Ralph A. Schmid

Detection of extrathoracic metastases by positron emission tomography in lung cancer

BACKGROUNDnAccurate staging of non-small cell lung cancer is essential for treatment planning. We evaluated in a prospective study the role of whole-body 2-[18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) in mediastinal nodal staging with a positive predictive value of 96%. The study was continued to further evaluate the value of whole-body FDG PET in detecting unexpected extrathoracic metastases (ETMs) in patients qualifying for surgical treatment by conventional staging.nnnMETHODSnOne hundred patients underwent clinical evaluation, chest and upper abdominal computed tomography scan, mediastinoscopy (lymph nodes greater than 1 cm on computed tomography), and routine laboratory tests. In 94 patients with stage IIIa or less and 6 with suspected N3 a whole-body FDG PET was performed. If clinical signs of ETMs were present additional diagnostic methods were applied. All findings in the FDG PET were confirmed histologically or radiologically.nnnRESULTSnUnexpected ETMs were detected in 13 (14%) of 94 patients (stage IIIa or less) at 14 sites. In addition 6 of 94 patients were restaged up to N3 after PET. The suspected N3 disease (stage IIIb) on computed tomography was confirmed by PET in all 6 patients. There was no false positive finding of ETM. Weight loss was correlated with the occurrence of ETM: more than 5 kg, 5 of 13 patients (38%); more than 10 kg, 4 of 6 patients (67%). Pathologic laboratory findings were not predictive for ETM.nnnCONCLUSIONSnWhole-body FDG PET improves detection of ETMs in patients with non-small cell lung cancer otherwise elegible for operation. In 14% of patients (stage IIIa or less), ETMs were detected, and in total, 20% of the patients were understaged.

Buttressing the staple line in lung volume reduction surgery: a randomized three-center study

BACKGROUNDnThe intention of buttressing the staple line in lung volume reduction surgery is to reduce air leaks and to shorten the hospital stay. A randomized three-center study was carried out to test this hypothesis.nnnMETHODSnSixty-five patients with a mean age of 59.2 +/- 1.2 years underwent bilateral lung volume reduction surgery by video-assisted thoracoscopy using endoscopic staplers (ET 45B; Ethicon Endo-Surgery, Cincinnati, OH) either without or with bovine pericardium for buttressing (Peri-Strips Dry; Bio-Vascular, Inc, Saint Paul, MN). There were no differences between the control and treatment groups in lung function, degree of dyspnea, and arterial blood gases before and 3 months after LVRS.nnnRESULTSnSeven patients (3 in the treatment group) needed a reoperation because of persistent air leak. The median duration of air leaks was shorter in the treatment group (0.0 day [range, 0 to 28 days versus 4 days [range, 0 to 27 days); p < 0.001), confirmed by a shorter median drainage time in this group (5 days [range, 1 to 35 days] versus 7.5 days [range, 2 to 29 days); p = 0.045). Hospital stay was comparable between the two groups (9.5 days [range, 6 to 44 days] versus 12.0 days [range, 5 to 46 days]; p = 0.14).nnnCONCLUSIONSnButtressing the staple line significantly shortens the duration of air leaks and the drainage time. As hospital stay did not differ significantly between the two groups, cost-effectiveness may depend on the local situation.

Apoptosis induced by ischemia and reperfusion in experimental lung transplantation.

