The Prognostic Long-Term Impact of Chronic Obstructive Pulmonary Disease and Postoperative Mucostasis in Patients with Curatively Resected Non-Small Cell Lung Cancer.

Chronic obstructive pulmonary disease (COPD) serves as risk factor for the development of lung cancer and seems to have a prognostic impact after surgery for non-small cell lung cancer (NSCLC). The aim was to investigate the impact of COPD and postoperative mucostasis on the long-term survival after resected NSCLC. We retrospectively reviewed the data from 342 patients with curatively resected NSCLC. The prognostic long-term impact of COPD and postoperative mucostasis on overall survival (OS), recurrence free survival (RFS) and cancer specific survival (CSS) was calculated using univariable and multivariable Cox regression analyses. We found that 52.3% suffered from COPD and 25.4% had postoperative mucostasis. COPD was significantly more common among smokers (59.9%) compared with non-smokers (21.3%), (p < 0.001). There was a significant relationship between COPD and postoperative mucostasis (p = 0.006) and between smoking and mucostasis (p = 0.023). Patients with postoperative mucostasis had a significantly worse OS (p < 0.001), RFS (p = 0.009) and CSS (p = 0.008). The present analysis demonstrated that postoperative mucostasis, but not COPD, was associated with both worse short- and long-term outcomes for OS, RFS and CSS in curatively resected NSCLC.

Role of Tumor-Associated Neutrophils in the Molecular Carcinogenesis of the Lung.

Tumorigenesis is largely influenced by accompanying inflammation. Myeloid cells account for a significant proportion of pro-inflammatory cells within the tumor microenvironment. All steps of tumor formation and progression, such as the suppression of adaptive immune response, angio- and lymphangiogenesis, and the remodeling of the tumor stroma, are to some degree influenced by tumor-associated immune cells. Tumor-associated neutrophils (TANs), together with tumor-associated macrophages and myeloid-derived suppressor cells, count among tumor-associated myeloid cells. Still, the exact molecular mechanisms underlying the tumorigenic effects of TANs have not been investigated in detail. With this review of the literature, we aim to give an overview of the current data on TANs, with a special focus on lung cancer.

A nomogram illustrating the probability of anastomotic leakage following cervical esophagogastrostomy.

BACKGROUND: Early diagnosis of anastomotic dehiscence following cervical esophagogastrostomy may become difficult. Estimation of an individual probability could help to establish preventive and diagnostic measures. The predictive impact of epidemiological, surgery-related data and laboratory parameters on the development of anastomotic dehiscence was investigated in the immediate perioperative period. METHODS: Retrospective study in 412 patients with cervical esophagogastrostomy following esophagectomy. Epidemiological data, risk factors, underlying disease, pre-treatment- and surgery-related data, C-reactive protein and albumin levels pre-and post-operatively were evaluated. We applied univariable and multivariable logistic regression analysis and developed a nomogram for individual risk assessment. RESULTS: There were 345 male, 67 female patients, mean aged 61.5 years; 284 had orthotopic, 128 retrosternal gastric pull-up; 331 patients had carcinoma, 81 non-malignant disease. Mean duration of operation was 184 min; 235 patients had manual, 113 mechanical and 64 semi-mechanical suturing; 76 patients (18.5%) developed anastomotic dehiscence clinically evident at mean 11.4 days after surgery. In univariable testing young age, retrosternal conduit transposition, manual suturing, high body mass index, high ASA and high postoperative levels of C-reactive protein were predictors for anastomotic leakage. These six parameters which had yielded a p < 0.1 in the univariable analysis, were entered into a multivariable analysis and a nomogram allowing the determination of the patient's individual risk was created. CONCLUSION: By using the nomogram as a supportive measure in the perioperative management, the patient's individual probability of developing an anastomotic leak could be quantified which may help to take preventive measures improving the outcome.

Hazard Curves for Tumor Recurrence and Tumor-Related Death Following Esophagectomy for Esophageal Cancer.

