Research Interests:
Background and ObjectivesLung cancer is one of the leading causes of cancer‐related deaths in the world. Although the origin still remains to be resolved, a prevailing hypothesis implies the involvement of cancer stem cells (CSCs)... more
Background and ObjectivesLung cancer is one of the leading causes of cancer‐related deaths in the world. Although the origin still remains to be resolved, a prevailing hypothesis implies the involvement of cancer stem cells (CSCs) responsible for tumor initiation, maintenance, and progression. Embryonic stem cell marker, OCT4, encoding the spliced variants OCT4A and OCT4B, has recently been shown to have a dual role; as a potential adult stem cell marker and as a CSC marker in germline and somatic tumors.MethodsWe investigated the expression and intracellular distribution of OCT4A and OCT4B using flow cytometry, Western blot and quantitative RT‐PCR analyses in normal and lung adenocarcinoma cell lines, primary cultures and tissue biopsies.ResultsWe demonstrate for the presence of rare OCT4A+ and OCT4B+ cells in normal lung. Notably, we observed higher levels of expression and atypical cytoplasmic distribution of OCT4A and not OCT4B, in the malignant setting, strongly indicating an oncogenic role in lung adenocarcinoma.ConclusionsWe postulate that OCT4A+ cells are involved in the oncogenesis of lung adenocarcinoma. Identification of these cells and the biological processes vital for their subsistence, will guide the development of diagnostic and therapeutic clinical approaches with the goal of eliminating lung adenocarcinoma. J. Surg. Oncol. 2010;102:689–698. © 2010 Wiley‐Liss, Inc.
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests: Molecular Biology, Medicine, DNA, Lung Function, Genetic Enhancement, and 15 moreAnimals, Gene transfer techniques, Male, Plasmids, Lung, Gene Delivery, Polyethylenimine, Plasmid DNA, Polyethyleneimine, Gene Transfer, Gas Exchange, Pulmonary Gas Exchange, Adverse effect, Genetic Therapy, and Cardiovascular medicine and haematology
Asymptomatic anthracosis is the accumulation of black carbon particles in adult human lungs. It is a common occurrence, but the pathophysiologic significance of anthracosis is debatable. Using in situ high mass resolution matrix-assisted... more
Asymptomatic anthracosis is the accumulation of black carbon particles in adult human lungs. It is a common occurrence, but the pathophysiologic significance of anthracosis is debatable. Using in situ high mass resolution matrix-assisted laser desorption/ionization (MALDI) fourier-transform ion cyclotron resonance (FT-ICR) mass spectrometry imaging analysis, we discovered noxious carbon-bound exogenous compounds, such as polycyclic aromatic hydrocarbons (PAH), tobacco-specific nitrosamines, or aromatic amines, in a series of 330 patients with lung cancer in highly variable and unique patterns. The characteristic nature of carbon-bound exogenous compounds had a strong association with patient outcome, tumor progression, the tumor immune microenvironment, programmed death-ligand 1 (PD-L1) expression, and DNA damage. Spatial correlation network analyses revealed substantial differences in the metabolome of tumor cells compared with tumor stroma depending on carbon-bound exogenous compounds. Overall, the bioactive pool of exogenous compounds is associated with several changes in lung cancer pathophysiology and correlates with patient outcome. Given the high prevalence of anthracosis in the lungs of adult humans, future work should investigate the role of carbon-bound exogenous compounds in lung carcinogenesis and lung cancer therapy. Significance: This study identifies a bioactive pool of carbon-bound exogenous compounds in patient tissues associated with several tumor biological features, contributing to an improved understanding of drivers of lung cancer pathophysiology.