BACKGROUNDnApoptosis is a distinct form of single-cell death in response to injury. Time course of apoptosis in lung parenchymal cells during posttransplant reperfusion and the influence of oxygen content during preservation on apoptosis of parenchymal cells are studied.nnnMETHODSnOrthotopic syngenic single left lung transplantation was performed in male Fischer (F344) rats after 18 hours of cold ischemia (n = 5 in all groups). Apoptotic cells were stained by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) technique. Strictly TUNEL-positive pneumocytes were counted on anonymized slides by a pathologist on 100 fields (x400) per specimen (mean +/- SEM).nnnRESULTSnThe peak of apoptotic pneumocytes occurred 2 hours after reperfusion (16.8 +/- 2.2 pneumocytes/100 fields [p/100f]; p = 0.000012 vs controls, lungs fixed after 18 hours of ischemia), whereas the lowest level of apoptotic pneumocytes was seen in lungs fixed after harvest (1.4 +/- 0.51 p/100f) and lungs not undergoing reperfusion (2.8 +/- 0.49 p/100f). Four hours after reperfusion, the number of apoptotic pneumocytes was lower than 2 hours after reperfusion (13.6 +/- 3.1 p/100f; p = 0.00032 vs controls), with a further decline at 8 hours (6.4 +/- 1.5 p/100f) and 12 hours after reperfusion (4.0 + 1.2 p/100f). Interestingly, lungs inflated with N2 before storage revealed a significantly lower level of TUNEL-positive pneumocytes 2 hours after reperfusion (8.8 2.0 p/100f) compared with lungs inflated with 100% O2 (p = 0.0052).nnnCONCLUSIONSnApoptosis of pneumocytes after posttransplant lung reperfusion is a very early event. Prolonged hypothermic preservation without reperfusion, however, does not lead to an elevated rate of apoptotic pneumocytes in lung grafts.

Two years’ outcome of lung volume reduction surgery in different morphologic emphysema types ☆

BACKGROUNDnLung volume reduction surgery (LVRS) improves dyspnea, pulmonary function, and quality of life in selected patients with severe emphysema. We investigated the role of emphysema morphology in 37 patients as an outcome predictor for up to 2 years after operation.nnnMETHODSnPatients selected for bilateral thoracoscopic LVRS were divided, according to a simplified emphysema morphology classification, into three groups (homogeneous, moderately heterogeneous, and markedly heterogeneous) based on a preoperative chest computed tomogram. Pulmonary function, walking distance, and dyspnea were assessed.nnnRESULTSnFunctional improvement after LVRS was best in markedly heterogeneous emphysema with an increase from preoperative forced expiratory volume in 1 second of 31% +/- 2% (mean +/- standard error of the mean) to 52% +/- 4% of predicted postoperatively. It was significantly higher than in homogeneous emphysema (from 26% +/- 1% to 38% +/- 2% predicted) and in intermediately heterogeneous emphysema (from 29% +/- 2% to 44% +/- 45% predicted). At 24 months postoperatively, forced expiratory volume in 1 second and dyspnea score continued to be significantly better than preoperative levels in all three morphologic groups. The survival rate was highest in patients with markedly heterogeneous emphysema.nnnCONCLUSIONSnFunctional and subjective improvements were maintained after LVRS for at least 24 months in patients with heterogeneous or homogeneous emphysema type.

Complications in the native lung after single lung transplantation

OBJECTIVESnSingle lung transplantation is a viable option for patients with end-stage pulmonary disease; despite encouraging results, we observed serious complications arising in the native lung. We retrospectively reviewed 36 single lung transplants to evaluate the incidence of complications arising in the native lung, their treatment and outcome.nnnMETHODSnBetween 1991 and 1997, 35 patients received 36 single lung transplants for emphysema (16), pulmonary fibrosis (14), lymphangioleiomyomatosis (4), primary pulmonary hypertension (1) and bronchiolitis obliterans (1). The clinical records were reviewed and the complications related to the native lung were divided into early (up to 6 weeks after the transplant) and late complications.nnnRESULTSnNineteen complications occurred in 18 patients (50%), leading to death in nine (25%). Early complications (within 6 weeks from the transplant) were bacterial pneumonia (1), overinflation (3), retention of secretions with bronchial obstruction and atelectasis (1), hemothorax (1), pneumothorax (1) and invasive aspergillosis (3); one patient showed active tuberculosis at the time of transplantation. Two patients developed bacterial pneumonia and invasive aspergillosis leading to sepsis and death. The other complications were treated with separate lung ventilation (1), bronchoscopic clearance (1), chest tube drainage (1) and wedge resection and pleurodesis (mechanical) by VATS (1). One patient with hyperinflation of the native lung eventually required pneumonectomy and died of sepsis. The patient with active tuberculosis is alive and well after 9 months of medical treatment. Late complications were recurrent pneumothorax (4), progressive overinflation with functional deterioration (2), aspergillosis (1) and pulmonary nocardiosis (1). Recurrent pneumothorax was treated with chest tube drainage alone (1), thoracoscopic wedge resection and/or pleurodesis (2) and pneumonectomy (1); hyperinflation was treated with thoracoscopic lung volume reduction in both cases; both patients with late infectious complications died.nnnCONCLUSIONSnAfter single lung transplantation, the native lung can be the source of serious problems. Early and late infectious complications generally result in a fatal outcome; the other complications can be successfully treated in most cases, even if surgery is required.

