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Background: Deep Neck Infections (DNIs) spread along fascial planes and involve neck spaces. Recently, their incidence has decreased due to the introduction of antibiotics; nevertheless, complications related to DNIs are often life-threatening. Objective: The purpose of this article is focused on the identification of predisposing factors of these complications, as well as on the development of a reliable therapeutic algorithm. Method: Sixty patients with DNIs were enrolled from 2006 to 2019 for a retrospective study. The exclusion criteria for the present study were cellulitis, small abscesses responding to empiric or specific antibiotic therapy, or involvement of only one deep neck space. During the analysis, the following parameters of interest have been evaluated: gender, age, site of origin, pathways of spread, comorbidities, clinical features, bacteriology data, type of surgical approach required, complications, duration of hospitalization and mortality rate. On admission, microbial swab analysis was performed. Results: Diabetes Mellitus (DM), Chronic Obstructive Pulmonary Disease (COPD), iron deficiency anemia and the involvement of multiple spaces have been associated with a significantly higher risk of developing complications. Most of our patients had polymicrobial infections. All patients underwent surgical drainage. The complication rate had occurred in 56.6% of patients, while death in 18.3%. Conclusion: DNIs represent a medical and surgical emergency with potentially serious complications; thus, avoidance of diagnostic delay is mandatory. Our preliminary data suggest the importance of evaluating the extent of infections because the involvement of multiple spaces requires timely surgery due to the higher risk of complications and mortality.

OBJECTIVES A significant gap in our knowledge of how to manage pulmonary ground-glass opacities (GGOs) still exists. Accordingly, there is a lack of consensus among clinicians on this topic. The Italian Society of Thoracic Surgery (Società Italiana di Chirurgia Toracica, SICT) promoted a national expert meeting to provide insightful guidance for clinical practice. Our goal was to publish herein the final consensus document from this conference. METHODS The working panel of the PNR group (Pulmonary Nodules Recommendation Group, a branch of the SICT) together with 5 scientific supervisors (nominated by the SICT) identified a jury of expert thoracic surgeons who organized a multidisciplinary meeting to propose specific statements (n = 29); 73 participants discussed and voted on statements using a modified Delphi process (repeated iterations of anonymous voting over 2 rounds with electronic support) requiring 70% agreement to reach consensus on a statement. RESULTS Consensus was reached on several critical points in GGO management, in particular on the definition of GGO, radiological and radiometabolic evaluation, indications for a non-surgical biopsy, GGO management based on radiological characteristics, surgical strategies (extension of pulmonary resection and lymphadenectomy) and radiological surveillance. A list of 29 statements was finally approved. CONCLUSIONS The participants at this national expert meeting analysed this challenging topic and provided a list of suggestions for health institutions and physicians with practical indications for GGO management.

Objectives CCDC6 (coiled-coil domain containing 6) is a player of the HR response to DNA damage and has been predicted to interact with BAP1, another HR-DNA repair gene highly mutated in Malignant Pleural Mesothelioma (MPM), an aggressive cancer with poor prognosis. CCDC6 levels are modulated by the deubiquitinase USP7, and CCDC6 defects have been reported in several tumors determining PARP-inhibitors sensitivity. Our aim was to investigate the functional role of CCDC6 in MPM carcinogenesis and response to PARP-inhibitors. Materials and Methods The interaction between CCDC6 and BAP1 was confirmed in MPM cells, by co-immunoprecipitation. Upon USP7 inhibition, that induces CCDC6 degradation, the ability to repair the DSBs and the sensitivity to PARP inhibitors, was explored by HR reporter and by cells viability assays, respectively. A TMA including 34 MPM cores was immunostained for CCDC6, USP7 and BAP1 and the results correlated by statistical analysis. Results MPM cells depleted of CCDC6 showed defects in DSBs repair and sensitivity to PARP inhibitors. The silencing of CCDC6 when combined with the overexpression of BAP1-mutant (Δ221-238) enhanced the HR-DNA repair defects and the PARP inhibitors sensitivity. In the TMA of MPM primary samples, the staining of CCDC6 and of its de-ubiquitinase USP7 showed a significant correlation in the tested primary samples (p = 0.01). CCDC6 was barely detected in 30% of the tumors that also carried BAP1 defects. Conclusion The combination of CCDC6 and BAP1 staining may indicate therapeutic options for DDR targeting, acting in synergism with cisplatinum.

