Visions and revisions--a society visiting its roots.
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Career Choice↗
Biomedical subjects
Walter Klepetko
Publications and source records attributed to Walter Klepetko.
Prognosis of patients with non-small cell lung cancer with isolated brain metastases undergoing combined surgical treatment.
OBJECTIVE: To compare survival of patients with isolated synchronous and metachronous brain metastases from non-small cell lung cancer (NSCLC) after combined surgical treatment. METHODS: A total of 991 patients underwent surgical resection of primary NSCLC between January 1994 and November 1999. Out of these, 32 patients (21 males and 11 females) were further treated for isolated brain metastases. In a retrospective survey, the outcome of patients with either synchronous (group 1, n = 16) or metachronous (group 2, n = 16) brain metastases was evaluated. Five patients out of each group received either adjuvant or neo-adjuvant chemotherapy. Data analysis includes descriptive statistics, Wilcoxon test, Kaplan-Meier method and Cox's proportional hazards model. RESULTS: There was no significant difference in local tumour stage and histology of the primary tumour between both groups. Median of the disease free interval (DFI) after primary lung surgery (group 2) was 10 months, range 3-60 months. Median survival after lung surgery was 8.5 months in group 1 and 16.4 months in group 2 (P = 0.094). Median survival after cerebral procedures was 9.3 and 6.2 months, respectively (P = 0.127). Estimated survival rates by Kaplan-Meier method after cerebral procedures operation in group 1 were 37.5% at 1 year, 25.0% at 2 years and 18.8% at 5 years; in group 2 estimated survival rates were 31.3% at 1 year, 15.6% at 2 years and 0% at 5 years (P = 0.148). Calculated survival rates after lung surgery were identical in group 1; in group 2 survival rates were 62.5, 43.8 and 18.8% at 1, 2 and 5 years, respectively (P = 0.101). In the univariate model, none of the following variables had effect on survival: sex, age, T stage of the tumour, nodal status, timing of metastatic lesions, number of cerebral metastases, complete resection of primary tumour and histological type. Multivariate analysis did not reveal any risk factor, which significantly predicted survival. DFI did not correlate with survival of patients in group 2. CONCLUSIONS: Once isolated synchronous or metachronous brain metastases from NSCLC have developed, there is no difference in prognosis after combined surgery between analysed groups. This questions the value of lung resection in patients with isolated synchronous brain metastases.
Adult↗
Reverse cardiac remodelling in patients with primary pulmonary hypertension after isolated lung transplantation.
OBJECTIVE: Pulmonary hypertension eventually leads to severe distortion of the cardiac geometry with consequent impact on cardiac function. The purpose of this study was to prove reverse cardiac remodelling after isolated bilateral lung transplantation (LuTX) in patients with advanced primary pulmonary hypertension (PPH) and severe alterations of cardiac morphology and function. METHODS: In the period of 2000-2002 17 (10 female, seven male) patients with advanced PPH underwent isolated bilateral LuTX. Median age was 30 years (range 16-53). All patients were in NYHA III or IV, most of them with intractable ascites, established renal impairment, malnutrition and immobility, continuously deteriorating despite various forms of pharmacological treatment including i.v. and inhalative prostacyclin, diuretics, Ca-antagonists, bosentan and catecholamines. Echocardiography and Doppler echocardiography measurements were performed before and 3 months after transplantation. Left and right ventricular diameters and function were assessed and tricuspid valve regurgitation was determined. RESULTS: Mortality after 3 months was 17.5% (cerebral bleeding, multi-organ failure and diffuse myocardial infarction in one patient each). Three months after LuTX the 14 surviving patients were in NYHA I or II. Echocardiography showed normal left ventricular function and markedly improved right ventricular function with normal size of the RV. The leftward shifted flattened interventricular septum had returned in its physiological position and the high-grade tricuspid insufficiency had disappeared in all patients. CONCLUSIONS: Advanced alterations of cardiac morphology and function normalize completely and pre-existing tricuspid insufficiency disappears in PPH patients after isolated bilateral LuTX. Quality of life is excellent. Therefore, LuTX is preferred and safe in patients with advanced PPH even with severe cardiac dysfunction.
