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Mediastinitis secondary to esophageal perforation is a rare, progressive, and destructive disease that may often lead to an imminent risk of death. We describe a single center experience showing how early diagnosis and prompt intervention can reduce mortality and complications. Methods From February 2016 to December 2019, 15 consecutive patients were referred to the Emergency Unit of The AORN Cardarelli (Naples) with clinical and radiological (CT scan) diagnosis of acute mediastinitis secondary to oesophageal perforation (post endoscopy or after foreign body ingestion) and furthermore, referred to the Thoracic Surgery Unit, they underwent to early surgical treatment (cervicotomy and\or thoracotomy and chest drainage. Results For early detected case (occurred within 24 hours) an emergency thoracotomy/cervicotomy was performed with surgical repair. For late detected (referred from other hospitals) a Surgical esclusion (abdominal plus cervical) and toilette thoracotomy was performed in emergency. Reconstruction occurred in 5 cases with a median of 46 days after firts care. All patient were admitted to ICU unit and susbsequentily to the thoracic surgery ward. 30 days mortality occurred in two cases. Median hospital staying was 28 days, in six cases a redo surgery was necessary. Empiric antibiotic treatment was started before operation and reviewed under Infectivologist. Conclusion Mediastinitis secondary to esophageal perforation has a fulminating course with a potential risk of sepsis, pericarditis, and multiple organ failure. A prompt identification and an invasive treatment is the best and most successful option to reduce mortality and improve patient’s recovery.

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.

Major adverse cardiac events, defined as death or myocardial infarction, are common causes of perioperative mortality and major morbidity in patients undergoing non-cardiac surgery. Reduction of perioperative cardiovascular risk in relation to non-cardiac surgery requires a stepwise patient evaluation that integrates clinical risk factors, functional status and the estimated stress of the planned surgical procedure. Major guidelines on preoperative cardiovascular risk assessment recommend to establish, firstly, the risk of surgery per se (low, moderate, high) and the related timing (elective vs. urgent/emergent), evaluate the presence of unstable cardiac conditions or a recent coronary revascularization (percutaneous coronary intervention or coronary artery bypass grafting), assess the functional capacity of the patient (usually expressed in metabolic equivalents), determine the value of non-invasive and/or invasive cardiovascular testing and then combine these data in estimating perioperative risk for major cardiac adverse events using validated scores (Revised Cardiac Risk Index (RCRI) or National Surgical Quality Improvement Program (NSQIP)). This stepwise approach has the potential to guide clinicians in determining which patients could benefit from cardiovascular therapy and/or coronary artery revascularization before non-cardiac surgery towards decreasing the incidence of perioperative morbidity and mortality. Finally, it should be highlighted that there is a need to implement specific strategies in the 2019 Coronavirus disease (COVID-19) pandemic to minimize the risk of transmission of COVID-19 infection during the preoperative risk assessment process.

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.

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.

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 index

8566 Background: Thymic epithelial tumors (TETs) are rare thoracic malignancies. Widely recognized as different histopathological entities, thymoma (T) and thymic carcinoma (TC), show a different biological behavior with a higher tendency to hematogenous dissemination for TC and thoracic recurrence for T, sharing, however, a poor prognosis when characterized by high tumor burden. Up to date, there are no specific biomarkers for monitoring the biological course of these rare tumors. Analysis of circulating cell-free DNA (cfDNA) has potential applications throughout the natural course of cancer development, diagnosis and treatment, never the less several studies have suggested that cfDNA levels closely parallel overall tumor burden. For the first time the detection and the correlation of cfDNA levels with tumor burden and histological subtype of TET, has been carried on in this monocentric study. Methods: Starting from July 2018, serum samples from 19 patients with TET, 4 with completely resected TET (rTET) and 15 with advanced (aTET), were prospectively obtained before the initiation of therapy. Serum samples from 15 healthy donors were used as control. Five ml of blood was collected and processed within one hour or less, followed by centrifugation at 3000g for 10 minutes and storage at -80°C. The serum samples were processed for QiAamp MinElute cell-free DNA mini kit extraction (Qiagen). cfDNA quantification was assessed using Qubit Fluorometric Quantitation (Thermo Fisher Scientific). Clinical, and histo-pathological features of TET were assessed. Results: A median cfDNA amount in healthy donors of 0.108 ng/µl (0.083-0.868) was registered. A median cfDNA of 0.512 ng/µl (0.178-1.42) resulted for the rTET, including the value of 0.178 for the resected TC. A median cfDNA of 2.53 ng/µl (1.20-6.11) resulted for the aTET, with respectively a median of 2.845 ng/µl (1.3-5.24) and of 1.5 ng/µl (1.2-6.11) for TC and T. The highest registered level for both group of thymoma (6.11 ng/µl) and thymic carcinoma (5.24 ng/µl) correlates with the highest tumor burden. Conclusions: To the best of our knowledge, this is the first study that explore detection and quantification of cfDNA in TET. Higher baseline levels than the control group and the rTET group have been registered for both advanced T and TC. Highest levels of cfDNA may be associated with high tumor burden despite the histological subtype. We envision that further valuable information will be obtained with mutational analysis.

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.

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.