in communication and facilitate further research in the nature and optimal treatment of these entities.

Introduction Soluble mesothelin related peptide (SMRP) was proposed as a promising diagnostic marker for malignant pleural mesothelioma (MPM). In a previous study, we found that rs1057147 within the 3′ untranslated region of MSLN gene was associated with SMRP levels. Thus, we aimed to (1) confirm the previous association on a large series of volunteers and (2) test the hypothesis that the SNP could affect microRNA binding sites. Methods The association analysis was verified in 759 subjects. Then, in silico predictions highlighted miR-611 and miR-887 as candidate miRNAs binding to the polymorphic site. Thus, chimeric constructs bearing the alternative alleles (G > A) were assayed alone or in cotransfection with the miRNA mimics, with dual luciferase reporter assay in non-MPM Met-5A cells. The miRNAs were also assayed by western blot analysis for their ability to down-regulate endogenous mesothelin in the MPM Mero-14 cell line. Results We confirmed that, among non-MPM volunteers, GG homozygotes have the lowest SMRP levels. When the genotype is taken into account, the specificity of SMRP as biomarker improves from 79.7% to 85.3%. Dual-luciferase assays showed a significantly lower reporter activity when the vector harbored the G allele as compared to A allele. miR-887 mimic caused a reduced reporter activity of vectors harboring A or G alleles, while miR-611 was effective only on the vector harboring the G allele. Transfection of these miRNAs into Mero-14 cells significantly reduced endogenous MSLN protein. Conclusion SMRP performance as diagnostic biomarker improved by considering the genotype rs1057147. This polymorphism most likely affects a binding site for miR-611.

Thymomas are neoplasms arising from the epithelial thymic cells, with a recurrence rate after complete resection ranging from 5 to 50%, according to the initial stage of disease. The pleura is the most frequent site of relapse, while distant metastases occur in less than 5% of the cases. Data in the literature show that recurrences can occur several years after the resection of a thymoma; unfortunately, few reports have analyzed the treatment of recurrences of thymoma. There is no standard treatment for the recurrent disease, and most of the treatments proposed by the authors are based more on their personal experience and individualized treatment than on an evidence-based method. Moreover, most series concerning surgery for recurrent thymomas suffer from a selection bias: patients with limited disease and better performance status are usually selected for surgery, with an anticipated survival advantage in the surgical group. Surgery for recurrent thymoma is indicated if complete resection is feasible, whereas in the case of predicted debulking surgery, it may be considered as part of a multidisciplinary protocol. In the literature, a few case reports of the surgical treatment of metachronous distant metastases to liver or brain from thymoma have been described, but they are really rare, and a decision about their treatment is always on a single patient basis. We can conclude that reoperation for thymoma recurrences is feasible and relatively safe, and it should always be considered because the other treatment modalities are not curative.

Tissue microarray technology allows the immediate evaluation of molecular profiles of numerous different tissues, with savings of money and time. It was created for rapid, large-scale molecular studies, and the main concern regarding its possible broad acceptance is that the analysis of tissue microarrays instead of whole tissue sections may lead to false negative or positive results because of tissue heterogeneity. In the present study, we analyzed in 54 small cell lung cancers, by immunohistochemistry, the expression of the antigen c-kit, which seems to be important in these neoplasms' tumorigenesis, and compared the staining obtained on whole sections with that of the corresponding tissue microarrays. Although c-kit expression of the whole sections agreed with that of the corresponding biopsies in many cases, the correlation between whole sections and all the companion nonlost single cores or their mean value turned out to be highly significant only if the 36 double negatives (ie, both whole sections and companion tissue microarrays negative) were included (P0.0001). In fact, if only cases positive to at least 1 of the tests (i.e. whole sections or corresponding tissue microarrays positive) were considered, the correlation was not significant (P=0.055). Tissue microarrays showed a good specificity (94.2% for all single cores and 92.3% for their mean value) but a rather poor sensitivity (respectively, 69.4% and 71.4%). Moreover, a high percentage (13.4%) of cores was lost, and this loss was not random. To sum up, in our experience, tissue microarray technology cannot be a substitute for whole sections in clinical diagnosis of individual cases.

The aim of this study was to investigate the expression of p53 and bcl2 proteins in a series of 107 non-small cell lung cancers (NSCLC), and to relate such protein expression to neovascularisation and the expression of vascular endothelial growth factor (VEGF). Moreover, we analysed the prognostic impact of these biological parameters on overall survival, both in univariate and multivariate analyses. An inverse association was found between bcl2 expression and microvessel count (MVC; P = 0.0004) and bcl2 and VEGF (P = 0.007). In contrast, a significant association was found between p53 expression and MVC (P = 0.03) and p53 and VEGF expression (P = 0.04). In univariate analysis, nodal status (P0.000001), MVC (P0.000001), bcl2 (P = 0.002), p53 (P = 0.03) and VEGF expression (P0.000001) significantly affected overall survival, but in multivariate analysis only MVC and VEGF expression retained their prognostic influence. Our results suggest that bcl2 and p53 possibly control the development of tumour angiogenesis in NSCLC, with putative mediation by VEGF. Moreover, the important influence of angiogenesis in the progression of NSCLC is further highlighted.