Adolescent↗
Heterotopic tracheal transplantation with omentum wrapping in the abdominal position preserves functional and structural integrity of a human tracheal allograft.
OBJECTIVES: Transplantation of a human trachea has been reported only twice in the literature with limited documentation of the functional and structural properties of the allograft. PATIENTS AND METHODS: A 57-year-old patient with chronic obstructive pulmonary disease with low segment tracheal stenosis was accepted for lung transplantation and 2-stage tracheal allotransplantation. Standard bilateral sequential lung transplantation was performed with the transfer of the donor trachea into the recipient's abdomen, which was wrapped in the greater omentum and sutured into the abdominal wall, similar to a stoma. The patient received immunosuppression consisting of cyclosporine A, mycophenolate mofetil, and cortisone. Sixty days later, the tracheal allograft presented with macroscopically normal appearance with maintained elasticity and rigidity. The patient underwent a cricotracheal resection 6 months after lung transplantation. However, reconstruction with direct end-to-end anastomosis was achievable. The tracheal allograft, therefore not needed for reconstruction, was harvested and underwent complete investigations. RESULTS: Cross-section of the graft revealed a mechanically stable and macroscopically intact trachea. Hematoxylin-eosin staining demonstrated vital cartilage covered by respiratory epithelium. Angiography, followed by corrosion studies and electromicroscopy, demonstrated excellent vascularization of the tracheal wall. CONCLUSION: The patient is alive 31 months posttransplantation and remains in bronchiolitis obliterans syndrome stage 0. Human trachea wrapped in omentum maintains its functional and structural integrity and may be used for 2-stage allotransplantation.
Abdominal Wall↗
International experience with conversion from cyclosporine to tacrolimus for acute and chronic lung allograft rejection.
OBJECTIVE: A retrospective study involving 13 institutions was performed to assess the efficacy of conversion from cyclosporine (INN: ciclosporin) to tacrolimus. METHODS: Data from 244 patients were analyzed. Indications for conversion were recurrent-ongoing rejection (n = 110) and stage 1 to 3 bronchiolitis obliterans syndrome (n = 134). RESULTS: The incidence of acute rejection decreased significantly within 3 months after versus before the switch from cyclosporine to tacrolimus (P <.01). For patients with recurrent-ongoing rejection, the forced expiratory volume in 1 second decreased by 1.96% of predicted value per month (P =.08 vs zero slope) before and increased by 0.34% of predicted value per month (P =.32 vs zero slope) after conversion (P <.06). For patients with stage 1 to 3 bronchiolitis obliterans syndrome, a significant reduction of rejection episodes was observed (P <.01). In single transplant recipients a decrease of the forced expiratory volume in 1 second averaged 2.25% of predicted value per month (P <.01 vs zero slope) before and 0.29% of predicted value per month after conversion. Corresponding values for bilateral transplant recipients were 3.7% of predicted value per month (P <.01 vs zero slope) and 0.9% of predicted value per month (P = 0.04 vs zero slope), respectively. No significant difference in the incidence of infections within 3 months before and after conversion was observed. CONCLUSIONS: Conversion from cyclosporine to tacrolimus after lung transplantation is associated with reversal of recurrent-ongoing rejection. Conversion for bronchiolitis obliterans syndrome allows short-term stabilization of lung function in most patients.
Acute Disease↗
Longitudinal analysis of perfusion lung scintigrams of patients with unoperated chronic thromboembolic pulmonary hypertension.