Background: The natural history and the best modality of follow-up of atypical lung carcinoids (AC) remain ill defined. The aim of this study was to analyze recurrence-free survival (RFS) after complete resection (R0) of stage I-III pulmonary AC. Secondary objectives were prognostic parameters, the location of recurrences, and the modality of follow-up. Methods: A retrospective review of 540 charts of AC patients treated between 1998 and 2008 at 10 French and Italian centers with experience in lung neuroendocrine tumor management was undertaken. The exclusion criteria were MEN1-related tumor, history of another cancer, referral after tumor relapse, and being lost to follow-up. A central pathological review was performed in each country. Results: Sixty-two patients were included. After a median follow-up time of 91 months (mean 85, range 6-165), 35% of the patients experienced recurrence: 16% were regional recurrences and 19% were distant metastases. Median RFS was not reached. The 1-, 3-, and 5-year RFS rate was 90, 79, and 68%, respectively. In univariate analysis, lymph node involvement (p = 0.0001), stage (p = 0.0001), mitotic count (p = 0.004), and type of surgery (p = 0.043) were significantly associated with RFS. In multivariate analysis, lymph node involvement was significantly associated with RFS (HR 95% CI: 0.000-0.151; p = 0.004). During follow-up, somatostatin receptor scintigraphy, fibroscopy, and abdominal examination results were available for 22, 12, and 25 patients, respectively. The median time interval for imaging follow-up was 10 months. Conclusions: After complete resection of AC, recurrences were observed mostly within the first 5 years of follow-up, within bronchi, mediastinal nodes, the liver, and bones. In R0 patients, lymph node involvement could help to stratify follow-up intervals. Suboptimal imaging is evidenced.

Background Several gray areas and controversies exist concerning the management of pulmonary ground-glass opacities (GGOs), and there is a lack of consensus among clinicians on this topic. One of the main aims of the Italian Society of Thoracic Surgery is to promote education and research, so we decided to perform a survey on this topic to estimate current trends in practice in a large sample of thoracic surgeons. Methods A total of 160 thoracic surgeons responded, namely, completed our questionnaire (response rate, 53%; 160 of 302). The survey was composed of 36 questions divided into six subsections: (1) demographic characteristics of the respondents; (2) terminology and taxonomy; (3) radiologic and radiometabolic evaluation; (4) diagnostic approach and indications for surgery; (5) surgical management; and (6) radiologic surveillance. Results We observed some divergence of opinion regarding the definition of mixed GGOs, the role of 18F fluorodeoxyglucose positron emission tomography and computed tomography scans, indications for nonsurgical biopsy, intraoperative techniques for localizing GGOs, indications for surgery, extension of lung resection and lymph node dissection according to the radiologic scenario, use of intraoperative frozen section analysis, and radiologic surveillance of pure GGOs. Conclusions This topic warrants more investigation in the future. An upcoming consensus conference of Italian Society of Thoracic Surgery experts (also open to experts in other specialties) could provide updated indications for GGO management based on the literature, expert opinions, and the results of the present survey.

Lung cancer is the most common cancer worldwide. Disappointingly, despite great effort in encouraging screening or, at least, a close surveillance of high-risk individuals, most of lung cancers are diagnosed when already surgically unresectable because of local advancement or metastasis. In these cases, the treatment of choice is chemotherapy, alone or in combination with radiotherapy. Here, we will briefly review the most successful and recent advances in the identification of novel lung cancer genetic lesions and in the development of new drugs specifically targeting them. However, lung cancer is still the leading cause of cancer-related mortality also because, despite impressive initial responses, the patients often develop resistance to novel target therapies after a few months of treatment. Thus, it is literally vital to continue the search for new therapeutic options. So, here, on the basis of our recent findings on the role of the tumor suppressor CCDC6 protein in lung tumorigenesis, we will also discuss novel therapeutic approaches we envision for lung cancer.

Objectives CCDC6 gene product is a tumor-suppressor pro-apoptotic protein, substrate of ATM, involved in DNA damage response and repair. Altered levels of CCDC6 expression are dependent on post-translational modifications, being the de-ubiquitinating enzyme USP7 responsible of the fine tuning of the CCDC6 stability. Thus, our aim was to investigate CCDC6 and USP7 expression levels in Lung-Neuroendocrine Tumors (L-NETs) to verify if they correlate and may be exploited as novel predictive therapeutic markers. Materials and methods Tumor tissues from 29 L-NET patients were investigated on tissue microarrays. CCDC6 levels were scored and correlated with immunoreactivity for USP7. Next generation sequencing (NGS) of a homogenous group of Large Cell Neuroendocrine Carcinoma (LCNEC) (N=8) was performed by Ion AmpliSeq NGS platform and the Ion AmpliSeq Cancer Hotspot Panel v2. The inhibition of USP7, using P5091, was assayed in vitro to accelerate CCDC6 turnover in order to sensitize the neuroendocrine cancer cells to PARP-inhibitors, alone or in association with cisplatinum. Results The immunostaining of 29 primary L-NETs showed that the intensity of CCDC6 staining correlated with the levels of USP7 expression (p≤0.05). The NGS analysis of 8 LCNEC revealed mutations in the hot spot regions of the p53 gene (in 6 out of 8). Moreover, gene polymorphisms were identified in the druggable STK11, MET and ALK genes. High intensity of p53 immunostaining was reported in the 6 tissues carrying the TP53 mutations. The inhibition of USP7 by P5091 accelerated the degradation of CCDC6 versus control in cycloheximide treated L-NET cells in vitro and sensitized the cells to PARP-inhibitors alone and in combination with cisplatinum. Conclusion Our data suggest that CCDC6 and USP7 have a predictive value for the clinical usage of USP7 inhibitors in combination with the PARP-inhibitors in L-NET in addition to standard therapy.