Research Interests:
The aim of this study was to determine the influence of comorbidity on outcome after pulmonary resection in patients over 75 years old. Three hundred and thirty-three patients with non-small-cell lung cancer operated on between 1998 and... more
The aim of this study was to determine the influence of comorbidity on outcome after pulmonary resection in patients over 75 years old. Three hundred and thirty-three patients with non-small-cell lung cancer operated on between 1998 and 2002 were divided into 3 age groups: < 60 years (group 1), 60–75 years (group 2), > 75 years (group 3). Overall operative mortality was 0.3%; 30-day mortality was 1%. There were more major complications with re-operation in groups 1 and 2, but minor complications occurred significantly more frequently in group 3 (36% vs 16%). Overall mean hospital stay was 12 days, with no significant difference among groups. Three-year survival rates were: 80%, 70%, and 65% in groups 1, 2, and 3, respectively, with no significant difference among groups. Age or the presence of comorbidity should not be considered contraindications for lung resection. With proper patient selection and careful preoperative evaluation, many major complications after pneumonectomy are avoidable.
Research Interests: Algorithms, Aging, Risk assessment, Medicine, Comorbidity, and 15 moreLung Cancer, Humans, Female, Male, Length of Stay, Aged, Middle Aged, Retrospective Studies, Age Factors, Risk Factors, Risk Assessment, Patient selection, Cardiovascular medicine and haematology, lung neoplasms, and Pneumonectomy
Research Interests: Oncology, Chemotherapy, Medicine, Lung Cancer, Humans, and 15 moreInternal Medicine, Female, Male, Cisplatin, Aged, Middle Aged, Adult, Overall Survival, Non small Cell Lung Cancer, Docetaxel, Combined Modality Therapy, neoadjuvant therapy, Disease Free Survival, Neoplasm staging, and lung neoplasms
Research Interests:
Research Interests:
Objectives This meta-analysis sought to determine whether videoassisted thoracic surgery (VATS) improves clinical and resource outcomes compared with thoracotomy (OPEN) in adults undergoing lobectomy for nonsmall cell lung cancer. Methods... more
Objectives This meta-analysis sought to determine whether videoassisted thoracic surgery (VATS) improves clinical and resource outcomes compared with thoracotomy (OPEN) in adults undergoing lobectomy for nonsmall cell lung cancer. Methods A comprehensive search was undertaken to identify all randomized (RCT) and nonrandomized (non-RCT) controlled trials comparing VATS with OPEN thoracotomy available up to April 2007. The primary outcome was survival. Secondary outcomes included any other reported clinical outcome and resource utilization. Odds ratios (OR), weighted mean differences (WMD), or standardized mean differences (SMD), and their 95% confidence intervals (95% CI) were analyzed as appropriate. Results Baseline prognosis was more favorable for VATS (more females, smaller tumor size, less advanced stage, histology associated with peripheral location and with more indolent disease) than for OPEN in non-RCTs, but not RCT. Postoperative complications were significantly reduced in the VATS group compared with OPEN surgery when both RCT and non-RCT were considered in aggregate (OR 0.48, 95% CI 0.32–0.70). Although overall blood loss was significantly reduced with VATS compared with OPEN (–80 mL, 95% CI −110 to −50 mL), the incidence of excessive blood loss (generally defined as >500 mL) and incidence of re-exploration for bleeding was not significantly reduced. Pain measured via visual analog scales (10-point VAS) was significantly reduced by <1 point on day 1, by >2 points at 1 week, and by <1 point at week 2 to 4. Similarly, analgesia requirements were significantly reduced in the VATS group. Postoperative vital capacity was significantly improved (WMD 20, 95% CI 15–25), and at 1 year was significantly greater for VATS versus OPEN surgery (WMD 7, 95% CI 2–12). The incidence of patients reporting limited activity at 3 months was reduced (OR 0.04, 95% CI 0.00–0.82), and time to full activity was significantly reduced in the VATS versus OPEN surgery (WMD −1.5, 95% CI −2.1 to −0.9). Overall patient-reported physical function scores did not differ between groups at 3 years follow-up. Hospital length of stay was significantly reduced by 2.6 days despite increased 16 minutes of operating time for VATS versus OPEN. The incidence of cancer recurrence (local or distal) was not significantly different, but chemotherapy delays were significantly reduced for VATS versus OPEN (OR 0.15, 95% CI 0.06–0.38). The need for chemotherapy reduction was also decreased (OR 0.37, 95% CI 0.16–0.87), and the number of patients who did not receive at least 75% of their planned chemotherapy without delays were reduced (OR 0.41, 95% CI 0.18–0.93). The risk of death was not significantly reduced when RCTs were considered alone; however, when non-RCTs (n = 18) were included, the risk of death at 1 to 5 years was significantly reduced (OR 0.72, 95% CI 0.55–0.94; P = 0.02) for VATS versus OPEN. Stage-specific survival to 5 years was not significantly different between groups. Conclusions This meta-analysis suggests that there may be some short term, and possibly even long-term, advantages to performing lung resections with VATS techniques rather than through conventional thoracotomy. Overall, VATS for lobectomy may reduce acute and chronic pain, perioperative morbidity, and improve delivery of adjuvant therapies, without a decrease in stage specific long-term survival. However, the results are largely dependent on non-RCTs, and future adequately powered randomized trials with long-term follow-up are encouraged.
