Thymic Epithelial Tumors phenotype relies on miR-145-5p epigenetic regulation.

BACKGROUND: Thymoma and thymic carcinoma are the most frequent subtypes of thymic epithelial tumors (TETs). A relevant advance in TET management could derive from a deeper molecular characterization of these neoplasms. We previously identified a set of microRNA (miRNAs) differentially expressed in TETs and normal thymic tissues and among the most significantly deregulated we described the down-regulation of miR-145-5p in TET. Here we describe the mRNAs diversely regulated in TETs and analyze the correlation between these and the miRNAs previously identified, focusing in particular on miR-145-5p. Then, we examine the functional role of miR-145-5p in TETs and its epigenetic transcriptional regulation. METHODS: mRNAs expression profiling of a cohort of fresh frozen TETs and normal tissues was performed by microarray analysis. MiR-145-5p role in TETs was evaluated in vitro, modulating its expression in a Thymic Carcinoma (TC1889) cell line. Epigenetic transcriptional regulation of miR-145-5p was examined by treating the TC1889 cell line with the HDAC inhibitor Valproic Acid (VPA). RESULTS: Starting from the identification of a 69-gene signature of miR-145-5p putative target mRNAs, whose expression was inversely correlated to that of miR-145-5p, we followed the expression of some of them in vitro upon overexpression of miR-145-5p; we observed that this resulted in the down-regulation of the target genes, impacting on TETs cancerous phenotype. We also found that VPA treatment of TC1889 cells led to miR-145-5p up-regulation and concomitant down-regulation of miR-145-5p target genes and exhibited antitumor effects, as indicated by the induction of cell cycle arrest and by the reduction of cell viability, colony forming ability and migration capability. The importance of miR-145-5p up-regulation mediated by VPA is evidenced by the fact that hampering miR-145-5p activity by a LNA inhibitor reduced the impact of VPA treatment on cell viability and colony forming ability of TET cells. Finally, we observed that VPA was also able to enhance the response of TET cells to cisplatin and erlotinib. CONCLUSIONS: Altogether our results suggest that the epigenetic regulation of miR-145-5p expression, as well as the modulation of its functional targets, could be relevant players in tumor progression and treatment response in TETs.

Correlation between collateral ventilation and interlobar lung fissures.

BACKGROUND: New bronchoscopic techniques for end-stage emphysema treatment are nowadays available; the presence of interlobar collateral ventilation (CV) and interlobar lung fissures (ILF) is crucial for patient selection. OBJECTIVES: Assessment of these variables has been reported previously, but it has never been anatomically validated in vivo. This is the purpose of our study. METHODS: Twenty-one patients undergoing lung resection for lung cancer were prospectively enrolled in this study. At operation, CV was assessed by the Chartis catheter system. ILF completeness at high-resolution computed tomography (HRCT) was retrospectively reviewed. The ILF status at HRCT and at surgery was compared; furthermore, the relationship between CV and ILF status was assessed. RESULTS: At HRCT, ILF were incomplete in 18 cases; at catheter evaluation, CV was present in 11 cases; 15 patients had incomplete ILF at operation. HRCT specificity, sensitivity and accuracy were 33, 93 and 76% compared with ILF status at surgery. HRCT accuracy was 90% on the right and 63% on the left. We demonstrated a high grade of probability of CV presence and incomplete ILF at surgery (odds ratio = 10.0). CONCLUSIONS: There is a correlation between ILF status and CV. Both catheter evaluation of CV and HRCT assessment of ILF show some limitations. However, the cumulative information provided by these techniques allows to reliably assess the anatomical ILF status.

Lung Cancer Surgery in Octogenarians: Implications and Advantages of Artificial Intelligence in the Preoperative Assessment.