Endobronchial carcinoids may recur even if radically resected. This retrospective study investigates the clinical and prognostic relevance of lymph node micrometastasis in these neoplasms.Fifty-five patients underwent standard anatomic resection (lobectomy or pneumonectomy) with systematic routine (hilar and mediastinal) lymphadenectomy. After an evaluation of conventional prognostic factors, we reanalyzed lymph nodes of pN0 patients for micrometastasis using immunohistochemistry (anti-cytokeratin AE1/AE3 and anti-chromogranin A antibodies).We performed 9 pneumonectomies, 41 lobectomies, and 5 bilobectomies. Histologic examination showed 47 (85%) typical carcinoid and 8 (14.5%) atypical. Twelve patients were pN1 (8 typical, 4 atypical); after reanalysis another 8 revealed micrometastasis, 6 N1 micrometastasis (5 typical, 1 atypical), and 2 N2 micrometastasis (2 atypical), increasing subjects with nodal involvement (pN1 and N micrometastasis) from 12 (21.8%) to 20 (36.4%; p = 0.01). Micrometastases were more frequent in atypical carcinoids (p = 0.002). Local recurrence developed in 3 (5.4%) patients: 2 pN1 (1 typical, 1 atypical) and 1 N1-micrometastasis (1 typical). Distant relapse occurred in 2 (3.6%) patients, both N2 micrometastasis (2 atypical). After reanalysis, recurrence rate in patients with nodal disease increased from 16.7% to 25% (p = 0.01). All patients with recurrence died: all had pN1 or N micrometastasis. No patient confirmed as N0 had recurrence. Only histologic pattern and node status significantly influenced disease-free (p = 0.002 and p = 0.05) and overall survivals (p = 0.02 and p0.001), respectively. Micrometastasis worsen both disease-free (p0.0001) and overall (p0.001) survival rates at 5 and 10 years.Routine systematic lymphadenectomy with immunohistochemical detection of lymph node micrometastasis contributes to identification of a larger population at risk with a higher recurrence rate, allowing a more accurate staging of endobronchial carcinoids.

// Francesco Morra 1,2,* , Chiara Luise 1,* , Francesco Merolla 1,3 , Ina Poser 4 , Roberta Visconti 1 , Gennaro Ilardi 3 , Simona Paladino 2 , Hiroyuki Inuzuka 5 , Gianluca Guggino 6 , Roberto Monaco 7 , David Colecchia 8 , Guglielmo Monaco 6 , Aniello Cerrato 1 , Mario Chiariello 8 , Krista Denning 9 , Pier Paolo Claudio 10 , Stefania Staibano 3 and Angela Celetti 1 1 Istituto per l’Endocrinologia e l’Oncologia Sperimentale “Gaetano Salvatore”, CNR, Napoli, Italy 2 Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Universita Federico II, Napoli, Italy 3 Dipartimento di Scienze Biomediche Avanzate, Universita Federico II, Napoli, Italy 4 Max Plank Institute, MPI-CBG Dresden, Germany 5 Harvard Medical School, Beth Israel Deaconess Medical Center, MA, USA 6 UOC Chirurgia Toracica, Azienda Ospedaliera di Rilievo Nazionale “A.Cardarelli”, Napoli, Italy 7 UOC Anatomia Patologica, Azienda Ospedaliera di Rilievo Nazionale “A.Cardarelli”, Napoli, Italy 8 Istituto Toscano Tumori, Core Research Laboratory, Siena, Italy 9 Department of Pathology, Joan C. Edwards Cancer Center, Huntington, WV, USA 10 Department of Biochemistry and Microbiology & Dept. of Surgery, Marshall University, Joan C. Edwards Cancer Center, Huntington, WV, USA * These authors have contributed equally to this work Correspondence to: Angela Celetti, email: // Keywords : CCDC6, FBXW7, USP7, mitotic kinases, cisplatinum Received : January 20, 2015 Accepted : March 03, 2015 Published : March 30, 2015 Abstract CCDC6 gene product is a pro-apoptotic protein substrate of ATM, whose loss or inactivation enhances tumour progression. In primary tumours, the impaired function of CCDC6 protein has been ascribed to CCDC6 rearrangements and to somatic mutations in several neoplasia. Recently, low levels of CCDC6 protein, in NSCLC, have been correlated with tumor prognosis. However, the mechanisms responsible for the variable levels of CCDC6 in primary tumors have not been described yet. We show that CCDC6 turnover is regulated in a cell cycle dependent manner. CCDC6 undergoes a cyclic variation in the phosphorylated status and in protein levels that peak at G2 and decrease in mitosis. The reduced stability of CCDC6 in the M phase is dependent on mitotic kinases and on degron motifs that are present in CCDC6 and direct the recruitment of CCDC6 to the FBXW7 E3 Ubl. The de-ubiquitinase enzyme USP7 appears responsible of the fine tuning of the CCDC6 stability, affecting cells behaviour and drug response. Thus, we propose that the amount of CCDC6 protein in primary tumors, as reported in lung, may depend on the impairment of the CCDC6 turnover due to altered protein-protein interaction and post-translational modifications and may be critical in optimizing personalized therapy.