BACKGROUND: The knowledge of both patterns and risk of relapse following resection for esophageal cancer is crucial for establishing appropriate surveillance schedules. The aim of this study was to evaluate the pattern of hazards for tumor recurrence and tumor-related death in the postoperative long-term follow-up after esophagectomy. METHODS: Retrospective single-center analysis of 362 patients, with resected esophageal cancer. Multivariate Cox proportional hazard model was used. RESULTS: A total of 192 (53%) had postoperative tumor recurrence. The relapse patterns of adenocarcinoma and squamous-cell carcinoma showed that each had a single peak, 12 months after surgery. After induction there was one peak at 5 months, the non-induced patients peaked 11 months, postoperatively. At 18 months, the recurrence hazard declined sharply in all cases. The hazard curves for tumor-related death were bimodal for adenocarcinoma, with two peaks at 6 and 22 months and one single peak for squamous-cell carcinoma at 18 months after surgery, showing pronounced decline later on. CONCLUSION: In curatively resected esophageal cancer, both tumor recurrence hazard and hazard for tumor-related death showed distinct, partly bimodal patterns. It could be justified to intensify the surveillance during the first two postoperative years by initiating a close-meshed follow-up to detect and treat tumor recurrence, as early as possible.

Hazards of Recurrence, Second Primary, or Other Tumor at Ten Years After Surgery for Non-Small-Cell Lung Cancer.

INTRODUCTION: Better treatment options entail the risk of multiple tumors in a patient's lifetime. We studied the incidence, risk factors, and prognostic impact of second primaries and other malignancies in patients with operated non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We retrospectively analyzed 342 consecutive patients with curatively resected NSCLC between 2003 and 2007. RESULTS: Among the 342 patients analyzed, 172 (50.3%) developed locoregional and/or distant recurrence; 25 (7.3%) had a second primary lung cancer, 97 (28.3%) had 1 or more malignancies other than NSCLC either in their history (n = 61; 17.8%) or following resection (n = 64; 18.7%). One hundred fifteen patients (33.6%) had a malignancy other than primary NSCLC. Eight patients developed both a second primary lung cancer and another malignancy. Older age and lower N-stage were significantly correlated with the occurrence of an additional tumor, as shown by a logistic regression nomogram. Whereas the risk of recurrence decreases over time, the risk of developing a second tumor, particularly a second primary lung cancer, remains high during up to 10 years of follow-up. One hundred seventy patients (49.7%) died of the primary (n = 158; 46.2%) or second primary (n = 12; 3.5%) NSCLC, 23 (6.7%) died of another malignancy, and 66 (19.3%) died due to unrelated causes (overall 10-year survival, 33.3%). CONCLUSIONS: Second primary lung cancer or other malignancy occurs in 33% of patients with NSCLC; 26% of patients are affected within 10 years after resection of lung cancer. With curative treatment of secondary tumors, there is no negative influence on long-term prognosis of NSCLC; therefore, follow-up beyond 5 years is strongly advisable.

Preoperative Peak Oxygen Consumption: A Predictor of Survival in Resected Lung Cancer.

The peak oxygen consumption (VO2 peak) serves as a prognostic factor in cardio-respiratory diseases and plays an important role in cancer patients. The long-term prognostic relevance of VO2 peak in lung cancer patients has not been investigated extensively. The aim of this study was to evaluate the impact of the preoperative VO2 peak on the postoperative long-term survival in patients with operated lung cancer. Retrospective analysis of 342 patients with curatively resected non-small-cell lung cancer using a multivariate Cox proportional hazard model. Results: Preoperative VO2 peak ranged from 10.2 to 51.8 mL/kg/min (mean: 18.3 ± 4.6), VO2 peak % of predicted ranged from 32 to 172% (mean: 65.2 ± 18.0%). Overall 10-year survival was 23%. A Log-rank test comparing predicted VO2 peak ≥ 60% with predicted VO2 peak < 60% showed overall survival of 30% and 17%, respectively (p < 0.001) and non-tumour-related survival of 71% and 51% (p = 0.001) at 10 years. In multivariable Cox analysis, overall 10-year survival correlated with a high predicted VO2 peak% (p = 0.001) and low N-stage corresponding to N0 and N1 (p < 0.001). Non-tumour-related death correlated with low VO2 peak% of predicted (p = 0.001), and age (p < 0.001). Low preoperative VO2 peak was associated with both decreased postoperative overall survival and decreased non-tumour-related survival during the 10-year follow-up.

