Targeting cancer stem cell OXPHOS with tailored ruthenium complexes as a new anti-cancer strategy.

BACKGROUND: Previous studies by our group have shown that oxidative phosphorylation (OXPHOS) is the main pathway by which pancreatic cancer stem cells (CSCs) meet their energetic requirements; therefore, OXPHOS represents an Achille's heel of these highly tumorigenic cells. Unfortunately, therapies that target OXPHOS in CSCs are lacking. METHODS: The safety and anti-CSC activity of a ruthenium complex featuring bipyridine and terpyridine ligands and one coordination labile position (Ru1) were evaluated across primary pancreatic cancer cultures and in vivo, using 8 patient-derived xenografts (PDXs). RNAseq analysis followed by mitochondria-specific molecular assays were used to determine the mechanism of action. RESULTS: We show that Ru1 is capable of inhibiting CSC OXPHOS function in vitro, and more importantly, it presents excellent anti-cancer activity, with low toxicity, across a large panel of human pancreatic PDXs, as well as in colorectal cancer and osteosarcoma PDXs. Mechanistic studies suggest that this activity stems from Ru1 binding to the D-loop region of the mitochondrial DNA of CSCs, inhibiting OXPHOS complex-associated transcription, leading to reduced mitochondrial oxygen consumption, membrane potential, and ATP production, all of which are necessary for CSCs, which heavily depend on mitochondrial respiration. CONCLUSIONS: Overall, the coordination complex Ru1 represents not only an exciting new anti-cancer agent, but also a molecular tool to dissect the role of OXPHOS in CSCs. Results indicating that the compound is safe, non-toxic and highly effective in vivo are extremely exciting, and have allowed us to uncover unprecedented mechanistic possibilities to fight different cancer types based on targeting CSC OXPHOS.

Postoperative morbidity after anatomical lung resections by VATS vs thoracotomy: Treatment and intention-to-treat analysis of the Spanish Video-Assisted Thoracic Surgery Group.

OBJECTIVES: In recent years, video-assisted thoracoscopic lung resections (VATS) have been associated with lower morbidity than open surgery. The aim of our study is to compare postoperative morbidity among patients from the national database of the Spanish Group of Video-Assisted Thoracic Surgery (GE-VATS) after open and video-assisted anatomic lung resections using a propensity score analysis. METHODS: From December 2016 to March 2018, a total of 3533 patients underwent anatomical lung resection at 33 centers. Pneumonectomies and extended resections were excluded. A propensity score analysis was performed to compare the morbidity of the thoracotomy group (TG) vs the VATS group (VATSG). Treatment and intention-to-treat (ITT) analyses were conducted. RESULTS: In total, 2981 patients were finally included in the study: 1092 (37%) in the TG and 1889 (63%) in the VATSG for the treatment analysis; and 816 (27.4%) in the TG and 2165 patients (72.6%) in the VATSG for the ITT analysis. After propensity score matching, in the treatment analysis, the VATSG was significantly associated with fewer overall complications than the TG OR 0.680 [95%CI 0.616, 0.750]), fewer respiratory (OR 0.571 [0.529, 0.616]) cardiovascular (OR 0.529 [0.478, 0.609]) and surgical (OR 0.875 [0.802, 0.955]) complications, lower readmission rate (OR 0.669 [0.578, 0.775]) and a reduction of hospital length of stay (-1.741 ([-2.073, -1.410]). Intention-to-treat analysis showed only statistically significant differences in overall complications (OR 0.76 [0.54-0.99]) in favor of the VATSG. CONCLUSION: In this multicenter population, VATS anatomical lung resections have been associated with lower morbidity than those performed by thoracotomy. However, when an intention-to-treat analysis was performed, the benefits of the VATS approach were less prominent.

Surgical and non-surgical management of thoracic and cervical paraganglioma.

Thoracic and cervical paragangliomas (PGLs) are rare neuroendocrine tumors arising from chromaffin cells of the neural crest progenitors located outside the adrenal gland. We describe our current protocol as a multidisciplinary team for the management of cervical and thoracic PGLs. Surgery is generally considered the treatment of choice as it offers the best chance for cure. For resection of thoracic PGLs, video-assisted thoracoscopic surgery (VATS) is the main surgical approach, while open thoracotomy is preferred in case of tumors > 6cm, lacking confirmation of a plane of separation with adjacent structures, or with technical difficulties during VATS. In cervical PGLs, the surgical approach should be individualized according to location, mainly based on the Glasscock-Jackson and the Fisch-Mattox classifications. Surgery is the treatment of choice for most cervical and thoracic PGLs, but radiotherapy or observation could be more suitable options in unresectable cervical and thoracic PGLs or when resection has been incomplete.