Non-small cell lung cancer (NSCLC) is the main cause of cancer-related death worldwide and new therapeutic strategies are urgently needed. In this study, we have characterized a panel of NSC lung cancer cell lines for the expression of coiled-coil-domain containing 6 (CCDC6), a tumor suppressor gene involved in apoptosis and DNA damage response. We show that low CCDC6 protein levels are associated with a weak response to DNA damage and a low number of Rad51 positive foci. Moreover, CCDC6 deficient lung cancer cells show defects in DNA repair via homologous recombination. In accordance with its role in the DNA damage response, CCDC6 attenuation confers resistance to cisplatinum, the current treatment of choice for NSCLC, but sensitizes the cells to olaparib, a small molecule inhibitor of the repair enzymes PARP1/2. Remarkably, the combination of the two drugs is more effective than each agent individually, as demonstrated by a combination index1. Finally, CCDC6 is expressed at low levels in about 30% of the NSCL tumors we analyzed by TMA immunostaining. The weak CCDC6 protein staining is significatively correlated with the presence of lymph node metastasis (p ≤ 0.02) and negatively correlated to the disease free survival (p ≤ 0.01) and the overall survival (p ≤ 0.05). Collectively, the data indicate that CCDC6 levels provide valuable insight for OS. CCDC6 could represent a predictive biomarker of resistance to conventional single mode therapy and yield insight on tumor sensitivity to PARP inhibitors in NSCLC.

Objective: Analysis of a single institution experience with completion pneumonectomy. Methods: From 1989 to 2002, 55 consecutive cancer patients received completion pneumonectomy (mean age 62 years; 25 – 79). Indications were bronchogenic carcinoma in 38 patients (4 first cancers, 8 recurrent cancers, 26 second cancers), lung metastases in three (one each from breast cancer, colorectal neoplasm and lung cancer), lung sarcoma in one, and miscellaneous non-malignant conditions in 13 patients having been surgically treated for a non-small cell lung cancer previously (bronchopleural fistula in 4, radionecrosis in 3, aspergilloma in 2, pachypleura in 1, massive hemoptysis in 1 and pneumonia in 2). Before completion pneumonectomy, 50 patients had had a lobectomy, three a bilobectomy, and two lesser resections. The mean interval between the two procedures was 51 months for the whole group (1 – 469), 60 months for lung cancer (12 –469), 43 months for pulmonary metastases (21– 59) and 29 months for non-malignant disorders (1 – 126). Results: There were 35 right (64%) and 20 left (36%) resections. The surgical approaches were a posterolateral thoracotomy in 50 cases (91%) and a lateral thoracotomy in five cases (9%). Intrapericardial route was used in 49 patients (89%). Five patients had an extended resection (2 chest wall, 1 diaphragm, 1 subclavian artery and 1 superior vena cava). Operative mortality was 16.4% (n ¼ 9): 11.9% for malignant disease ðn ¼ 5Þ and 30.8% for benign disease ðn ¼ 4Þ: Operative mortality was 20% for right completion pneumonectomies ðn ¼ 7Þ and 10% for left-sided procedures ðn ¼ 2Þ: Twentythree patients (42%) experienced non-fatal major complications. Actuarial 3- and 5-year survival rates from the time of completion pneumonectomy were 48.4 and 35.2% for the entire group. Three- and five-year survival for patients with bronchogenic carcinoma were 56.9 and 43.4%, respectively. Conclusions: These results suggest that completion pneumonectomy in the setting of lung malignancies can be done with an operative risk similar to the one reported for standard pneumonectomy. In contrast, in cancer patients, completion pneumonectomy for inflammatory disorders is a very high-risk procedure. q 2003 Elsevier B.V. All rights reserved.