Prediction of Postoperative Clinical Outcomes in Resected Stage I Non-Small Cell Lung Cancer Focusing on the Preoperative Glasgow Prognostic Score.

Background: The Glasgow Prognostic Score (GPS), which consists of albumin and C-reactive protein (CRP), may predict overall survival (OS) in cancer patients. The aim of this retrospective analysis was to evaluate the clinical impact of the preoperative GPS on patients with resected early stage non-small cell lung cancer (NSCLC). Methods: 300 patients with curatively resected stage I NSCLC were followed-up for OS, recurrence-free survival (RFS), cancer-specific survival (CSS), and death from other causes. Results: 229 patients (76%) had a preoperative GPS of 0, and 71 (24%) a GPS ≥ 1. The three-year probabilities of RFS, OS, CSS, and death from other causes were 81%, 84%, 88%, and 96% in patients with GPS = 0, and 79%, 74%, 91%, and 82% in patients with a GPS ≥ 1, respectively. GPS ≥ 1 was significantly associated with a higher risk of death from other causes (p = 0.022), serving as an independent predictor of death from other causes (p = 0.034). Pathologically elevated CRP levels (CRP > 5 mg/L) were found in 91 patients (30%). The mean CRP level was 7.88 ± 15.80 mg/L (0.5-135.6 mg/L). Pre-treatment CRP level was significantly associated with coronary heart disease (p < 0.0001), histology (p = 0.013), tumor size (p = 0.018), tumor stage (p = 0.002), and vascular invasion (p = 0.017). Conclusion: The preoperative GPS predicts adverse survival outcomes in patients with resected stage I NSCLC.

The Biological and Clinical Relevance of Inhibitor of Growth (ING) Genes in Non-Small Cell Lung Cancer.

Carcinogenic mutations allow cells to escape governing mechanisms that commonly inhibit uncontrolled cell proliferation and maintain tightly regulated homeostasis between cell death and survival. Members of the inhibition of growth (ING) family act as tumor suppressors, governing cell cycle, apoptosis and cellular senescence. The molecular mechanism of action of ING genes, as well as their anchor points in pathways commonly linked to malignant transformation of cells, have been studied with respect to a variety of cancer specimens. This review of the current literature focuses specifically on the action mode of ING family members in lung cancer. We have summarized data from in vitro and in vivo studies, highlighting the effects of varying levels of ING expression in cancer cells. Based on the increasing insight into the function of these proteins, the use of ING family members as clinically useful biomarkers for lung cancer detection and prognosis will probably become routine in everyday clinical practice.

Interposition of Retrosternal Pedicled Jejunum After Hypopharyngolaryngo-Esophagogastrectomy.

Reconstruction of the upper gastrointestinal tract presents a surgical challenge after esophagogastrectomy, especially when it includes hypopharyngolaryngectomy. Reconstruction is generally undertaken with interposed colon as a substitute conduit, but it carries several risks. Alternative reconstruction of the foregut with pedicled retrosternal jejunum anastomosed at the level of the base of the tongue is described.

Influence of eukaryotic translation initiation factor 6 on non-small cell lung cancer development and progression.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide. Dysregulation of protein synthesis plays a major role in carcinogenesis, a process regulated at multiple levels, including translation of mRNA into proteins. Ribosome assembly requires correct association of ribosome subunits, which is ensured by eukaryotic translation initiation factors (eIFs). eIFs have become targets in cancer therapy studies, and promising data on eIF6 in various cancer entities have been reported. Therefore, we hypothesised that eIF6 represents a crossroad for pulmonary carcinogenesis. High levels of eIF6 are associated with shorter patient overall survival in adenocarcinoma (ADC), but not in squamous cell carcinoma (SQC) of the lung. We demonstrate significantly higher protein expression of eIF6 in ADC and SQC than in healthy lung tissue based on immunohistochemical data from tissue microarrays (TMAs) and on fresh frozen lung tissue. Depletion of eIF6 in ADC and SQC lung cancer cell lines inhibited cell proliferation and induced apoptosis. Knockdown of eIF6 led to pre-rRNA processing and ribosomal 60S maturation defects. Our data indicate that eIF6 is upregulated in NSCLC, suggesting an important contribution of eIF6 to the development and progression of NSCLC and a potential for new treatment strategies against NSCLC.

