Erlotinib has comparable clinical efficacy to chemotherapy in pretreated patients with advanced non-small cell lung cancer (NSCLC): A propensity-adjusted, outcomes research-based study.

OBJECTIVES: Controversy exists about the integration of erlotinib in patients with EGFR wildtype, advanced NSCLC. MATERIALS AND METHODS: We included patients with advanced NSCLC receiving at least two lines of palliative systemic treatment between January 2005 and December 2014 and not harbouring targetable driver mutations. Primary study endpoint was overall survival (OS), secondary endpoint progression-free survival (PFS). We used Kaplan-Meier statistics, multivariate Cox regression and Propensity score or Inverse Probability Weights (IPW) matching to compare clinical outcome between patients receiving erlotinib in second or further line and those receiving chemotherapy only. The study had a power of 90% to detect a survival superiority of 30%. RESULTS: From a total of 827 patients, we excluded 171 patients with potentially curative treatment, 189 receiving treatment outside of our institute, 206 receiving no or only one line of systemic treatment, 6 with ALK translocations and 28 with EGFR mutations. From 227 patients in the final efficacy analysis, 125 patients received erlotinib in second (89 patients), third (28) or further-line (8), and 102 patients received chemotherapy only. Women and never smokers were significantly overrepresented in the erlotinib group. Both OS (hazard ratio (HR)=1.14, 95% CI 0.80-1.63, P=0.448) and PFS (HR=1.20, 95% CI 0.95-1.52, P=0.119) were similar in the erlotinib compared to the chemotherapy group using IPW-adjusted Cox regression analysis treating the use of erlotinib as a time-dependent covariate starting from second-line treatment and stratified for ECOG performance status and treatment line. ECOG performance status was the most powerful covariate to select patients for erlotinib treatment. CONCLUSION: The present study suggests erlotinib to have similar clinical efficacy compared to chemotherapy in patients with pretreated advanced NSCLC and no known molecular targetable alterations.

Extra-anatomical VATS lung resection: the outpatient experience with the aid of a digital chest drain device.

OBJECTIVE: The aim of the present study was to evaluate of the feasibility of video-assisted thoracic surgery (VATS) wedge resections in an outpatient setting using a digital air leak detection device. PATIENTS AND METHODS: Data from all patients who underwent outpatient VATS wedge resections from November 2010 to November 2013 was analyzed. The thoracoscopic approach was done in all cases under general anesthesia, with double lumen intubation, three port sites and one or two wedge resections without the reinforcement of the suture line. The chest-drain with continuous suction (-20 cm/H2O) placed after surgery was removed when no air leak (0-10 ml/min) was detected digitally within two hours after surgery. Patients were discharged after exclusion of pneumothorax by chest x-ray. Patient distribution according to gender, smoking habit, indication for resection, number of wedge resections, and histological findings was compared. RESULTS: In the study period, 66 VATS patients (44.3%) of al VATS procedures were eligible for the outpatient procedure. Fifty-five of them (83.3%) were discharged on the same day, while 11 were admitted due to patients preference, presence of an air leak or for other medical reasons. In the outpatient group (OG) the indications for surgery were lung nodules in 90.9% (50 cases) and interstitial disease in the remaining 9.1%. In the OG, 18 patients (32.7%) received two wedge resections. All patients had no leak detected by digital device prior to drainage removal. The overall re-admission rate was 7.3% (4/55). Statistical analysis did not show any difference regarding sex, smoking habits, indications for surgery, number of parenchymal resection, disease localization, and malignant histology. All patients who had an outpatient procedure confirmed that they would repeat the procedure. CONCLUSIONS: Outpatient thoracoscopic non-anatomic resections managed with a digital chest drain device have both low complication rates as well as lead to fewer re-admissions. Because of the growing number of VATS Wedge Resections due to pre-identified lung nodules, this could have important implications. Further research should identify the most suitable subgroup of patients for this approach.

Advanced Lemierre syndrome requiring surgery.