The general world population is aging and patients are often diagnosed with early-stage lung cancer at an advanced age. Several studies have shown that age is not itself a contraindication for lung cancer surgery, and therefore, more and more octogenarians with early-stage lung cancer are undergoing surgery with curative intent. However, octogenarians present some peculiarities that make surgical treatment more challenging, so an accurate preoperative selection is mandatory. In recent years, new artificial intelligence techniques have spread worldwide in the diagnosis, treatment, and therapy of lung cancer, with increasing clinical applications. However, there is still no evidence coming out from trials specifically designed to assess the potential of artificial intelligence in the preoperative evaluation of octogenarian patients. The aim of this narrative review is to investigate, through the analysis of the available international literature, the advantages and implications that these tools may have in the preoperative assessment of this particular category of frail patients. In fact, these tools could represent an important support in the decision-making process, especially in octogenarian patients in whom the diagnostic and therapeutic options are often questionable. However, these technologies are still developing, and a strict human-led process is mandatory.

A multicentric evaluation of pediatric lung transplantation in Italy.

BACKGROUND: Pediatric lung transplantation is performed in highly experienced centers due to the peculiar population characteristics. The literature is limited and not representative of individual countries' differences. The purpose of this study was to analyze the Italian experience. METHODS: A multicentric retrospective analysis was performed on 110 pediatric patients (<18 years old) who underwent lung transplantation from 1992 to 2019 at 9 Italian centers. Heart-lung transplantations and lung retransplantations were excluded. RESULTS: The population was composed of 44 male and 66 female patients, with a median age of 15 years. The most frequent indication was cystic fibrosis (83%). One quarter of patients were transplanted in an emergency setting. Median donors' Oto score and age were 1 and 15 years, respectively, with 43% of adult donors. In 17% of patients a graft reduction was performed. Postoperatively, the median duration of mechanical ventilation, intensive care unit, and in-hospital stay were 48 hours, 11 and 35 days, respectively. Thirty-day mortality was 6%, and 1-, 5-, and 10-year survival was 72%, 52%, and 33%, respectively. Risk factors for mortality were Oto score and recipients' body mass index. CONCLUSIONS: The outcomes of pediatric lung transplantation in Italy are comparable with current literature. Particular attention should be paid to the Oto score and recipient body mass index. Conversely, adult donors and graft reductions can be safely used to expand the donor pool.

Long-term follow-up after bronchoscopic lung volume reduction in patients with emphysema.

Bronchoscopic lung volume reduction (BLVR) is a novel emphysema therapy. We evaluated long-term outcome in patients with heterogeneous emphysema undergoing BLVR with one-way valves. 40 patients undergoing unilateral BLVR entered our study. Pre-operative mean forced expiratory volume in 1 s (FEV(1)) was 0.88 L · s(-1) (23%), total lung capacity was 7.45 L (121%), intrathoracic gas volume was 6 L (174%), residual volume (RV) was 5.2 L (232%), and the 6-min walk test (6MWT) was 286 m. All patients required supplemental oxygen; the Medical Research Council (MRC) dyspnoea score was 3.9. High-resolution computed tomography (HRCT) results were reviewed to assess the presence of interlobar fissures. 33 patients had a follow-up of >12 months (median 32 months). 37.5% of the patients had visible interlobar fissures. 40% of the patients died during follow-up. Three patients were transplanted and one underwent lung volume reduction surgery. Supplemental oxygen, FEV(1), RV, 6MWT and MRC score showed a statistically significant improvement (p ≤ 0.0001, p = 0.004, p = 0.03, p = 0.003 and p<0.0001, respectively). Patients with visible fissures had a functional advantage. BLVR is feasible and safe. Long-term sustained improvements can be achieved. HRCT-visible interlobar fissures are a favourable prognostic factor.

A challenging upper digestive tract continuity restoration after recurrent esophago-colonic anastomosis complications.