Chronic thromboembolic pulmonary hypertension (CTEPH) is the result of single or recurrent pulmonary thromboemboli that are thought to develop into organized pulmonary arterial obstructions by recurrent embolism and in situ thrombosis. Radioisotopic ventilation-perfusion scanning (V/Q scan) is a safe and highly sensitive test for pulmonary thromboembolic disease. The aim was to assess the natural history of thrombus expansion. We performed a prospective quantitative evaluation of ventilation/perfusion scintigrams (V/Q scans) in 20 patients with severe unoperated CTEPH. The baseline V/Q scan of each patient served as a reference for the second scan 21.7 +/- 8.2 months later. Planar images with intravenous 99mTc-labeled human albumin macroaggregates were reconstructed in six standard projections. Perfusion scans were analyzed by a semi-quantitative evaluation. In parallel, hemodynamics and clinical condition were prospectively observed. Lung perfusion scintigrams analyzed by a semi-quantitative method in patients with severe unoperated CTEPH show an apparent decrease of segmental flow abnormalities over time, paralleling right ventricular decline.
Adult↗
[Lung harvesting in Hungary--results of the first two years].
OBJECTIVE: Hungarian patients undergo lung transplantation within bilateral cooperation in Vienna, Austria since 1995. Lung harvesting was introduced in 2002 in Hungary. Before 2002 Hungarian patients get 16 donor lungs from abroad, and 4 patients died while being on the waiting list for transplantation. METHODS: Between 15/1/2002 and 31/12/2003 Hungarotransplant offered 164 potential lung donors to the Korányi National Institute for Pulmonology. Donor selection was performed according to international guidelines. All operations were performed as part of multiorgan harvesting. Immediately before cross clamping the aorta 500 microg epoprostenol (Flolan) was administered intravenously for opening the pulmonary vascular bed. The lung was perfused through the main pulmonary trunk with a single flush of 6 litre 4 degrees C extra cellular type low potassium dextran solution (Perfadex). During the perfusion both thoraces were cooled topical by 0.9% saline ice slush. After back table separation the donor lungs was packed and transported with topical cooling. RESULTS: The offer was refused in 27 cases due to donor history, in 31 cases due to allograft pathology. In 57 cases the harvesting was not performed due to logistic reasons. Forty three donor lungs have been transplanted, 6 harvested lungs underwent only histopathology. From 43 harvested lungs 41 bilateral and 3 single lung transplant procedures were performed. The mean cold ischaemic time (=CIT) was 3 75 +/- 50 minutes (range: 230-560 min). Forty two donor lungs showed excellent primary graft function. One allograft underwent down-sizing lobectomy, where the histology of the specimen showed multiple microembolization, and signs of fibrosis, bronchiolitis and anthracosis. In this case the cold ischaemic time was 385 min. The patient needed an extracorporeal membrane oxygenation (ECMO) support immediately postoperatively, and died on the 4th postoperative day. After induction of lung harvesting in Hungary the average waiting time of Hungarian citizens dropped within one year from 14 +/- 8 weeks (range: 2-36 weeks) to 2.6 +/- 1.3 weeks (range: 1-4 weeks). In 2002 3 Hungarian patients died while being on the waiting list, their waiting time was 1, 1, and 7 days. In 2003 the waiting list mortality for Hungarian patients was 0%. CONCLUSIONS: After the introduction of lung harvesting both the waiting time and the waiting list mortality for Hungarian patients decreased. The potential yearly lung donor pool of Hungary is in the range of 5/1 million people.
Adult↗
Thoracic transplantation and stem cell therapy.
Lung and heart transplantations are accepted standard therapies for end stage diseases and will maintain their importancy in the future. Potentially, transplantation at a cellular level using various forms of stem cells becomes an additional therapeutic approach.
Heart Diseases↗
[Therapy of patients with end-stage pulmonary disease. Review of lung transplantation based on four cases of our own].
The pathogenesis of infiltrative pulmonary diseases is largely unknown, and their final outcome is variable. These inflammatory processes may involve the alveoli and the pulmonary interstices, and they may lead to pulmonary fibrosis. The development of end-stage pulmonary disease is irreversible. Patients with respiratory failure have a poor prognosis. For young patients at the end-stage of their pulmonary disease, lung transplantation is a promising therapeutic modality. The therapeutic protocols for unilateral or bilateral lung transplantation and heart-lung transplantation were established only in the last 10 years. In Hungary there is no center yet performing lung transplantation. This therapy is available only for those who could be effectively rehabilitated with this method. Four patients 27-35 years of age suffering pulmonary fibrosis, despite their young age developed honey-comb lungs with therapy resistant respiratory failure. No other organic symptoms were detected by detailed examination, so their predicted survival was dependent on their pulmonary status alone. Cases of four young patients, who were effectively treated with lung transplantation, are discussed from pre-operative preparations to post-operative follow-up, with the review of the literature.