The nitric oxide synthase cofactor tetrahydrobiopterin reduces allograft ischemia-reperfusion injury after lung transplantation.

OBJECTIVEnExogenous nitric oxide reduces ischemia-reperfusion injury after solid organ transplantation. Tetrahydrobiopterin, an essential cofactor for nitric oxide synthases, may restore impaired endothelium-dependent nitric oxide synthesis. We evaluated whether tetrahydrobiopterin administration to the recipient attenuates lung reperfusion injury after transplantation in swine.nnnMETHODSnUnilateral left lung transplantation was performed in 15 weight-matched pigs (24-31 kg). Donor lungs were flushed with 1.5 L cold (1 degrees C) low-potassium-dextran solution and preserved for 20 hours. Group I animals served as controls. Group II and III animals were treated with a bolus of tetrahydrobiopterin (20 mg/kg). In addition, in group III a continuous infusion of tetrahydrobiopterin (10 mg/kg per hour over 5 hours) was given. One hour after reperfusion, the recipient right lung was occluded. Cyclic guanosine monophosphate levels were measured in the pulmonary venous and central venous blood. Extravascular lung water index, hemodynamic variables, lipid peroxidation, and neutrophil migration to the allograft were assessed.nnnRESULTSnIn group III a significant reduction of extravascular lung water was noted in comparison with the controls (P =.0047). Lipid peroxidation in lung allograft tissue was significantly reduced in group II (P =.0021) and group III ( P =. 0077) in comparison with group I. Pulmonary venous levels of cyclic guanosine monophosphate increased up to 23 +/- 1 pmol/mL at 5 hours in group II and up to 40 +/- 1 pmol/mL in group III (group I, 4.1 +/- 0.5 pmol/mL [I vs III]; P <.001), whereas central venous levels of cyclic guanosine monophosphate were unchanged in all groups.nnnCONCLUSIONnTetrahydrobiopterin administration during lung allograft reperfusion may reduce posttransplantation lung edema and oxygen-derived free radical injury in the graft. This effect is mediated by local enhancement of the nitric oxide/cyclic guanosine monophosphate pathway.

Laparoscopic Roux-en-Y choledochojejunostomy

OBJECTIVEnAlthough surgical biliary bypass for nonresectable periampullary tumors is superior to endoscopic stent placement, the latter has become popular because of the minimally invasive approach. Laparoscopic biliary bypass would appear to offer the advantages of both. However, this technique remains technically difficult using existing instrumentation. This study investigates the efficacy of a new endoscopic device designed for rapidly completing a small-diameter intestinal anastomosis under laparoscopic guidance.nnnMETHODSnEighteen female pigs (mean weight 35 kg, range 31 to 44) were randomly divided into three groups: animals undergoing handsewn (group H) or instrumental transient endoluminally stented anastomosis (TESA; groups P and D) laparoscopic Roux-en-Y choledochojejunostomy. For TESA two different reabsorbable stents were used, polyglycolic acid (PGA; group P) and polyurethane ester (Degrapol; group D). Blood chemistry, weight gain, and abdominal X-rays were taken weekly to document any possible migration or reabsorption of the radio-opaque stents. After 3 months, necropsy was performed. Patency of the biliary bypass and choledochojejunostomy were examined using fluoroscopy and measured by introducing graduated dilators into the anastomosis.nnnRESULTSnFluoroscopy revealed immediate passage of contrast through the anastomosis in all animals. Weight gain, bilirubin, and alkaline phosphatase were within normal range in all groups. Diameter of the bile duct (group H 10.7 +/- 2.9 mm/group P 9.5 +/- 3.6 mm/group D 11.0 +/- 4.6 mm) and choledochojejunostomy (group H 4.5 +/- 1.1 mm/group P 4.7 +/- 1.8 mm/group D 3.6 +/- 1.9 mm) did not differ. The time required to complete the biliary bypass was significantly decreased when TESA was applied (group H 152 +/- 13 min/group P 86 +/- 14 min, P <0.001/group D 110 +/- 20 min, P <0.002).nnnCONCLUSIONSnApplying TESA, laparoscopic choledochojejunostomy can be performed rapidly and safely, revealing good bypass function over a period of 3 months. With regard to treatment for nonresectable periampullary tumors, TESA may offer a new therapeutic approach combining the benefits of minimally invasive endoscopic stent placement with the functional results and lower readmission of conventional Roux-en-Y choledochojejunostomy.