BACKGROUND: Acute and chronic complications in esophago-colonic anastomosis have a significant impact in the postoperative course of patients with colonic transposition. Evidence about their management is poor and surgical treatment is mostly based on tailored approaches, so each new experience could be useful to improve knowledge about this peculiar condition. We report a unique case of an esophago-colonic resection and re-anastomosis without sternal approximation after recurrent anastomosis failure and strictures. CASE PRESENTATION: A 69-year-old woman was referred to our hospital for worsening dysphagia. The patient had undergone esophago-gastrectomy with right colon interposition 12 years prior due to caustic ingestion. The esophago-colonic anastomosis was initially complicated by an enterocutaneous fistula, which was treated with anastomosis resection and left colon transposition. This was then further complicated by dehiscence and sternal infection treated with resection of the distal portion of the sternum and a new colo-jejunal anastomosis. Finally, a chronic anastomotic stricture occurred, refractory to endoscopic dilatation and prothesis positioning. We planned a new colonic-esophageal resection and re-anastomosis. The main technical challenges were addressing the adhesions resulting from previous surgery and mobilizing an adequate length of the intestinal tract to allow conduit continuity restoration. Blood supply was assessed through Indocyanine Green Fluorescence. To avoid compression of the digestive conduit sternal margins were not re-approximated, and the transposed tube was covered and protected using both pectoralis major muscles flap. We decided to avoid the use of any prosthetic material to reduce the risk of infection. The patient was able to resume oral food intake on the 12th day postoperatively after a barium swallowing test showed an adequate conduit caliber. CONCLUSION: Esophago-colonic anastomosis complications represent a life-threatening condition. Therefore, reports and sharing of knowledge are important to improve expertise in management of these conditions.

Intraoperative use of extracorporeal CO2 removal (ECCO2R) and emergency ECMO requirement in patients undergoing lung transplant: a case-matched cohort retrospective study.

BACKGROUND: The use of extracorporeal carbon dioxide removal (ECCO2R) is less invasive than extracorporeal membrane oxygenation (ECMO), and intraoperative control of gas exchange could be feasible. The aim of this study in intermediate intraoperative severity patients undergoing LT was to assess the role of intraoperative ECCO2R on emergency ECMO requirement in patients. METHODS: Thirty-eight consecutive patients undergoing lung transplantation (LT) with "intermediate" intraoperative severity in the intervals 2007 to 2010 or 2011 to 2014 were analyzed as historical comparison of case-matched cohort retrospective study. The "intermediate" intraoperative severity was defined as the development of intraoperative severe respiratory acidosis with maintained oxygenation function (i.e., pH <7.25, PaCO2 >60 mmHg, and PaO2/FiO2 >150), not associated with hemodynamic instability. Of these 38 patients, twenty-three patients were treated in the 2007-2010 interval by receiving "standard intraoperative treatment," while 15 patients were treated in the 2011-2014 interval by receiving "standard intraoperative treatment + ECCO2R." RESULTS: ECMO requirement was more frequent among patients that received "standard intraoperative treatment" alone than in those treated with "standard intraoperative treatment + ECCO2R" (17/23 vs. 3/15; p = 0.004). The use of ECCO2R improved pH and PaCO2 while mean pulmonary artery pressure (mPAP) decreased. CONCLUSION: In intermediate intraoperative severity patients, the use of ECCO2R reduces the ECMO requirement.

Coaxial Drainage versus Standard Chest Tube after Pulmonary Lobectomy: A Randomized Controlled Study.

Chest tubes are routinely inserted after thoracic surgery procedures in different sizes and numbers. The aim of this study is to assess the efficacy of Smart Drain Coaxial drainage compared with two standard chest tubes in patients undergoing thoracotomy for pulmonary lobectomy. Ninety-eight patients (57 males and 41 females, mean age 68.3 ± 7.4 years) with lung cancer undergoing open pulmonary lobectomy were randomized in two groups: 50 received one upper 28-Fr and one lower 32-Fr standard chest tube (ST group) and 48 received one 28-Fr Smart Drain Coaxial tube (SDC group). Hospitalization, quantity of fluid output, air leaks, radiograph findings, pain control and costs were assessed. SDC group showed shorter hospitalization (7.3 vs. 6.1 days, p = 0.02), lower pain in postoperative day-1 (p = 0.02) and a lower use of analgesic drugs (p = 0.04). Pleural effusion drainage was lower in SDC group in the first postoperative day (median 400.0 ± 200.0 mL vs. 450.0 ± 193.8 mL, p = 0.04) and as a mean of first three PODs (median 325.0 ± 137.5 mL vs. 362.5 ± 96.7 mL, p = 0.01). No difference in terms of fluid retention, residual pleural space, subcutaneous emphysema and complications after chest tubes removal was found. In conclusion, Smart Drain Coaxial chest tube seems a feasible option after thoracotomy for pulmonary lobectomy. The SDC group showed a shorter hospitalization and decreased analgesic drugs use and, thus, a reduction of costs.