A 38-year-old homeless man was admitted with a 2-week history of a sore throat, increasing shortness of breath, and high fever. Clinical examination showed enlarged and tender submandibular and anterior cervical lymph nodes and a pronounced enlargement of the left peritonsillar region (Figure 1a). CT scan of the throat and the chest showed left peritonsillar abscess formation, occlusion of the left internal jugular vein with inflammatory wall thickening and perijugular soft tissue infiltration, pulmonary abscesses, and bilateral pleural effusions (Figures 1b-e, arrowed). Anaerobe blood cultures grew Fusobacterium necrophorum, leading to the diagnosis of Lemierre's syndrome. Treatment with high-dose amoxicillin and clavulanic acid improved the oropharyngeal condition, but the patient's general status declined further, marked by dyspnea and tachypnea. Repeated CT scans showed progressive lung abscesses and bilateral pleural empyema. Bilateral tonsillectomy, ligation of the left internal jugular vein, and staged decortication of bilateral empyema were performed. Total antibiotic therapy duration was 9 weeks, including a change to peroral clindamycin. Clinical and laboratory findings had returned to normal 12 weeks after surgery.The patient's history and the clinical and radiological findings are characteristic for Lemierre's syndrome. CT scans of the neck and the chest are the diagnostic methods of choice. F. necrophorum is found in over 80% of cases of Lemierre's syndrome and confirms the diagnosis. Prolonged antibiotic therapy is usually sufficient, but in selected patients, a surgical intervention may be necessary. Reported mortality rates are high, but in surviving patients, the recovery of pulmonary function is usually good.

Transbronchial administration of adenoviral-mediated interleukin-10 gene to the donor improves function in a pig lung transplant model.

Interleukin-10 (IL-10) gene transfection of donor lungs prior to transplantation is an attractive strategy to reduce ischemia-reperfusion induced lung injury. However, experimental data with gene therapy in large animal models of lung transplantation are generally lacking. We have developed a simple clinically applicable technique for adenoviral-mediated gene delivery of human IL-10 to the lung of large animals that provides homogenous gene expression after 12-24 h of transfection. Using this technique of gene delivery, we have studied the dynamics of adenoviral gene delivery to the lung in the setting of lung transplantation. Although there is a persistent inflammatory response to the adenoviral vector, we achieved significant expression of human IL-10 in lung tissue before lung retrieval to obviate the deleterious impact of the adenoviral vector on the donor lung. The administration of adenoviral-mediated human IL-10 to the donor lung reduced ischemia-reperfusion injury and improved graft function after lung transplantation in this pig lung transplantation model. Transfection of adenoviral-mediated human IL-10 to the donor lung prevented the release of inflammatory cytokines such as IL-6 in lung tissue and plasma. We have demonstrated that IL-10 gene therapy has significant potential to prevent or treat the inflammatory response associated with ischemia-reperfusion injury in lung transplantation. In the future, IL-10 gene therapy could also be used for immunomodulation or tolerance induction.

Normal gas exchange after 30-h ischemia and treatment with phosphodiesterase inhibitor PDI747.