Thoracoscopic segmentectomy versus lobectomy: A propensity score-matched analysis.

Objectives: The aim of this study is to compare the postoperative complications, perioperative course, and survival among patients from the multicentric Spanish Video-assisted Thoracic Surgery Group database who received video-assisted thoracic surgery lobectomy or video-assisted thoracic surgery anatomic segmentectomy. Methods: From December 2016 to March 2018, a total of 2250 patients were collected from 33 centers. Overall analysis (video-assisted thoracic surgery lobectomy = 2070; video-assisted thoracic surgery anatomic segmentectomy = 180) and propensity score-matched adjusted analysis (video-assisted thoracic surgery lobectomy = 97; video-assisted thoracic surgery anatomic segmentectomy = 97) were performed to compare postoperative results. Kaplan-Meier and competing risks method were used to compare survival. Results: In the overall analysis, video-assisted thoracic surgery anatomic segmentectomy showed a lower incidence of respiratory complications (relative risk, 0.56; confidence interval, 0.37-0.83; P = .002), lower postoperative prolonged air leak (relative risk, 0.42; 95% confidence interval, 0.23-0.78; P = .003), and shorter median postoperative stay (4.8 vs 6.2 days; P = .004) than video-assisted thoracic surgery lobectomy. After propensity score-matched analysis, prolonged air leak remained significantly lower in video-assisted thoracic surgery anatomic segmentectomy (relative risk, 0.33; 95% confidence interval, 0.12-0.89; P = .02). Kaplan-Meier and competing risk curves showed no differences during the 3-year follow-up (median follow-up in months: 24.4; interquartile range, 20.8-28.3) in terms of overall survival (hazard ratio, 0.73; 95% confidence interval, 0.45-1.7; P = .2), tumor progression-related mortality (subdistribution hazard ratio, 0.41; 95% confidence interval, 0.11-1.57; P = .2), and disease-free survival (subdistribution hazard ratio, 0.73; 95% confidence interval, 0.35-1.51; P = .4) between groups. Conclusions: Video-assisted thoracic surgery segmentectomy showed results similar to lobectomy in terms of postoperative outcomes and midterm survival. In addition, a lower incidence of prolonged air leak was found in patients who underwent video-assisted thoracic surgery anatomic segmentectomy.

Impact of neoadjuvant therapy on postoperative complications in non-small-cell lung cancer patients subjected to anatomic lung resection.

OBJECTIVE: To study the impact of neoadjuvant therapies on postoperative complications and mortality among non-small-cell lung cancer (NSCLC) patients subjected to anatomic lung resection and included in the Spanish cohort of the video-assisted thoracic surgery (GE-VATS) multicenter database. METHODS: The study included a total of 3085 patients from 33 centers between December 2016 and March 2018. We performed a comparative analysis of the complications and mortality in patients who received neoadjuvant therapies (n = 263) versus those who did not (n = 2822). A propensity score-matched analysis was used to adjust for potential confounders. Association between exposure in two groups and outcomes were estimated by logistic regression weighted by inverse of probability of receiving the treatment that actually received. RESULTS: In the unadjusted analysis, the chemotherapy (CT) and chemoradiotherapy (CRT) group presented a higher frequency of ICU readmissions, reinterventions, empyema, cardiovascular complications, a greater frequency of atrial fibrillation, and an increased need for blood product transfusions. In the adjusted group, CT and CRT patients had a higher rate of cardiovascular complications (CT p = 0.002; OR 2.29; 95% CI 1.34-3.94 and CRT p = 0.001; OR 2.90; 95% CI 1.52-5-52), arrhythmias (CT p = 0.013; OR 2.23; 95% CI 1.18-4.20 and CRT p = 0.046; OR 2.22; 95% CI 1.01-4.90) and transfussions (CT p = 0.042; OR 2.95; 95% CI 1.04-8.35 and CRT p < 0.001; OR 7.74; 95% CI 3.01-19-92). CONCLUSIONS: Based on our series, neoadjuvant CT and CRT were associated with a higher rate of cardiovascular complications, arrhythmias and transfussions in patients with NSCLC subjected to anatomic lung resection.

Bronchial Carcinoids: From Molecular Background to Treatment Approach.