Prognostic impact of spread through air spaces in lung adenocarcinoma.

OBJECTIVE: Spread through air spaces (STAS) is a pattern of invasion present in some adenocarcinomas (ADC). The goal of this study was to assess the impact of STAS in patients treated with different types of surgical resections and on the clinical outcome in patients with ADC of different diameters and with different degrees of nodal involvement. METHODS: A total of 109 patients were reviewed. Complete surgical resection with systematic nodal dissection was achieved in all patients. The median follow-up was 65 months (3-90 months). RESULTS: STAS was observed in 70 cases (64.2%); 13 patients (18.5%) had lymph node involvement (N1 and N2). Overall survival and progression-free survival were higher in patients without STAS (P = 0.042; P = 0.027). The presence of STAS in tumours ≤2 cm was a predictor of worse progression-free survival following sublobar resection compared to major resections (P = 0.011). Sublobar resection of N0 STAS-positive tumours was associated with worse long-term survival compared to a major resection (P = 0.04). Statistical analyses showed that age >70 years and recurrence were independent variables for survival; smoking pack-years >20, sublobar resection and nodal involvement were independent variables for recurrence; and smoking pack-years >20 were independent variables for a history of cancer and pleural invasion for local recurrence. CONCLUSIONS: STAS seems to play a role in long-term survival, particularly for patients with N0 and tumours smaller than 2 cm. Further studies are necessary to validate this hypothesis.

METTL3-dependent MALAT1 delocalization drives c-Myc induction in thymic epithelial tumors.

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

Comparison of preoperative scores predicting outcome in elderly undergoing lung malignancies resection.

BACKGROUND: Increased age of cancer patients is not an absolute contraindication to pulmonary resection. Different scores have been developed to determine the risk of morbidity and mortality. We have compared four scores in a series of elderly patients with primary or metastatic lung neoplasms who underwent pulmonary resection. METHODS: Data from 150 patients with an age equal or more than 75 years were reviewed. Mean age was 78.3 (range, 75-86) years. Based on medical history and preoperative tests 4 predicting scores were calculated. Statistical analysis was performed to identify which score correlates better with postoperative morbidity and mortality. RESULTS: Mortality at 30 days was observed in 3 patients (2%). Postoperative morbidity was observed in 38 patients (25.3%). Univariate analysis showed that risk factors significantly predicting the onset of postoperative complications were type of resection (P=0.02), American Society of Anesthesiology (ASA) score (P<0.001) and Glasgow Prognostic Score (GPS) (P=0.02). At multivariate analysis smoking and type of resection were significant prognostic factors for both overall and pulmonary morbidity; the ASA score and GPS showed an impact only on overall morbidity. The Cox regression showed significant results for GPS greater than zero and cancer-related death. Age above 80 years was not a negative prognostic factor. A significant difference in terms of 1-year survival was noted in ASA I-II vs. ASA III-IV (90% vs. 78%; P=0.022) and GPS 0 vs. GPS 1 or 2 (90% vs. 77%; P=0.02). CONCLUSIONS: Prognostic scores are useful to predict postoperative morbidity and mortality and GPS seems to correlate better with them.

Use of Ceftazidime-Avibactam and Ceftolozane-Tazobactam After Lung Transplantation.