OBJECTIVE: Phosphodiesterases (PDEs) negatively regulate the concentrations of cAMP and/or cGMP, which act as downstream second messengers to the prostaglandins. PDE type-4 (PDE4) is selective for cAMP and is found in high concentrations in endothelial, epithelial, and different blood cells. The aim of this study was to evaluate if PDI747, a novel selective inhibitor of PDE4, can restore pretransplant cAMP levels and thereby posttransplant organ function after prolonged cold ischemia. METHODS: Left lung transplantation was performed in pigs (25-31 kg). Donor lungs were flushed with low potassium dextran glucose (LPDG) solution only (control, n=5)or, in addition with 1 micromol of PDI747 (PDI747, n=5) and stored for 30 h at 1 degrees C. PDI747 animals further received a bolus of PDI747 (0.3 mg/kg) 15 min prior to reperfusion and a continuous infusion (0.3 mg/kg per hour) during the 5 h after reperfusion. After occlusion of the right pulmonary arteries and the right main bronchus, hemodynamic and gas exchange parameters and extravascular lung water (EVLW) levels of the transplanted lung were assessed. RESULTS: Two control animals died of severe lung edema leading to heart failure (control, n=3). One animal in the treatment group was excluded due to a patent ductus arteriosus (PDI747, n=4). Gas exchange at the end of the experiment was restored to normal levels in the PDI747 group (Pa, O(2) 47.6+/-11.2 kPa, Pa,CO(2) 6.4+/-1.8 kPa) but not in the control group (Pa, O(2) 7.7+/-2.9 kPa, Pa, CO(2) 11.9+/-3.0 kPa, P(PaO2)<0.0001, P(Pa, CO2)=0.06). Extravascular lung water (EVLW) was normal in the PDI747 group (8.5+/-1.1 ml/kg) and clearly elevated in the control group (16.2+/-5.6 ml/kg, P=0.007). Airway pressure in the PDI747 group was significantly lower than in the control group (7.8+/-0.5 cm H(2)O vs. 11.3+/-0.6 cm H(2)O, respectively, P<0.0001). The free radical mediated tissue injury measured by lipid peroxidation (TBARS) was significantly reduced (P=0.001) in the PDI747 group. CONCLUSIONS: With the inhibition of PDE4 with PDI747 we achieved normal gas exchange, no posttransplant lung edema, normal airway pressures, and a reduced free radical injury after 30 h of cold ischemia.

Trimetazidine protects the energy status after ischemia and reduces reperfusion injury in a rat single lung transplant model.

BACKGROUND: Ischemia-reperfusion injury involves free radical generation and polymorphonuclear neutrophil chemotaxis. Trimetazidine is an anti-ischemic drug that restores the ability of the ischemic cells to produce energy and reduces the generation of oxygen-derived free radicals. We evaluated the effect of trimetazidine against ischemia-reperfusion injury after lung transplantation. METHODS: Rat single lung transplantation was performed in 3 experimental groups (n = 5): (1) the immediate transplantation group was defined as animals undergoing transplantation immediately after harvest without treatment; (2) the ischemic control group was defined as animals undergoing transplantation after 18 hours of cold (4 degrees C) ischemia without treatment; and (3) the trimetazidine-treated group was defined as animals undergoing transplantation after 18 hours of cold (4 degrees C) ischemia and donor and recipient treatment with 5 mg/kg intravenous trimetazidine 10 minutes before harvest and reperfusion, respectively. All donor lungs were flushed with low-potassium dextran-glucose solution. After 2 hours of reperfusion, oxygenation was measured, and lung tissue was frozen and assessed for adenosine triphosphate content, myeloperoxidase activity, and thiobarbituric acid-reactive substances. Peak airway pressure was recorded throughout the reperfusion period. RESULTS: The trimetazidine group showed significantly higher levels of adenosine triphosphate content (1.73 +/- 0.8 pmol vs 0.72 +/- 0.2 pmol [ischemic control], P =.008), better oxygenation (238.82 +/- 113.9 mm Hg vs 89.39 +/- 14.7 mm Hg [ischemic control], P =.008), and reduced lipid peroxidation (1.28 +/- 0.1 nmol/g vs 2.09 +/- 0.4 nmol/g [ischemic control], P =.008). Adenosine triphosphate levels of the trimetazidine group were comparable with those of the immediate transplantation group (1.73 +/- 0.8 pmol vs 1.89 +/- 0.5 pmol, respectively; P =.31). Peak airway pressure and myeloperoxidase activity were comparable among groups. CONCLUSION: Donor and recipient treatment with trimetazidine provided a significant protection of the energy status, better oxygenation, and reduced lipid peroxidation in this experimental model. Our data suggest that trimetazidine may be an important adjunct to prolong ischemic time safely and to decrease lung ischemia-reperfusion injury.

