Publications

  • Lung cancer in never smokers.

    Szilvia Torok, Balazs Hegedus, Viktoria Laszlo, Mir Alireza Hoda, Bahil Ghanim, Walter Berger, Walter Klepetko, Balazs Dome, Gyula Ostoros

    Future oncology (London, England). 10/2011; 7(10):1195-211.

    Lung cancer in never smokers (LCINS) is the seventh leading cause of death among solid tumors. The main risk factor for lung cancer is smoking; however, approximately 15% of lung cancer patients have never smoked. LCINS is more frequent in women, irrespective of geographical location, nevertheless, ... [more] Lung cancer in never smokers (LCINS) is the seventh leading cause of death among solid tumors. The main risk factor for lung cancer is smoking; however, approximately 15% of lung cancer patients have never smoked. LCINS is more frequent in women, irrespective of geographical location, nevertheless, the highest incidence has been found in South-East Asia. The histological incidence of adenocarcinoma is higher in the group of never smokers than squamous cell carcinoma. There is a familial clustering of lung cancer that is more pronounced in never smokers, where the family history was associated with an increased risk. Genome-wide association studies identified certain chromosomal aberrations in LCINS. Furthermore, the oncogenic mutation pattern is distinct in nonsmoking patients: activating mutations of EGFR or anaplastic lymphoma kinase are more frequent. The etiology of LCINS includes several environmental factors as well, such as environmental tobacco smoke, viral and hormonal factors, a variety of pulmonary diseases and certain occupational exposures. It is now established that EGFR-tyrosine kinase inhibitor treatment (erlotinib and geftinib) in lung cancer is more effective in LCINS, owing to the higher incidence of EGFR mutation in nonsmokers. Despite the growing body of information on LCINS in recent years there is a need to further investigate the pathogenesis of this particular lung cancer. Future studies on LCINS should try to tackle the issues of prevention, early diagnosis and the exploration of novel therapeutic targets to combat lung cancer disease.
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    Temsirolimus inhibits malignant pleural mesothelioma growth in vitro and in vivo: synergism with chemotherapy.

    Mir Alireza Hoda, Amir Mohamed, Bahil Ghanim, Martin Filipits, Balazs Hegedus, Masaya Tamura, Judit Berta, Bernd Kubista, Balazs Dome, Michael Grusch, Ulrike Setinek, Michael Micksche, Walter Klepetko, Walter Berger

    Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer. 02/2011; 6(5):852-63.

    Human malignant pleural mesothelioma (MPM) is an asbestos-related malignancy characterized by frequent resistance to chemotherapy and radiotherapy. Here, we investigated the feasibility of mammalian target of rapamycin (mTOR) inhibition by temsirolimus as an antimesothelioma strategy. Phosphorylatio... [more] Human malignant pleural mesothelioma (MPM) is an asbestos-related malignancy characterized by frequent resistance to chemotherapy and radiotherapy. Here, we investigated the feasibility of mammalian target of rapamycin (mTOR) inhibition by temsirolimus as an antimesothelioma strategy. Phosphorylation of mTOR (p-mTOR) was assessed by immunohistochemistry in MPM surgical specimens (n = 70). Activation of mTOR and impact of mTOR inhibition by temsirolimus was determined in MPM cell lines in vitro (n = 6) and in vivo as xenografts in severe combined immunodeficiency mice (n = 2) either as single agent or in combination with cisplatin. Strong immunoreactivity for p-mTOR was predominantly detected in epitheloid and biphasic but not sarcomatoid MPM specimens while adjacent normal tissues remained widely unstained. Accordingly, all mesothelioma cell lines harbored activated mTOR, which was further confirmed by hyperphosphorylation of the downstream targets pS6K, S6, and 4EBP1. Temsirolimus potently blocked mTOR-mediated signals and exerted a cytostatic effect on mesothelioma cell lines in vitro cultured both as adherent monolayers and as nonadherent spheroids. Mesothelioma cells with intrinsic or acquired cisplatin resistance exhibited hypersensitivity against temsirolimus. Accordingly, cisplatin and temsirolimus exerted synergistic inhibition of the mTOR downstream signals and enhanced growth inhibition and/or apoptosis induction in mesothelioma cell lines. Finally, temsirolimus was highly active against MPM xenograft models in severe combined immunodeficiency mice both as a single agent and in combination with cisplatin. The mTOR inhibitor temsirolimus is active against mesothelioma in vitro and in vivo and synergizes with chemotherapy. These data suggest mTOR inhibition as a promising novel therapeutic strategy against MPM.
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    Intracellular protein binding patterns of the anticancer ruthenium drugs KP1019 and KP1339.

    Petra Heffeter, Katharina Böck, Bihter Atil, Mir Ali Reza Hoda, Wilfried Körner, Caroline Bartel, Ute Jungwirth, Bernhard K Keppler, Michael Micksche, Walter Berger, Gunda Koellensperger

    Journal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry. 03/2010; 15(5):737-48.