Adult↗
[Pulmonary hypertension in rheumatic diseases].
Pulmonary hypertension (PH) is a progressive disease of the pulmonary vasculature characterized by increased vascular resistance and pressure overload of the right ventricle. Histologically, PH lungs demonstrate medial hypertrophy of small pulmonary arteries and proliferation of endothelial cells resulting in plexiform lesions. Recent studies have identified mutations of the bone morphogenetic protein receptor 2 (BMPR2) gene and the activin-receptor-like kinase 1 (ALK1) gene, that affect the transforming growth factor beta (TGF-beta) receptor superfamily, a group of transmembrane signaling molecules with serine-threonine kinase activity that are involved in the regulation of cell growth. Several lines of evidence indicate that the development of PH is a multi-hit process, where one of the events is having a gene mutation and another might be a circumstantial condition or other disease-modifying genes. It is unknown which mechanism that is critical in rheumatic diseases causes pulmonary vascular disease. PH is most frequently associated with systemic sclerosis (SS), systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD), however, it is still a rare manifestation of these disorders. For example, approximately 10% of SS cases manifest pulmonary vascular disease. In recent years symptomatic vasodilator therapies have been employed and have been able to improve exercise capacity and survival in these patients.
Activin Receptors, Type I↗
Pleurovenous shunting in the treatment of nonmalignant pleural effusion.
BACKGROUND: The goals of treatment of chronic nonmalignant pleural effusion are relief of dyspnea and improved quality of life. Treatment options include needle thoracentesis, tube thoracostomy chemical pleurodesis, and pleurectomy. Pleurovenous shunting (PVS) represents an alternative, minimally invasive method. METHODS: Since 1999, 12 patients underwent pleurovenous shunting for right-sided pleural effusion in our center. Indications were hepatic hydrothorax (n = 6, one as bridging to liver transplantation), nephrotic syndrome (n = 4), and chylothorax (n = 2, one as bridging to lung transplantation). All patients received Denver shunt systems from the pleural cavity to either the subclavian or jugular vein. RESULTS: Shunt occlusion was observed in one case (chylothorax) 4 weeks after implantation. There was one early death, which was not related to the procedure (hepatic failure). No air embolism or infection was observed. All systems were patent throughout the observation period of 1 to 40 months (mean = 13.3 months), and none of the patients required further treatment for pleural effusion. CONCLUSION: Pleurovenous shunting offers an efficient, minimally invasive alternative to other surgical methods for treatment of recurrent nonmalignant pleural effusion.
Aged↗
External vocal fold medialization in patients with recurrent nerve paralysis following cardiothoracic surgery.
OBJECTIVES: Recurrent laryngeal nerve injury is a possible complication following cardiothoracic surgery. Due to insufficient glottal closure, dysphonia and dysphagia with aspiration may occur. The purpose of the study was to outline the effect of vocal fold medialization thyroplasty on voice, swallowing and breathing impairments. METHODS: Between 1999 and 2001, medialization thyroplasty using the titanium implant (TVFMI) according to Friedrich was performed in 14 patients with postoperative left-sided recurrent nerve paralysis (five female and nine male patients, mean age 64 years) by an external approach. Previous surgical procedures comprised six lobectomies (combined with resection and replacement of the subclavian artery in one case), two pneumonectomies, one resection of a schwannoma in the aortopulmonary window, two replacements of the descending aorta, one aortocoronary bypass procedure (with LIMA), and two esophageal resections using Akiyama technique, respectively. Before and after thyroplasty, the patients underwent an otolaryngological/phoniatric examination including videostroboscopy, voice sound analysis, voice range profile measurement, pulmonary function testing, and in selected cases videofluoroscopy of swallowing. RESULTS: Following thyroplasty, all patients reported on subjective improvement of voice, swallowing and breathing functions. Videostroboscopy revealed an improved glottal closure (six complete, six with posterior gap). All voice related parameters (e.g. roughness, breathiness, hoarseness, maximum sound pressure levels of the singing and shouting voices) were significantly improved. CONCLUSIONS: Due to potential risk of recurrent nerve alteration in left-sided intrathoracic procedures, a preoperative and postoperative laryngoscopic examination is recommended. The external medialization of the vocal folds can be regarded as an excellent method for improvement of voice, swallowing and breathing, in particular, when the quality of life is impaired due to persistent recurrent nerve paralysis.