Accelerated treatment for early and late postpneumonectomy empyema.

BACKGROUND: Postpneumonectomy empyema is a rare but serious complication of pneumonectomy. Despite use of various therapeutic approaches and techniques during the last five decades, successful therapy remains difficult and is often associated with high morbidity and prolonged hospitalization. METHODS: We evaluated a concept for accelerated treatment, which consists of radical debridement of the pleural cavity and packing with wet dressings of povidoneiodine. This was repeated in the operating theater every second day, until the chest cavity was macroscopically clean. If present, bronchial stump insufficiency was closed and secured by omentopexy. Finally, the pleural space was obliterated with antibiotic solution. RESULTS: Twenty patients, 13 with early postpneumonectomy empyema (10 to 89 days; mean, 37 days) and 7 with late postpneumonectomy empyema (124 to 7,200 days; mean, 1,126 days) were treated. Fifteen patients presented with bronchopleural fistula (11 right, 4 left), which developed after chemotherapy (n = 6) or after radiotherapy (n = 3) (unknown cause in 4 patients). Six patients were referred after previously unsuccessful surgical attempts. Pleural cultures were positive in 17 cases for one or several bacteria including fungoides (n = 2). The average number of interventions was 3.5 (3 to 5). The chest was definitively closed in all patients within 8 days. Mean hospitalization time was 17 days (7 to 35 days). During the same hospitalization, 2 patients needed reoperation because of an undetected bronchopleural fistula. Postpneumonectomy empyema was successfully treated in all patients. There was no in-hospital or 3-month postoperative mortality. CONCLUSIONS: Repeated surgical debridement combined with closure of bronchopleural fistula and antimicrobial therapy enables successful treatment of early and late postpneumonectomy empyema within a short period and is a well-tolerated concept.

Recipient treatment with trimetazidine improves graft function and protects energy status after lung transplantation.

BACKGROUND: Ischemia-reperfusion injury remains an important obstacle to successful lung transplantation. Trimetazidine is an anti-ischemic drug that restores the ability of ischemic cells to produce energy and reduces the generation of oxygen-derived free radicals. The aim of this study was to assess the protective effect of trimetazidine after prolonged ischemia in lung transplantation. METHODS: Rat single-lung transplantation was performed in 4 experimental groups (n = 5 each). In all groups, transplantation was performed after 18 hours of cold (4 degrees C) ischemia. All donor lungs were flushed with low-potassium dextran-glucose (LPDG) solution that also contained 500 microg/liter prostaglandin estradiol (E(1)). Groups studied included: Group I: flush solution was administered containing 10(-6) mol/liter trimetazidine (TMZ), neither donor nor recipient treatment given; Group II: donors were treated with 5 mg/kg intravenous TMZ 10 minutes prior to harvest, but the flush solution did not contain TMZ; Group III: recipients treated with 5 mg/kg intravenous TMZ 10 minutes before reperfusion, and flush solution contained 10(-6) mol/liter trimetazidine; Group IV: ischemic control group. After 2 hours of reperfusion, oxygenation was measured and lung tissue was frozen and assessed for adenosine triphosphate (ATP) content, myeloperoxidase (MPO) activity and thiobarbituric acid-reactive substances (TBARS). Peak airway pressure (PawP) was recorded throughout the reperfusion period. RESULTS: Group III showed significantly higher levels of ATP content (11.1 +/- 5.01 pmol vs Group I, 3.36 +/- 1.8 pmol, p = 0.008; vs Group II, 4.7 +/- 1.9 pmol, p = 0.03; vs Group IV, 0.7 +/- 0.2 pmol, p = 0.008), better oxygenation (442.5 +/- 26.5 mm Hg, vs Group I, 161.06 +/- 54.5 mm Hg; vs Group II, 266.02 +/- 76.9 mm Hg; vs Group IV, 89.4 +/- 14.7 mm Hg, p = 0.008) and reduced lipid peroxidation (TBARS) (0.15 +/- 0.03 nmol/g; vs Group I, 1.04 +/- 0.76 nmol/g; vs Group II, 0.69 +/- 0.4 nmol/g; vs Group IV, 2.29 +/- 0.4 nmol/g, p = 0.008). PawP and MPO activity were comparable in the 4 study groups. CONCLUSION: Recipient treatment with TMZ provided significant protection of energy status, better oxygenation and reduced lipid peroxidation. Our data suggest that TMZ may be an important adjunct in the prevention of post-transplant lung ischemia-reperfusion injury.