    The ruthenium compound KP1019 has demonstrated promising anticancer activity in a pilot clinical trial. This study aims to evaluate the intracellular uptake/binding patterns of KP1019 and its sodium salt KP1339, which is currently in a phase I-IIa study. Although KP1339 tended to be moderately less ... [more] The ruthenium compound KP1019 has demonstrated promising anticancer activity in a pilot clinical trial. This study aims to evaluate the intracellular uptake/binding patterns of KP1019 and its sodium salt KP1339, which is currently in a phase I-IIa study. Although KP1339 tended to be moderately less cytotoxic than KP1019, IC(50) values in several cancer cell models revealed significant correlation of the cytotoxicity profiles, suggesting similar targets for the two drugs. Accordingly, both drugs activated apoptosis, indicated by caspase activation via comparable pathways. Drug uptake determined by inductively coupled plasma mass spectrometry (ICP-MS) was completed after 1 h, corresponding to full cytotoxicity as early as after 3 h of drug exposure. Surprisingly, the total cellular drug uptake did not correlate with cytotoxicity. However, distinct differences in intracellular distribution patterns suggested that the major targets for the two ruthenium drugs are cytosolic rather than nuclear. Consequently, drug-protein binding in cytosolic fractions of drug-treated cells was analyzed by native size-exclusion chromatography (SEC) coupled online with ICP-MS. Ruthenium-protein binding of KP1019- and KP1339-treated cells distinctly differed from the platinum binding pattern observed after cisplatin treatment. An adapted SEC-SEC-ICP-MS system identified large protein complexes/aggregates above 700 kDa as initial major binding partners in the cytosol, followed by ruthenium redistribution to the soluble protein weight fraction below 40 kDa. Taken together, our data indicate that KP1019 and KP1339 rapidly enter tumor cells, followed by binding to larger protein complexes/organelles. The different protein binding patterns as compared with those for cisplatin suggest specific protein targets and consequently a unique mode of action for the ruthenium drugs investigated.
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    Antivascular agents for non-small-cell lung cancer: current status and future directions.

    Eitan Amir, Laszlo Mandoky, Fiona Blackhall, Nick Thatcher, Walter Klepetko, Hendrik Jan Ankersmit, Mir Ali Reza Hoda, Gyula Ostoros, Magdolna Dank, Balazs Dome

    Expert opinion on investigational drugs. 11/2009; 18(11):1667-86.

    Background: Despite improvements in surgery and chemo(radio)therapy which have allowed for modest advances in the treatment of patients with non-small-cell lung cancer (NSCLC), survival remains poor and further improvements are needed. Attention over recent years has focused, therefore, on targeted ... [more] Background: Despite improvements in surgery and chemo(radio)therapy which have allowed for modest advances in the treatment of patients with non-small-cell lung cancer (NSCLC), survival remains poor and further improvements are needed. Attention over recent years has focused, therefore, on targeted therapies, with notable success in the development of antivascular drugs. Objective: To summarize the current knowledge on antivascular therapy in patients with NSCLC. Method: Review of randomized controlled trials exploring treatment of NSCLC patients with antivascular drugs. Results/conclusion: Bevacizumab, a humanized monoclonal antibody against the vascular endothelial growth factor (VEGF), when added to cytotoxic chemotherapy, was the first treatment to prolong the overall survival of patients with advanced NSCLC beyond 12 months, a significant breakthrough in the management of advanced NSCLC. Small-molecule tyrosine kinase inhibitors and alternative antivascular strategies such as VEGF-trap and vascular disrupting agents are also being investigated and have shown promise in clinical trials. This review summarizes the most recent and important findings in antivascular agents in NSCLC.
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    Current treatment paradigms of superior sulcus tumours.

    Masaya Tamura, Mir Alireza Hoda, Walter Klepetko

    European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. 09/2009;

    Pancoast or superior pulmonary sulcus tumours are a rare subset of non-small-cell lung carcinomas (NSCLCs) which occur with an incidence of less than 5% of all lung cancers. Today, induction chemoradiation followed by surgical resection has become the established standard treatment approach for pati... [more] Pancoast or superior pulmonary sulcus tumours are a rare subset of non-small-cell lung carcinomas (NSCLCs) which occur with an incidence of less than 5% of all lung cancers. Today, induction chemoradiation followed by surgical resection has become the established standard treatment approach for patients with sulcus superior tumours in the absence of other contraindications. This review focusses on the historical change of the treatment strategy, the evolution of surgical and multimodality management of this disease and the most recent published clinical outcome data of patients suffering from superior pulmonary sulcus carcinoma.
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    Cytomegalovirus prevention in high-risk lung transplant recipients: comparison of 3- vs 12-month valganciclovir therapy.

    Peter Jaksch, Barbara Zweytick, Heidrun Kerschner, Ali Mir Hoda, Maya Keplinger, György Lang, Clemens Aigner, Walter Klepetko

    The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 08/2009; 28(7):670-5.