Research Interests:
Asymptomatic anthracosis is the accumulation of black carbon particles in adult human lungs. It is a common occurrence, but the pathophysiologic significance of anthracosis is debatable. Using in situ high mass resolution matrix-assisted... more
Asymptomatic anthracosis is the accumulation of black carbon particles in adult human lungs. It is a common occurrence, but the pathophysiologic significance of anthracosis is debatable. Using in situ high mass resolution matrix-assisted laser desorption/ionization (MALDI) fourier-transform ion cyclotron resonance (FT-ICR) mass spectrometry imaging analysis, we discovered noxious carbon-bound exogenous compounds, such as polycyclic aromatic hydrocarbons (PAH), tobacco-specific nitrosamines, or aromatic amines, in a series of 330 patients with lung cancer in highly variable and unique patterns. The characteristic nature of carbon-bound exogenous compounds had a strong association with patient outcome, tumor progression, the tumor immune microenvironment, programmed death-ligand 1 (PD-L1) expression, and DNA damage. Spatial correlation network analyses revealed substantial differences in the metabolome of tumor cells compared with tumor stroma depending on carbon-bound exogenous compounds. Overall, the bioactive pool of exogenous compounds is associated with several changes in lung cancer pathophysiology and correlates with patient outcome. Given the high prevalence of anthracosis in the lungs of adult humans, future work should investigate the role of carbon-bound exogenous compounds in lung carcinogenesis and lung cancer therapy.Significance:This study identifies a bioactive pool of carbon-bound exogenous compounds in patient tissues associated with several tumor biological features, contributing to an improved understanding of drivers of lung cancer pathophysiology.
Research Interests:
supplementary dataset
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
The aim of this study was to evaluate [18F]fluorodeoxyglucose ( F-FDG) imaging of recurrent or inoperable lung cancer using a hybrid positron emission tomography (PET) device of the third generation. Examinations were compared with the... more
The aim of this study was to evaluate [18F]fluorodeoxyglucose ( F-FDG) imaging of recurrent or inoperable lung cancer using a hybrid positron emission tomography (PET) device of the third generation. Examinations were compared with the results of conventional staging. Thirty-six patients suffering from recurrent or primarily inoperable lung cancer (29 men, seven women; age 64.8+/-12.0 years) were examined using hybrid PET (Marconi Axis gamma-PET ) 60 min after injection of 370 MBq F-FDG. The data obtained were reconstructed iteratively. All patients received a computed tomography (CT) scan using either the spiral or multislice technique. All lesions suspicious for primary or recurrent tumour were verified by biopsy; mediastinal lymph nodes were considered as malignant, when positive histology or a small axis diameter of greater than 1 cm measured with CT in addition to progression of clinical course was found. Distant metastases were diagnosed by CT and bone scintigraphy. Using hybr...