Frequency and clinical impact of preoperative circulating tumor cells in resectable non-metastatic lung adenocarcinomas.

OBJECTIVES: Despite successful surgery, 30-50% of patients with resectable non-small cell lung cancer develop tumor recurrence within 5 years of surgery. MATERIALS AND METHODS: In this prospective study, we performed CTC enumerations in 40 patients with non-metastatic lung adenocarcinoma (NMLA) using a size-based microfilter. Additionally, cfDNA isolated from plasma was analyzed in 35 out of 40 patients. RESULTS: CTCs were identified in 15 out of 40 patients (37.5%) with a range of 1-44 cells, whereas mutated cfDNA was only detected in 3 out of 35 patients (8.6%). Disease-free survival (DFS) was significantly associated with CTC positivity (log-rank p=0.025), grading (log-rank p=0.019), tumor stage (log-rank p=0.025) and lymph node status (log-rank p=0.029). Multivariate analysis, including tumor stage and grading, showed that CTC positivity (p=0.006), grading (0.039) and tumor stage (p=0.022) were independently associated with DFS. CONCLUSION: Our study found that microfilter-based CTC enumeration in NMLA patients is an independent predictor of worse DFS. The used NGS-based cfDNA characterization had limited sensitivity to be clinically informative in our study cohort. CTC assessment before surgery can thus identify NMLA patients at high risk of disease recurrence.

Clinical impact of interleukin 6 as a predictive biomarker in the early diagnosis of postoperative systemic inflammatory response syndrome after major thoracic surgery: A prospective clinical trial.

BACKGROUND: Postoperative systemic inflammatory response syndrome and sepsis are associated with high morbidity and mortality rates. Early detection of postoperative systemic inflammatory response syndrome improves the outcome. The aim of this study was to evaluate the feasibility of interleukin 6 as a predictive biomarker in the early diagnosis of postoperative systemic inflammatory response syndrome after a major thoracic operation. METHODS: A total of 94 patients were enrolled in this prospective, clinical, single-center study. The enrolled subjects underwent either lung resection or esophageal operation. Interleukin 6, procalcitonin, C-reactive protein, and leucocytes were measured sequentially before, during, and after the operation. These levels were compared between patients who developed postoperative systemic inflammatory response syndrome and those who did not. RESULTS: The enrollees who completed the study included of 55 males (79.7%) and 14 females (20.3%) with a mean age of 60.9 years. Twenty patients (29.0%) developed systemic inflammatory response syndrome at a median time of 33.0 hours postoperatively. In cases of postoperative systemic inflammatory response syndrome, interleukin 6 was the most predictive biomarker, showing a striking increase on the day of operation and preceding the median onset of postoperative systemic inflammatory response syndrome, which occurred the next day (P ≤ .001). Peak procalcitonin and C-reactive protein occurrence were significantly delayed at 24 hours (P = .012) and 48 hours (P = .012). There was no mortality 30 days postoperatively. CONCLUSION: Interleukin 6 is a reliable predictor of postoperative systemic inflammatory response syndrome, and it is able to detect postoperative system inflammatory response syndrome before the onset of related clinical symptoms. When identifying patients at high risk, it would be beneficial to include interleukin 6 in conventional postoperative monitoring, particularly after extended surgical resection.

Stage-based treatment for thymoma in due consideration of thymectomy: a single-center experience and comparison with the literature.