INTRODUCTION: After lung transplantation (LTx), infections caused by multidrug-resistant (MDR) bacteria are frequent and difficult to treat. Some new antibiotics seem to be effective in treating these infections. MATERIAL AND METHODS: We describe our experience in treatment of Klebsiella pneumoniae MDR and Pseudomonas aeruginosa MDR infections with ceftazidime-avibactam (CEF-AVI) and ceftazidime-tazobactam (CEFT-TAZ) in patients who underwent LTx. RESULTS: In 3 patients who underwent double LTx and in 4 patients who underwent single LTx, strains of K. pneumoniae and P. aeruginosa were isolated from bronchoalveolar lavage. All patients showed worsening of respiratory functions, increasing in inflammation indexes, and, in some cases, onset of pulmonary consolidation. P. aeruginosa was treated with CEFT-TAZ for 10 days average (7-15 days) and K. pneumoniae with CEF-AVI for 14 days average (4-24 days). One patient developed a septic state caused by K. pneumoniae, requiring 24 days of therapy. None had shown side effects caused by drugs administration. One patient died after 15 days from lung transplant owing to primary graft dysfunction. CONCLUSIONS: CEF-AVI and CEFT-TAZ seems to be effective in treatment of infections caused by MDR bacteria after lung transplant.

LINC00174 is a novel prognostic factor in thymic epithelial tumors involved in cell migration and lipid metabolism.

Long non-coding RNAs are emerging as new molecular players involved in many biological processes, such as proliferation, apoptosis, cell cycle, migration, and differentiation. Their aberrant expression has been reported in variety of diseases. The aim of this study is the identification and functional characterization of clinically relevant lncRNAs responsible for the inhibition of miR-145-5p, a key tumor suppressor in thymic epithelial tumors (TETs). Starting from gene expression analysis by microarray in a cohort of fresh frozen thymic tumors and normal tissues, we identified LINC00174 as upregulated in TET. Interestingly, LINC00174 expression is positively correlated with a 5-genes signature in TETs. Survival analyses, performed on the TCGA dataset, showed that LINC00174 and its associated 5-genes signature are prognostic in TETs. Specifically, we show that LINC00174 favors the expression of SYBU, FEM1B, and SCD5 genes by sponging miR-145-5p, a well-known tumor suppressor microRNA downregulated in a variety of tumors, included TETs. Functionally, LINC00174 impacts on cell migration and lipid metabolism. Specifically, SCD5, one of the LINC00174-associated genes, is implicated in the control of lipid metabolism and promotes thymic cancer cells migration. Our study highlights that LINC00174 and its associated gene signature are relevant prognostic indicators in TETs. Of note, we here show that a key controller of lipid metabolism, SCD5, augments the migration ability of TET cells, creating a link between lipids and motility, and highlighting these pathways as relevant targets for the development of novel therapeutic approaches for TET.

Antibiotic and Anticoagulation Therapy in Lemierre's Syndrome: Case Report and Review.

Lemierre's syndrome is a rare and fatal disease and is also known as the forgotten disease to describe the rarity of this syndrome in the antibiotic era. However, in the last 20 years, the incidence of this disease has been increasing. Authors report a case of Lemierre's syndrome with extensive venous thrombosis involving right internal jugular veins with extension to the sigmoid and lateral sinus and also review the literature on the use of anticoagulant therapy in Lemierre's syndrome. A computerized Medline study was carried out through the use of PUBMED: using the Medical Subject Headings terms 'Lemierre Syndrome/diagnosis' and words 'Lemierre's syndrome and anticoagulation'. From this, authors found 64 articles from 2002 to January 2018 with a total of 165 patients. The purpose of our review is to emphasize that antibiotic therapy should be started immediately, while anticoagulant therapy should be started in selected cases. Anticoagulation should be carried out in absence of any contraindication or presumed risk following clinical anticoagulation guidelines and only in patients with poor clinical response despite antibiotics therapy, predisposing thrombophilia and intracranial thrombosis.