Research Interests:
Research Interests:
Purpose: The model of unilateral orthotropic left rat lung transplantation is well known and established experimental procedure. The author's personal learning curve of mastery process of this microsurgical procedure is presented.... more
Purpose: The model of unilateral orthotropic left rat lung transplantation is well known and established experimental procedure. The author's personal learning curve of mastery process of this microsurgical procedure is presented. Material and methods: During 18 months the author has performed 197 single left lung transplantations on the Thoracic Surgery Ward in University Hospital, Berne, Switzerland. There were 147 allogeneic and 50 isogeneic transplantations done. The allogeneic transplantations were carried out from Brown-Norway to Fischer F344 rats whereas isogeneic transplantations were done among Fischer F344 rats solely. Grafted lung was obtained from the intravenously anaesthetised, oxygen-ventilated donor. The implantation was carried out through left posterolateral thoracotomy on the gas anaesthetised, respirator ventilated recipient. The anastomoses of the vessels were done using the cuff technique, bronchi were sutured using continuous running over-and-over suture. Recipients were sacrificed on day 5 post-transplant. All recipients were divided into four consecutive groups. Warm ischaemia time and presence of perioperative pure technical complications were observed. Results: We observed time dependent decline of complications number of consecutive recipient groups, respectively 20, 5, 4, 1. The warm ischaemia time in minutes decreased from 35.6 +/- 5.4 in group I through 26.7 +/- 4.4 in group II, 24.8 +/- 2.3 in group III to 22.0 +/- 3.1 in group IV. Conclusions: Continuous training of the procedure shortens the average warm ischaemia time and reduces the number of complications. This tedious microsurgical procedure is possible to master by the surgeon.
Research Interests:
Research Interests: Endocrinology, Cytokines, Diet, Calcium, Medicine, and 15 moreTransplantation, Internal Medicine, Animals, Male, Lung, Calcitriol, Rats, Oxygen, Biological markers, Blood gas analysis, Graft Rejection, Heart and Lung Transplantation, Acute Disease, Lung Transplantation, and Cardiovascular medicine and haematology
Three different nonviral vectors and naked DNA were evaluated for in vivo transfer of plasmid DNA to rat lungs through airways in either atelectatic or ventilated lungs. The F344 rats underwent instillation of 300 microg DNA (pCIluc,... more
Three different nonviral vectors and naked DNA were evaluated for in vivo transfer of plasmid DNA to rat lungs through airways in either atelectatic or ventilated lungs. The F344 rats underwent instillation of 300 microg DNA (pCIluc, luciferase) to the left lung. Naked DNA, linear polyethylenimine, branched polyethylenimine, and lipid GL-67 (in either atelectatic or ventilated lungs) were assessed (n = 5 per group). After 24 hours, left lung PaO2 (mm Hg) and luciferase activity (RLU/mg) were measured. The median (range) was given, and the analysis of variance was applied, followed by the planned comparison on log-transformed data. In atelectatic lungs, lipid GL-67 was best (927 [330 to 4112] RLU/mg; p < 0.001 versus other groups of atelectatic lung; p < 0.001 versus all other groups), but highest luciferase activity in all groups was measured in ventilated lungs using linear polyethylenimine (1,240 [922 to 2519] RLU/mg; p < 0.001 versus other groups of ventilated lung; p < 0.001 versus all other groups). In comparison with naked DNA, all nonviral vector systems significantly impaired PaO2 24 hours after airway transfection (p < 0.001; naked DNA versus all other groups). Regardless of transfection technique, PaO2 was worst in lungs transfected by linear polyethylenimine. Highest transfection was achieved with GL-67 in atelectatic lungs and with linear polyethylenimine in ventilated lungs. All gene delivery systems impaired gas exchange of the transduced lung in comparison with naked DNA.