BACKGROUND: Thymomas represent an uncommon and heterogeneous group of intrathoracic malignancies which require different treatments corresponding to their individual tumor stage. The objective of this study was to review the efficacy of our applied stage-based treatment for thymoma in due consideration of thymectomy. METHODS: This is a single-center, institutional review board-approved retrospective study of 50 consecutive patients with thymoma treated at our division within 10 years. RESULTS: There were 29 women (58 %) and 21 men (42 %), mean age 58.3 years. Twenty nine (58 %) had clinical symptoms and 14 (28 %) had myasthenia gravis. Forty-five patients (90 %) underwent thymectomy and complete resection was done in 42 cases (93.3 %). Histologic results were 6 subtype A, 5 AB, 8 B1, 12 B2, 12 B3, and 7 C. The Masaoka staging system revealed 20 stage I, 18 stage II, 6 stage III, and 6 stage IV. Two patients had neoadjuvant therapy and 25 received postoperative treatment. Five (11.1 %) had tumor recurrence, treated with re-resection. The 5-year disease-free survival was 91.5 %. Two patients died of tumor progression and three died of other causes (10 %). The 5-year overall survival was 82.3 % and the median survival time was 92.1 months. The 5-year survival rate after thymectomy was 87.2 % and the median survival was 92.1 months. CONCLUSIONS: Complete resection still remains the mainstay in the treatment of non-metastatic thymoma and should be performed whenever feasible. Close multidisciplinary teamwork is mandatory to optimize the neurologic outcome and to prolong postoperative survival.

Severe methaemoglobinaemia treated with adjunctive hyperbaric oxygenation.

Methaemoglobinaemia results from exposure to oxidizing substances such as nitrates or nitrites. Iron within haemoglobin is oxidized from the ferrous to the ferric state, which blocks the transport of oxygen and carbon dioxide, with subsequent inhibition of the respiratory chain. We describe the case of a 23-year-old male suffering from severe methaemoglobinaemia of 68% after consumption of nitrites ('poppers') in association with considerable ethanol consumption. Toluidine-blue was administered as first-line antidotal therapy immediately followed by hyperbaric oxygenation (HBOT). HBOT resulted in enhanced reduction of methaemoglobin, and rapid tissue re-oxygenation by the oxygen dissolved in plasma was provided, independent of the degree of methaemoglobinaemia. The patient recovered uneventfully and was discharged three days later. This case illustrates the potential of supportive HBOT as a time-saving therapeutic tool in this unusual situation, enabling a quick and sustained reduction in methaemoglobinaemia.

Application of Hyperbaric Oxygen Reduce Oxidative Damage of Plasmatic Carbonyl Proteins and 8-OHdG by Activating Glutathion Peroxidase.

BACKGROUND: It is postulated that application of hyperbaric oxygenation may induce the production of radicals after HBO. Higher oxygenation and transport of oxygen increase the mitochondrial energy turnover, whereas inner mitochondrial radical formation decreases. METHODS: Several markers of oxidative stress in healthy volunteers (n = 21), including plasma carbonyl proteins (CP), malondialdehyde (MDA), oxidized LDL (oxLDL), 8-hydroxy-deoxyguanosine (8-OHdG), and erythrocyte glutathione peroxidase (GPx) activity are measured before, during, and after HBO. RESULTS: Median plasma concentrations of CP decreased significantly during HBO compared to CP levels before HBO (from 77.1 to 61.7 pmol/mg; p < 0.001) and increased again after HBO (to 78.1 pmol/mg; p = 0.035). 8-OHdG decreased significantly during HBO (8.1 ng/mL; p < 0.001) and remained constant after HBO (8.1 ng/mL) compared to "before HBO" (9.4 ng/mL). MDA increased significantly from 0.92 µM (before HBO) to 1.26 µM (during HBO, p < 0.01) and decreased again to 1.00 µM (after HBO, p = 0.023). Erythrocyte GPx activity also increased significantly during HBO (26.5 ± 14.7; p = 0.005), but not after HBO (25.6 ± 17.2 IU/mg). A negative correlation was observed between GPx and MDA only during HBO (r = -0.518; p = 0.016). CONCLUSIONS: We assume that higher oxygen consumption decreases, on the one hand, the inner mitochondrial generation of free radicals and, on the other, RONS by activation of detoxifying enzymes like GPx.

The influence of elevated levels of C-reactive protein and hypoalbuminemia on survival in patients with advanced inoperable esophageal cancer undergoing palliative treatment.