From June 1990 to December 1993, 36 patients were enrolled in a phase II study, aimed at determining the feasibility of surgery, patterns of disease recurrence and survival after neoajuvant chemotherapy in non-small cell lung cancer (NSCLC) stage IIIA-N2. Twenty-seven patients underwent invasive staging procedures (i.e. mediastinoscopy or needle biopsy). Two CHT schedules were used. Cisplatin (P) 90 mg/mq, day 1, mitomycin (M) 6 mg/mq, day 1, and vindesine (V) 5 mg/mq, days 1, 8, 15, were administered every 3 weeks for 3 cycles in the first 20 patients. The last 16 patients were treated with cisplatin (P) 90 mg/mq, day 1, mitomycin (M) 6 mg/mq, day 1, and vinorelbina 20 mg/mq, days 1, 8, 15. Thoracotomy was performed 15-20 days after haematological recovery in the objective-responders. Thirty-two patients were evaluable for response to CHT. The overall objective response (OR) rate was 78.1%. There were three complete (CR) (9.4%) and 22 partial responses (PR) (68.7%). The 25 patients with OR underwent radical surgery (16 pneumonectomies, one bilobectomy, seven lobectomies and one wedge resection). The only morbidity reported was a late broncho-pleural fistula (on post-operative day 37). There were three post-operative deaths in patients who underwent pneumonectomy: two due to an empyema following a broncho-pleural in fistula and one by pulmonary embolism. Histology was negative for the three CRs. Six patients with residual nodal involvement at surgery underwent radiotherapy. Relapse occurred in seven resected patients. Presently 14 patients are alive, all but one being disease-free, with a median follow-up of 30.5 months (15-47). Median survival was 31 months (5-47). Actuarial 3-year survival rate is 49%. Our results confirm the high response rate of CHT, as well as the feasibility and the overall low complication rate of both treatments (CHT and surgery).

Objectives The objectives of this collaborative study were to characterize patients with thymic carcinoma, their treatment patterns, and association with overall survival (OS) and recurrence-free survival (RFS). Methods Clinical, pathologic, treatment, and follow-up information were analyzed. OS and RFS were the primary outcome measures. Results In 1042 cases of thymic carcinoma, 42 (5%) patients had pathologic Masaoka stage I, 138 (17%) had stage II, 370 (45%) had stage III, and 274 (33%) had stage IV disease. Overall, 166 patients (22%) underwent induction chemotherapy and 48 (6%) had preoperative radiation therapy. An R0 resection was performed in 447 cases (61%), R1 in 102 cases (14%), and R2 in 184 cases (25%). Squamous cell carcinoma was the predominant histologic subtype (n = 560; 79%). Adjuvant chemotherapy was administered to 237 (31%) patients, and 449 (60%) received adjuvant radiation therapy. The median OS was 6.6 years (95% confidence interval [CI], 5.8-8.3) and the cumulative incidence of recurrence at 5 years was 35% (95% CI, 30%-40%). In univariate analysis, early Masaoka stage, R0 resection, chemotherapy, and radiation therapy were associated with OS. Early Masaoka stage and R0 resection were also associated with RFS. On multivariable analysis, R0 resection and radiation therapy were associated with prolonged OS. Radiation therapy and male gender were associated with prolonged RFS. Conclusions R0 resection and radiation therapy are associated with improved OS, whereas radiation therapy and male gender are associated with longer RFS.

Aim: To investigate the molecular aberrations of thymic epithelial tumors (TETs) which, currently, are largely unknown, hampering progress in diagnosis, prognostication and targeted therapy. Methods: Frozen tumor and normal blood were available for 28 TETs with a high proportion of cancer cell content (>80%). Exome capture was performed using Sure Select All Exon (Agilent) and TruSeq Exome Enrichment kit (Illumina) in 21 and 35 samples, respectively. Sequencing was performed using Genome Analyzer-II (Illumina) and HiSeq2000 (Illumina) in 21 and 35 samples, respectively. Reads were aligned using Novoalign (Novocraft) and somatic mutations were detected comparing exome sequencing of tumor and normal DNA of each patients using VarScan2. A single nucleotide missense mutation of GTF2I was the most common in TETs, and was confirmed in an independent cohort of 268 formalin fixed paraffin embedded TETs. Results: Thymic carcinomas had a higher number of mutations than thymomas with a mean of 43.5 and 17.4, respectively (p=0.001). In thymic carcinomas (11), genes with recurrent mutations included TP53 (4), CYLD (3), BAP1 (2), CDKN2A (2) and PBRM1 (2). A single nucleotide mutation of GTF2I (chr7:74146970T/A) was observed in 35% of thymomas (17). The mutation was missense (leucine to histidine), not previously described in cancer or as a polymorphism in dbSNP137 database. The mutation was predicted to alter the structure of the protein or its function according to Poliphen2 and SIFT algorithms. The presence of GTF2I mutation was confirmed in an extended cohort of 268 TETs: 82% of A (56), 74% of AB (54), 32% of B1 (28), 22% of B2 (32), 21% of B3 thymomas (62) and 8% of thymic carcinomas (36). The mutation was more frequent in stages I-II (57%) than in stages III-IV (19%; p Conclusions: GTF2I mutation is frequent in thymic epithelial tumors, especially in A-AB histotypes and is associated with a better outcome. Disclosure: All authors have declared no conflicts of interest.