Adult↗
General thoracic surgery--optimising opportunities at a European level.
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Clinical Competence↗
Lung transplantation. Donor selection.
The demand for donor lungs currently exceeds the supply of suitable grafts by a significant margin. Legal backgrounds and organizational and logistic issues are of major impact on the available donor pool. Re-evaluation of the donor criteria currently in use and new, innovative approaches such as living donor lung transplantation and non-heart-beating donation will hopefully contribute to improve this situation and reduce waiting time and waiting list mortality.
Brain Death↗
Cyclosporine A versus tacrolimus in combination with mycophenolate mofetil and steroids as primary immunosuppression after lung transplantation: one-year results of a 2-center prospective randomized trial.
OBJECTIVES: Cyclosporine (INN: ciclosporin) A or tacrolimus have been used mostly in combination with azathioprine as primary immunosuppression after lung transplantation. Benefit or risk deriving from the combination with mycophenolate mofetil are yet unknown. METHODS: In a prospective, 2-center, open randomized trial, the combination of cyclosporine A, mycophenolate mofetil, and steroids was compared with tacrolimus, mycophenolate mofetil, and steroids as primary therapy after primary lung transplantation. All patients underwent induction therapy with rabbit antithymocyte globulin for 3 days. The 2 groups were compared with regard to patient survival, freedom from acute rejection, bronchiolitis obliterans, infectious episodes, and side effects. RESULTS: Between September 1997 and April 1999, 74 lung transplant recipients were randomized to receive either cyclosporine A (n = 37) or tacrolimus (n = 37). Groups were comparable with regard to age, sex, transplant procedure, and cytomegalovirus match. Mean follow-up was 507 +/- 258 and 508 +/- 248 days, respectively. Six- and 12-month survival was similar in both groups (89% vs 84% and 82% vs 71%, respectively; P =.748 at 12 months). Two patients from the cyclosporine A group were retransplanted. Freedom from acute rejection at 6 and 12 months was comparable between groups (46% vs 51% and 35% vs 46%, respectively; P =.774 at 12 months). The mean number of treated acute rejection episodes per 100 patient-days was higher in the cyclosporine A than in the tacrolimus group, but the difference was not statistically significant (0.32 +/- 0.42 vs 0.22 +/- 0.30, respectively; P =.097). Four patients from the cyclosporine A group had to be switched to tacrolimus to control ongoing rejection, whereas no patient from the tacrolimus group had to be switched to cyclosporine A. There was a trend toward more infections (0.7 +/- 0.36 vs 0.55 +/- 0.31, P =.059) in the cyclosporine A group. New-onset diabetes mellitus was observed in the tacrolimus group only (11% vs 0%, P =.151), whereas there was a higher incidence of hypertension (60% vs 11%, P =.03) in the cyclosporine A group. CONCLUSION: This 2-center, prospective randomized study showed high immunosuppressive potency of both cyclosporine A and tacrolimus in combination with mycophenolate mofetil. No significant difference in incidence of acute rejection was observed between the 2 groups. Moreover, survival and incidence of infection were similar. Incidence of drug-related adverse events were similar, yet their spectrum was different.
Acute Disease↗
High prevalence of elevated clotting factor VIII in chronic thromboembolic pulmonary hypertension.