Research Interests: Molecular Biology, Medicine, DNA, Animals, Gene transfer techniques, and 15 moreMale, Luciferase, Lung, Clinical Sciences, Gene Delivery, Rats, Oxygen, Analysis of Variance, Polyethylenimine, Plasmid DNA, Gas Exchange, Genetic Therapy, Pulmonary atelectasis, Cardiovascular medicine and haematology, and Respiration Artificial
Lung transplantation is an acceptable treatment option for various end-stage pulmonary diseases, but long-term survival currently lags behind that after transplantation of other solid organs. We hypothesized that gene transfer to grafts... more
Lung transplantation is an acceptable treatment option for various end-stage pulmonary diseases, but long-term survival currently lags behind that after transplantation of other solid organs. We hypothesized that gene transfer to grafts before transplantation may be a useful method to deliver antioxidant and/or anti-inflammatory genes to modulate these processes. For this purpose, we assessed the efficiency of gene transfer and effects on lung function of the synthetic polycation, linear polyethylenimine (PEI), after airway instillation to the lungs of Fischer rats. Twenty-four hours after gene delivery, reporter gene activity in DNA/PEI treated rats was approximately 12-fold higher than that in rats treated with naked DNA, but by 72 hours there was no significant difference between groups and activity had decreased by at least 85%. Function of the transfected left lung was assessed by measuring arterial PaO(2) levels and was found to be significantly lower at 24 and 72 hours after gene transfer in the PEI/DNA group compared with the naked DNA group. The deterioration in lung function correlated with histological findings. Rats treated with PEI alone and sacrificed after 72 hours showed an impairment in lung function similar to that seen with PEI/DNA treatment. Our studies highlight the importance of assessing the functional capacity of a graft after gene transfer to determine suitability for subsequent transplantation.
Research Interests: Biology, Medicine, Biological Sciences, DNA, Lung Function, and 15 moreGenetic Enhancement, Functional Capacity, Animals, Gene transfer techniques, Male, Lung, Gene Delivery, Heart and Lung Transplantation, Molecular Targeted Therapy, Polyethylenimine, Pulmonary disease, Polyethyleneimine, Gene Transfer, Lung Transplantation, and Medical and Health Sciences
Research Interests:
The histone H3 lysine 36 (H3K36) methyltransferase NSD3, a neighboring gene of FGFR1, has been identified as a critical genetic driver of lung squamous cell carcinoma (LUSC). However, the molecular characteristics, especially the... more
The histone H3 lysine 36 (H3K36) methyltransferase NSD3, a neighboring gene of FGFR1, has been identified as a critical genetic driver of lung squamous cell carcinoma (LUSC). However, the molecular characteristics, especially the immunological roles of NSD3 in driving carcinogenesis, are poorly understood. In this study, we systematically integrated multi-omics data (e.g., genome, transcriptome, proteome, and TMA array) to dissect the immunological profiles in NSD3-amplified LUSC. Next, pharmaco-transcriptomic correlation analysis was implemented to identify the molecular underpinnings and therapeutic vulnerabilities in LUSC. We revealed that NSD3-amplified LUSC presents a non-inflamed tumor immune microenvironment (TIME) state in multiple independent LUSC patient cohorts. Predictably, elevated NSD3 expression was correlated with a worse immunotherapy outcome. Further molecular characterizations revealed that the high activity of unfolded protein response (UPR) signaling might be a ...
Research Interests:
Research Interests:
PD-L1 expression is the routine clinical biomarker for the selection of patients to receive immunotherapy in non-small cell lung cancer (NSCLC). However, the application and best timing of immunotherapy in the resectable setting is still... more
PD-L1 expression is the routine clinical biomarker for the selection of patients to receive immunotherapy in non-small cell lung cancer (NSCLC). However, the application and best timing of immunotherapy in the resectable setting is still under investigation. We aimed to study the effect of chemotherapy on PD-L1 expression and tumor infiltrating lymphocytes (TIL), which is to date still poorly understood. This retrospective, single-centre study cohort comprised 96 consecutive patients with NSCLC resected in 2000-2016 after neoadjuvant therapy, including paired chemo-naïve specimens in 57 cases. A biologically matched control cohort of 114 primary resected cases was included. PD-L1 expression, CD8+ TIL density and tertiary lymphoid structures were assessed on whole slides and correlated with clinico-pathological characteristics and survival.Seven/57 and 12/57 cases had lower respectively higher PD-L1 expressions after neoadjuvant therapy. Most cases (n = 38) had no changes in PD-L1 ex...