Combined treatment with endothelin- and PAF-antagonists reduces posttransplant lung ischemia/reperfusion injury

BACKGROUNDnPathophysiologic changes of posttransplant lung ischemia/reperfusion injury are mediated by redundant cellular and humoral mechanisms. We investigated the protective effect of combined administration of platelet activating factor (PAF) and endothelin (ET) antagonists after prolonged ischemia in a small animal lung transplantation model.nnnMETHODSnOrthotopic left lung transplantation was performed after 20 hours cold ischemia in male Fischer (F344) rats weighing 200-250 g. Group I served as control. In Group II, donors received 1 mg/kg body weight of the endothelin antagonist TAK-044, and recipients 2 mg/kg. Group III was treated with the PAF antagonist TCV-309 (donor: 50 microg/kg; recipient: 100 microg/kg) (Takeda Chemicals Ltd.). Group IV received a combined treatment with both substances at the same dosage. Twenty-four hours after reperfusion, the native contralateral lung was occluded to assess gas exchange of the graft only, and 5 minutes later the thoracic aorta was punctured for arterial blood gas analysis (n = 5). In other animals (n = 5), lung tissue was frozen 24 hours after reperfusion and assessed for myeloperoxidase activity (MPO) and thiobarbituric acid reactive substances.nnnRESULTSnCombined inhibition of PAF and ET-1 at the receptor level resulted in significantly improved graft function as compared to controls (Group I), and to groups treated with either TAK-044 or TCV-309. This was determined by a higher arterial oxygen content (112 +/- 9 mmHg, p = .00061 vs control, 48 +/- 5 mmHg), reduced MPO activity (0.35 +/- 0.02 deltaOD/mg/min, p = .000002 vs control, 1.1 +/- 0.1 deltaOD/mg/min) and reduced lipid peroxidation (59.5 +/- 2.5 pmol/g, p = .011 vs control, 78.5 +/- 4.1 pmol/g). The improvement of arterial oxygen (Group II 77 +/- 10 mmHg, p = .027 vs control; Group III 84 +/- 8 mmHg, p = .0081 vs control) and reduction of MPO activity (Group II 0.85 +/- 0.061 deltaOD/mg/min, p = .017; Group III 0.92 +/- 0.079 deltaOD/mg/min, p = .058) in groups treated with either a PAF antagonist or an ET antagonist was significantly less than in Group IV.nnnCONCLUSIONSnCombined donor and recipient treatment with an ET antagonist and a PAF antagonist results in superior posttransplant graft function 24 hours after reperfusion, suggesting a synergistic role of ET-1 and PAF in the mediation of reperfusion injury in this model. Single treatment with either of the antagonists revealed only a slight improvement compared to untreated controls.

Lung volume reduction surgery combined with cardiac interventions.