Chronic thromboembolic pulmonary hypertension (CTEPH) is an enigmatic disorder lacking signs, symptoms and classical risk factors for venous thromboembolism. The objective of the prospective case controlled study, carried out at the Pulmonary Hypertension Unit, University Hospital Vienna, Austria, was to investigate whether plasma FVIII is elevated in CTEPH patients. The study examined 122 consecutive patients diagnosed with CTEPH. Plasma FVIII was measured and compared with plasma FVIII of healthy controls (n = 82) and of patients with nonthromboembolic pulmonary arterial hypertension (PAH, n = 88). Results show that CTEPH patients had higher FVIII levels than controls (233 +/- 83IU/dl versus 123 +/- 40IU/dl, p < 0.0001) and PAH patients (158 +/- 61IU/dl, p < 0.0001). Plasma FVIII one year after surgery (212 +/- 94IU/dl) was statistically unchanged compared with preoperative values (FVIII: 226 +/- 88IU/dl, n = 25). FVIII > 230IU/dl was more prevalent in CTEPH patients (41%) than in controls (5%, p < 0.0001) and PAH patients (22%, p = 0.022). We can conclude that elevated plasma FVIII is the first prothrombotic factor identified in a large proportion of CTEPH patients.
Adult↗
VEGF-A and -C but not -B mediate increased vascular permeability in preserved lung grafts.
BACKGROUND: Vascular endothelial growth factor (VEGF) is a potent endothelial cell growth and permeability factor, expressed in the lung. Overexpression of VEGF is associated with increased vascular permeability in the early stage of acute lung injury in mice. The role of various forms of VEGF in transplantation-induced lung injury is not well understood. METHODS: VEGF mRNA and protein expression was measured in biopsies of preserved donor lung grafts as well as in control lung biopsies, using real-time reverse transcriptase-polymerase chain reaction and Western blot analysis. VEGF tissue expression was also evaluated by immunocytochemistry. Serum VEGF was measured in recipients after transplantation and in controls using ELISA. RESULTS: Although VEGF-A and VEGF-C protein expression was up-regulated, their mRNA levels were decreased in donor versus control lung biopsies (P<0.05). VEGF-B mRNA was decreased, but its protein level was unchanged in donors. Flt-1 was unchanged, KDR gene expression was down-regulated in donors (P<0.05), and both receptors' protein expression was under the detection level in donor and control lungs. VEGF-A was detected in pulmonary vessels and bronchi, whereas VEGF-C was only detectable in vessels of both donor and control lungs. After transplantation, serum VEGF increased (P<0.05) and returned to control baseline levels 12 weeks after surgery. Wet-to-dry lung weight was increased in donor versus control lungs. CONCLUSIONS: These results indicate that unventilated hypoxia increases vascular permeability in lung grafts and that this process is mainly regulated at VEGF-A and VEGF-C translational but not transcriptional level. Selective VEGF antagonism during graft preservation might be of benefit to counteract edema formation.
Capillary Permeability↗
The value of switching from cyclosporine to tacrolimus in the treatment of refractory acute rejection and obliterative bronchiolitis after lung transplantation.
Standard cyclosporine-based immunosuppression is ineffective in the treatment of refractory acute rejection (RAR) and obliterative bronchiolitis (OB) that follows lung transplantation. The aim of this study was to evaluate the results of switching from cyclosporine to tacrolimus in the treatment of these situations. Nineteen patients entered the study. The indication for switching was OB in 11 patients and RAR in 8. Mean age was 41.3 +/- 13.1 years. In patients with RAR, the number of acute rejections was 1.5 +/- 0.7 and there were zero episodes per patient per 100 days before and after switching, respectively ( P = 0.02). There was no significant reduction of the decline of forced expiratory volume (FEV(1)) within 6 months after switching in patients with OB. We conclude that the conversion from cyclosporine to tacrolimus was associated with favourable results in the treatment of RAR. Further studies are required to assess the influence of this approach in the treatment of OB.
Acute Disease↗