Thoracoscopic lobectomy for benign disease--a single centre study on 64 cases.

OBJECTIVE: Chronic lung infection is the main indication for lobectomy in benign pulmonary disease and may be technically demanding due to inflammatory changes such as adhesions, lymph node enlargement and neovascularization. The role of the thoracoscopic operation in these indications is yet ill-defined. METHODS: We retrospectively analyzed the results of patients who underwent thoracoscopic lobectomy (TL) between 1992 and June 1999 and compared this study group with patients who underwent open lobectomy (OL), all for benign disease. Data were not normally distributed, therefore, the median and range is given and nonparametric statistical analysis was applied. RESULTS: A total of 117 lobectomies for benign disease (64 TL) were analyzed. Indications included bronchiectasis (36 TL; 18 OL), chronic infections (13 TL; eight OL), tuberculosis (five TL; 15 OL), emphysema (five TL; one OL), AV-malformations (two TL; one OL), severe haemoptysis (four OL), and others (three TL; six OL). Twelve conversions to thoracotomy were necessary due to severe adhesions. One patient in the open lobectomy group died within 30 days postoperative. Drainage time was 5.0 (1-32) days in TL and 6.0 (3-21) days in OL, hospital stay was 8.5 (4-41) days and 10.0 (5-52) days, respectively. Blood loss was 0 (0-2000) ml in TL and 300 (0-6000) ml in OL. Operation time for thoracoscopic lobectomies significantly decreased from 2.5 (1-6) h for cases between 1992 and 1997 (n=49) to 1.5 (0.5-2.5) h for recent cases (n=15) (P<0.01). In addition, a trend towards less blood loss was noted (100 (0-2000) ml vs. 0 (0-400) ml; P=0.06). Drainage time and hospital stay did not differ significantly. CONCLUSIONS: Thoracoscopic lobectomy in chronic inflammatory disease can be performed safely in selected patients, especially with bronchiectasis. Conversion rate to thoracotomy is low. Operation time with this approach declined significantly over time.

Modified Elmslie-Trillat procedure for instability of the patella.

The purpose of this study was to determine whether or not the modified medial transfer of the ligamentum patellae in case of objective instability of the patella is an adequate therapy and if it is possible to improve the patellar congruence angle by this method. Between October 1987 and April 1993, 41 operations were performed in 37 patients with medialization of the medial third of the ligamentum patellae with the corresponding part of the tibial tubercule. Four patients needed a bilateral operation; the two interventions were not performed at the same time. Thirty-six operated knees (88%) were examined at a median clinical and radiological follow-up of 62.8 months (+/- 15.8 SD). For evaluation, the objective and subjective Turba score was used, and pre- and postoperative X-rays were compared. The patients' average age at the time of intervention was 23.2 years (+/- 7 years SD). The operation was performed 39 times for recurrent dislocation or subluxation, for patella alta with cartilage tissue damage, and for first time traumatic dislocation. The only postoperative complication was a temporary peroneal paresis. There were no redislocations seen at the follow-up. One patient with repeated subluxations underwent an additional lateral release combined with a repair of the medial retinaculum. In all other cases, the Turba score showed good or excellent results (subjective 1.9; objective 0.8), the patellar congruence angle was significantly improved (P < 0.001), and there were no medial subluxations. We conclude that the transfer of the medial third of the ligamentum patellae for objective instability of the patella is a minimally invasive and adequate technique to improve significantly a pathological patellar congruence angle.