Research Interests:
Introduction: Thymoma with pleural spread, whether de novo or in form of pleural relapse after surgical resection, is a difficult to treat disease. Hyperthermic intrathoracic chemotherapy (HITHOC) has recently been increasingly discussed... more
Introduction: Thymoma with pleural spread, whether de novo or in form of pleural relapse after surgical resection, is a difficult to treat disease. Hyperthermic intrathoracic chemotherapy (HITHOC) has recently been increasingly discussed as a possible beneficial adjunct to cytoreductive surgery with the aim of reducing pleural recurrence and prolonging survival in these patients. Methods: We searched the PubMed interface in order to present a comprehensive review on the topic. Results: More than 1600 papers were found using the reported search, of which 7 presented the best evidence to answer the clinical question whether HITHOC in combination with surgery might prolong survival in patients with pleural thymoma. Most patients included in these 7 studies were younger than 65 years, had only minor or no comorbidities and presented in good general condition. With these premises, surgical resection (both radical pleurectomy and extrapleuralpleuropneumonectomy) combined with HITHOC seeme...
Research Interests:
Percutaneous dilatational tracheostomy (PDT) is a frequently performed procedure in long-term intubated patients. Tracheal laceration is a rarely reported but life-threatening complication which often requires emergent surgical repair in... more
Percutaneous dilatational tracheostomy (PDT) is a frequently performed procedure in long-term intubated patients. Tracheal laceration is a rarely reported but life-threatening complication which often requires emergent surgical repair in order to re-establish continuity of the airway. This can be a tricky task in polymorbid patients and demands a multidisciplinary approach by intensive care physicians, anesthesiologists, pulmonologists and a surgical team experienced in airway surgery. We herein describe a case of severe iatrogenic tracheal injury occurring during PDT and its management.
Research Interests:
Exploration of the contralateral pleural cavity via transmediastinal access has been described for minor lung resections in close proximity to the mediastinum. Also simultaneous thoracoscopic bilateral bullectomy through mediastinal... more
Exploration of the contralateral pleural cavity via transmediastinal access has been described for minor lung resections in close proximity to the mediastinum. Also simultaneous thoracoscopic bilateral bullectomy through mediastinal access has been described as an alternative to bilateral sequential thoracoscopic procedures in highly selected patients with bilateral spontaneous pneumothorax. We herein describe a more complex procedure during which a video-assisted lung volume reduction surgery was performed through an anterior transmediastinal access following right sided thoracotomy and lobectomy of a completely destroyed upper lobe in a patient with borderline lung function and severe bilateral lung emphysema.
Research Interests:
Research Interests:
Research Interests:
Summary The aim of the review was to evaluate the routine use of sternal elevation techniques (SETs) during minimally invasive repair of pectus excavatum (MIRPE, the Nuss procedure). We performed a review of the literature between January... more
Summary The aim of the review was to evaluate the routine use of sternal elevation techniques (SETs) during minimally invasive repair of pectus excavatum (MIRPE, the Nuss procedure). We performed a review of the literature between January 1998 and September 2018 with focus on different methods of SET during MIRPE. Reported effects and side effects were evaluated and compared with our own experience concerning the routine use of the vacuum bell for sternal elevation during MIRPE during the last 13 years. SET is more often used in adult patients than in adolescents. SET improves visualization and safety of MIRPE. Advancement of the pectus introducer, retrosternal dissection and placement of the pectus bar are easier. The risk of cardial and/or pericardial lesion is reduced significantly. Different types of retractors, a crane combined with a wire and/or customized hooks are reported to be used as SET. Furthermore, routine use of a subxiphoid incision is reported. However, more technic...