A better understanding of the genetic and molecular background of bronchial carcinoids (BCs) would allow a better estimation of the risk of disease progression and the personalization of treatment in cases of advanced disease. Molecular studies confirmed that lungs neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs) are different entities; thus, no progression of NET to NEC is expected. In BCs, MEN1 gene mutations and deletions and decreased gene expression have been associated with a poor prognosis. ATRX mutation has also been linked to a shorter disease-specific survival. In terms of therapeutic targets, PI3K/AKT/mTOR pathway mutations have been described in 13% of typical carcinoids (TCs) and 39% of atypical carcinoids (ACs), representing a targetable mutation with kinase inhibitors. Regarding treatment, surgical resection is usually curative in localized BCs and adjuvant treatment is not routinely recommended. Multiple options for systemic therapy exist for patients with advanced BCs, although limited by a heterogeneity in the scientific evidence behind their use recommendation. These options include somatostatin analogues, everolimus, peptide receptor radionuclide therapy, chemotherapy, radiotherapy, antiangiogenic agents, and immunotherapy. In this article, we provide a comprehensive review about the molecular and genetic background of BCs, and about the treatment of local and metastatic disease, as well as the main paraneoplastic syndromes that have been associated with this tumor.

Treatment and intention-to-treat propensity score analysis to evaluate the impact of video-assisted thoracic surgery on 90-day mortality after anatomical resection for lung cancer.

OBJECTIVES: The aim of this study was to know the treatment effect of video-assisted thoracic surgery (VATS) on 90-day mortality after anatomical lung resection based on a nationwide cohort. METHODS: This is a multicentre prospective cohort of 2721 anatomical resections for lung cancer from December 2016 to March 2018. Treatment and intention-to-treat (ITT) analyses were performed after inverse probability score weighting and different propensity score matching algorithms. Covariate balance was assessed by standardized mean differences. The estimators reported were the average treatment effect, the average treatment effect on the treated and odds ratios after conditional logistic models with 95% confidence intervals. The unconfoundedness assumption was evaluated by sensitivity analysis for average treatment effect (c-dependence) and average treatment effect on the treated (Γ). RESULTS: VATS was the initial approach in 1911 patients (70.2%), though 273 cases (14.3%) had to be converted to thoracotomy. Ninety-day mortality rates were: treatment analysis (VATS 1.16% vs open 3.9%, P < 0.001), ITT analysis (VATS 1.78% vs open 3.36%, P = 0.012). After inverse probability score weighting and propensity score matching, in the treatment analysis, VATS meant absolute risk reductions between 2.25% and 2.96% and relative risk reductions between 65% and 70% [OR = 0.34 (95% confidence interval 0.15-0.79), all P-values <0.004). However, all the estimators turned out to be non-significant in the ITT analyses. A high sensitivity to unobservable confounders was proved (c-dependence 0.135, Γ = 1.5). CONCLUSIONS: VATS can reduce the risk of 90-day mortality after anatomical lung resection. However, the implications of conversion to thoracotomy, comparing ITT versus treatment analysis, and the potential impact of hidden bias should deserve further attention in the future.

Preoperative radio-guided localization of lung nodules with I-125 seeds: experience with 32 patients at a single institution.

OBJECTIVES: Videothoracoscopic visualization and/or palpation of pulmonary nodules may be difficult due to their location, small size or limited solid component. The purpose of this study is to present our experience with computed tomography (CT)-guided preoperative localization of pulmonary nodules by percutaneous marking with radio-labelled iodine-125 seeds. METHODS: A total of 34 pulmonary nodules were marked under CT with the placement of 33 radio-labelled iodine-125 seeds in 32 consecutive patients. RESULTS: All patients underwent biportal video-assisted thoracic surgery (VATS) and in no case was conversion to thoracotomy necessary. A total of 88.2% of the lung nodules were successfully resected. In the remaining 11.8%, migration of the seed to the pleural cavity occurred, although these nodules were still resected during VATS. Of all the patients with pneumothorax after the marking procedure, only one required chest tube placement (3.1%). No major postoperative complications were observed. CONCLUSIONS: Preoperative marking of pulmonary nodules with I-125 seeds under CT guidance is a feasible and safe technique that allows their intraoperative identification and resection.

Propranolol syrup to tablets change triggers electrical storm in Jervell-Lange-Nielsen syndrome.