BACKGROUND AND OBJECTIVES: Inflammation perpetuates individual tumor progression resulting in decreased survival in cancer patients. The aim of our study was to evaluate the influence of elevated levels of C-reactive protein (CRP) as well as low levels of albumin on patients with inoperable esophageal carcinoma. METHODS: The data of 218 patients with advanced esophageal cancer, who were treated at a single center within 12 years, were evaluated retrospectively. Patient's age, gender, body weight, dysphagia, plasma levels of CRP and albumin, the Glasgow Prognostic Score (GPS) combining both indicators, and survival were assessed for statistical evaluation. RESULTS: Thirty-nine (18.2%) had hypoalbuminemia and 161 (73.9%) had elevated CRP levels. Patients with hypoalbuminemia (P = 0.001) as well as patients with increased CRP levels (P = 0.001) showed a significantly shorter survival. Weight loss was correlated to elevated plasma CRP (P = 0.022), to diarrhea (P = 0.021), and to dysphagia (P = 0.008). Increasing GPS was significantly associated with poor survival (P = 0.001). CONCLUSIONS: Elevated CRP levels and hypoalbuminemia are significantly associated with reduced survival and are considered to be an appropriate predictor for poor outcome in advanced esophageal carcinoma. The GPS provides additional detailed prognostication and should be therefore taken into consideration when the individual palliative strategy has to be scheduled.

Management of esophageal perforation in 120 consecutive patients: clinical impact of a structured treatment algorithm.

INTRODUCTION: The therapy of esophageal perforation is still challenging. The aim of this study was to assess the etiology, specific treatment, and outcome of esophageal disruption in order to generate an optimal therapeutic approach to improve patient's outcome. METHODS: We reviewed the cases of 120 consecutive patients with esophageal perforation treated within 10 years. RESULTS: Iatrogenic perforation was the most frequent cause of esophageal perforation (58.3 %); Boerhaave's syndrome was detected in 15 cases (6.8 %). Surgery was performed in 66 patients (55 %), 17 (14 %) patients received conservative treatment and 37 (31 %) patients underwent endoscopic stenting after tumorous perforation. Statistically significant impact on mean survival had Boerhaave's syndrome (p = 0.005), initial sepsis (p = 0.002), pleural effusion/empyema (p = 0.001), mediastinitis (p = 0.003), peritonitis (p = 0.001), and redo-surgery (p = 0.000). Overall mortality rate was 11.7 %, in the esophagectomy group 17 % and in the patients with Boerhaave's syndrome 33.3 %. CONCLUSIONS: An approach considering etiology and extent of perforation, diagnostic delay, and septic status is required to improve patient's outcome. Primary repair is feasible in patients without intrinsic esophageal disease and evidence of sepsis. The greater the diagnostic delay, the more the destruction of the esophageal wall especially in the case of septic esophageal disease, thus the stronger the argument for esophagectomy if anatomically and/or oncologically possible.

Multimodal therapy of malignant pleural mesothelioma: is the replacement of radical surgery imminent?

OBJECTIVES: Malignant pleural mesothelioma (MPM) remains an aggressive thoracic malignancy associated with poor prognosis. There is no standard treatment regimen, and particularly, the impact of radical surgery remains controversial. The main goal of our retrospective single-centre study was to evaluate the surgical and non-surgical treatment modalities applied at our division regarding their effect on the patient's survival. METHODS: During the last decade, 82 patients with histologically confirmed MPM were treated at our division. The complete clinical records of 61 patients were eligible for statistical evaluation. RESULTS: There were 14 women (23%) and 47 men (77%) with a mean age of 63.7 years. Epitheloid subtype was found in 48 patients (78.7%), sarcomatoid in 3 (4.9%) and biphasic in 10 (16%). Surgery as the first treatment modality was performed in 44 patients (72.1%). Pleurectomy/decortication was done in 28 cases (45.9%), extended pleurectomy/decortication was performed in 13 (21.3%) and extrapleural pneumonectomy in 3 (4.9%). Additional intraoperative photodynamic therapy was administered in 20 patients, 34 underwent chemotherapy (55.7%) and 12 had radiotherapy (19.7%). Mean survival time for the collective was 18.3 months. Five-year survival was 17% in the epitheloid histology group, where patients treated with chemotherapy alone yielded a significant increase in survival (P = 0.049), and those with other subtypes survived for a maximum of 20.6 months. CONCLUSIONS: Chemotherapy and pleurectomy/decortication can extend the survival time of patients with MPM remarkably. The adequate treatment options have to be tailored to the specific particular needs of each patient considering histological subtype, tumour stage and patient's individual functional assessment as well as comorbidity.