OBJECTIVEnPostoperative course and functional outcome were evaluated in patients who underwent lung volume reduction surgery (LVRS) or in combination with valve replacement (VR), percutaneous transluminal coronary angioplasty (PTCA), placement of a stent, or coronary artery bypass grafting (CABG).nnnMETHODSnPatients with severe bronchial obstruction and hyperinflation due to pulmonary emphysema were evaluated for lung volume reduction surgery. Cardiac disorders were screened by history and physical examination and assessed by coronary angiography. Nine patients were accepted for LVRS in combination with an intervention for coronary artery disease (CAD). In addition, three patients with valve disease and severe emphysema were accepted for valve replacement (two aortic-, one mitral valve) only in combination with LVRS. Functional results over the first 6 months were analysed.nnnRESULTSnPulmonary function testing demonstrates a significant improvement in postoperative FEV1 in patients who underwent LVRS combined with an intervention for CAD. This was reflected in reduction of overinflation (residual volume/total lung capacity (RV/TLC)), and improvement in the 12-min walking distance and dyspnea. Median hospital stay was 15 days (10-33). One patient in the CAD group died due to pulmonary edema on day 2 postoperatively. One of the three patients who underwent valve replacement and LVRS died on day 14 postoperatively following intestinal infarction. Both survivors improved in pulmonary function, dyspnea score and exercise capacity. Complications in all 12 patients included pneumothorax (n = 2), hematothorax (n = 1) and urosepsis (n = 1).nnnCONCLUSIONnFunctional improvement after LVRS in patients with CAD is equal to patients without CAD. Mortality in patients who underwent LVRS after PTCA or CABG was comparable to patients without CAD. LVRS enables valve replacement in selected patients with severe emphysema otherwise inoperable.

8-Br-cGMP is superior to prostaglandin e1 for lung preservation

BACKGROUNDnSubstitution of the nitric oxide (NO) pathway reduces ischemia/reperfusion injury after lung transplantation. 8-Br-cGMP is a membrane-permeable analogue of cGMP, the second messenger of NO. In this study, we evaluated the effect of administration of 8-Br-cGMP in the flush solution on early graft function.nnnMETHODSnUnilateral left lung transplantation was performed in 10 weight-matched pairs of outbred pigs (24 to 31 kg). Donor lungs were flushed with 1.5 L cold (1 degree C) low potassium dextrane (LPD) solution and preserved for 20 hours. In group I (n = 5), 8-Br-cGMP (1 mg/kg) was added to the flush solution. In group II (n = 5), 8 microg/kg prostaglandin E1 (PGE1) was injected into the pulmonary artery (PA) before flush. One hour after reperfusion, the recipients contralateral right PA and bronchus were ligated to assess graft function only. cGMP levels in the PA and pulmonary vein were measured. Extravascular lung water index (EVLWI), pulmonary vascular resistance, mean PA pressure, and gas exchange (PaO2) were assessed during a 5-hour observation period. Lipid peroxidation (thiobarbituric acid-reactive substance) and neutrophil migration to the allograft (myeloperoxidase activity) were measured at the end of the assessment.nnnRESULTSnIn group I, a significant reduction of EVLWI (group I, 6.7 +/- 1.0 mL/kg vs group II, 10.1 +/- 0.6 ml/kg after 2 hours of reperfusion; p = 0.022), TBARS (group I, 65.6 +/- 10.0 pmol/g vs group II, 120.8 +/- 7.2 pmol/g, p = 0.0039), and MPO activity (group I, 0.8 +/- 0.1 change in optical density, (deltaOD)/mg/min vs group II, 1.7 +/- 0.3 deltaOD/mg/min, p = 0.036) was noted in comparison with group II. PaO2 levels tended to be higher in cGMP-treated animals, but the changes were not significant. Hemodynamic parameters did not differ between groups.nnnCONCLUSIONSnIn this large animal model of lung allograft ischemia/reperfusion injury, 8-Br-cGMP as additive to the flush solution improves posttransplant lung edema, lipid peroxidation, and neutrophil migration to the allograft. This effect is not attributable to improved flush by vasodilation, as we compared 8-Br-cGMP with PGE1 given before flush in control animals.