A 10-year-old girl with genetically confirmed Jervell-Lange-Nielsen syndrome treated with beta-blocker and developed electrical storm after changing propranolol syrup to tablets. Jervell-Lange-Nielsen is characterised by long QT and congenital sensorineural deafness, with high risk of malignant arrhythmias at early ages. Gastric involvement and achlorhydria may be present, with subsequent alteration of medication bioavailability which can trigger severe arrhythmic complications.

Innominate Artery Dissection Caused by Video-Mediastinoscopy.

Mediastinoscopy is considered a safe technique to biopsy mediastinal lesions. Among its complications, vascular ones are the most common. We present a rare case of intimal dissection of the innominate artery during the performance of a mediastinoscopy that caused an ischemic attack from which the patient recovered completely without long-term sequelae. We analyze the possible causes and risk factors of this complication.

Spanish Video-Assisted Thoracic Surgery Group: Method, Auditing, and Initial Results From a National Prospective Cohort of Patients Receiving Anatomical Lung Resections.

INTRODUCTION: Our study sought to know the current implementation of video-assisted thoracoscopic surgery (VATS) for anatomical lung resections in Spain. We present our initial results and describe the auditing systems developed by the Spanish VATS Group (GEVATS). METHODS: We conducted a prospective multicentre cohort study that included patients receiving anatomical lung resections between 12/20/2016 and 03/20/2018. The main quality controls consisted of determining the recruitment rate of each centre and the accuracy of the perioperative data collected based on six key variables. The implications of a low recruitment rate were analysed for "90-day mortality" and "Grade IIIb-V complications". RESULTS: The series was composed of 3533 cases (1917 VATS; 54.3%) across 33 departments. The centres' median recruitment rate was 99% (25-75th:76-100%), with an overall recruitment rate of 83% and a data accuracy of 98%. We were unable to demonstrate a significant association between the recruitment rate and the risk of morbidity/mortality, but a trend was found in the unadjusted analysis for those centres with recruitment rates lower than 80% (centres with 95-100% rates as reference): grade IIIb-V OR=0.61 (p=0.081), 90-day mortality OR=0.46 (p=0.051). CONCLUSIONS: More than half of the anatomical lung resections in Spain are performed via VATS. According to our results, the centre's recruitment rate and its potential implications due to selection bias, should deserve further attention by the main voluntary multicentre studies of our speciality. The high representativeness as well as the reliability of the GEVATS data constitute a fundamental point of departure for this nationwide cohort.

Supraclavicular excision of a cervical rib for treatment of thoracic outlet syndrome.

Cervical rib resection through a supraclavicular approach is a safe and feasible treatment for patients suffering from thoracic outlet syndrome caused by the presence of a cervical rib or by an anomalous first rib. This video tutorial illustrates the technical aspects of this procedure.

Video-assisted thoracoscopic left cardiac sympathetic denervation for congenital long QT syndrome.

Left cardiac sympathetic denervation is an effective therapy for patients with congenital long QT syndrome resistant to beta-blocker therapy. In this video tutorial we describe a minimally invasive video-assisted thoracoscopic technique for performing left cardiac sympathetic denervation.

Impact of DLK1-DIO3 imprinted cluster hypomethylation in smoker patients with lung cancer.

DNA methylation is important for gene expression and genome stability, and its disruption is thought to play a key role in the initiation and progression of cancer and other diseases. The DLK1-DIO3 cluster has been shown to be imprinted in humans, and some of its components are relevant to diverse pathological processes. The purpose of this study was to assess the methylation patterns of the DLK1-DIO3 cluster in patients with lung cancer to study its relevance in the pathogenesis of this disease. We found a characteristic methylation pattern of this cluster in smoking associated lung cancer, as compared to normal lung tissue. This methylation profile is not patent however in lung cancer of never smokers nor in lung tissue of COPD patients. We found 3 deregulated protein-coding genes at this locus: one was hypermethylated (DIO3) and two were hypomethylated (DLK1 and RTL1). Statistically significant differences were also detected in two different families of SNORDs, two miRNA clusters and four lncRNAs (MEG3, MEG8, MEG9 and LINC00524). These findings were validated using data from the cancer genome atlas (TCGA) database. We have then showed an inverse correlation between DNA methylation and expression levels in 5 randomly selected genes. Several targets of miRNAs included in the DLK1-DIO3 cluster have been experimentally verified as tumor suppressors. All of these results suggest that the dysmethylation of the imprinted DLK1-DIO3 cluster could have a relevant role in the pathogenesis of lung cancer in current and former smokers and may be used for diagnostic and/or therapeutic purposes.