    BACKGROUND: Cytomegalovirus (CMV) infections are common after lung transplantation (LuTx) and have an influence on acute rejection rates and chronic organ dysfunction. The objective of this study was to determine the incidence of CMV infections by comparing a prolonged valganciclovir prophylaxis wit... [more] BACKGROUND: Cytomegalovirus (CMV) infections are common after lung transplantation (LuTx) and have an influence on acute rejection rates and chronic organ dysfunction. The objective of this study was to determine the incidence of CMV infections by comparing a prolonged valganciclovir prophylaxis with a standard regimen in high-risk LuTx recipients. METHODS: A retrospective, single-center study was performed comparing two different CMV prophylactic regimens in high-risk LuTx recipients (D(+)/R(-)). The study population received either 3 months (Group A, 15 patients) or 12 months (Group B, 17 patients) of oral valganciclovir 900 mg/day in combination with CMV hyperimmune globulin in four doses (Days 1, 7, 14 and 21 post-transplant). RESULTS: CMV viremia was noted in 11 of 15 patients in Group A (75%) and 5 of 17 in Group B (33%) (p < 0.05) at 6 months after valganciclovir cessation. The incidence of symptomatic CMV disease/syndrome was 6 of 15 (44%) in Group A and 2 of 17 in Group B (13%) (p < 0.05). Histologically proven acute rejection episodes of ISHLT Grade > or =A2 were found in 4 patients in Group A and in 1 patient in Group B within the first year (p = 0.14). CONCLUSIONS: A 12-month CMV prophylaxis with oral valganciclovir is effective in significantly reducing CMV viremia and CMV disease/syndrome in high-risk lung transplant recipients. In addition, a reduction in acute and recurrent rejection episodes was observed, possibly due to less CMV viremia and subsequent immunomodulatory effects.
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    The Na(+)/K(+)-ATPase is the Achilles Heel of multi-drug-resistant cancer cells.

    Tatjana Mijatovic, Ute Jungwirth, Petra Heffeter, Mir Ali Reza Hoda, Rita Dornetshuber, Robert Kiss, Walter Berger

    Cancer letters. 04/2009;

    We recently reported that over-expressed Na(+)/K(+)-ATPase alpha subunits are new important anti-cancer targets. Cardiotonic steroids are the natural ligands of Na(+)/K(+)-ATPase and thus potentially potent anti-cancer agents with a novel mechanism of action. We report here that the hemi-synthetic c... [more] We recently reported that over-expressed Na(+)/K(+)-ATPase alpha subunits are new important anti-cancer targets. Cardiotonic steroids are the natural ligands of Na(+)/K(+)-ATPase and thus potentially potent anti-cancer agents with a novel mechanism of action. We report here that the hemi-synthetic cardenolide 19-hydroxy-2''oxovoruscharin is impressively active in cancer cells expressing diverse forms of multi-drug resistance (MDR) either conferred by the over-expression of selected drug-transporter proteins or induced by a range of chemotherapeutic agents. Together with the inability of tumor cells to acquire resistance to 19-hydroxy-2''oxovoruscharin, our data suggest that this novel compound could be especially applicable to notoriously drug-resistant cancers.
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    High VEGFR-3-positive Circulating Lymphatic/Vascular Endothelial Progenitor Cell Level Is Associated with Poor Prognosis in Human Small Cell Lung Cancer.

    Krisztina Bogos, Ferenc Renyi-Vamos, Judit Dobos, Istvan Kenessey, Jozsef Tovari, Jozsef Timar, Janos Strausz, Gyula Ostoros, Walter Klepetko, Hendrik Jan Ankersmit, Gyorgy Lang, Mir Alireza Hoda, Patrick Nierlich, Balazs Dome

    Clinical cancer research : an official journal of the American Association for Cancer Research. 03/2009;

    PURPOSE: The newly identified bone marrow-derived cell population, called lymphatic/vascular endothelial progenitor cells (LVEPC), has been shown to contribute to lymph capillary growth in experimental tumor systems. The clinical significance of these cells has not yet been investigated in a human m... [more] PURPOSE: The newly identified bone marrow-derived cell population, called lymphatic/vascular endothelial progenitor cells (LVEPC), has been shown to contribute to lymph capillary growth in experimental tumor systems. The clinical significance of these cells has not yet been investigated in a human malignancy. Our aim was to study whether peripheral blood circulating LVEPCs participate in the progression of human small cell lung cancer (SCLC).EXPERIMENTAL DESIGN: A total of 88 patients with limited-stage SCLC and 32 tumor-free control subjects were included. Peripheral blood circulating LVEPC labeled with CD34 and vascular endothelial growth factor receptor-3 (VEGFR3) antibodies and the serum levels of the key lymphangiogenic molecule VEGF-C were measured by flow cytometry and ELISA, respectively.RESULTS: CD34-positive/VEGFR3-positive LVEPC levels were significantly increased in patients (versus controls; P < 0.01), and there was also a significant relationship between LVEPC counts and lymph node metastasis (P < 0.01). High pretreatment circulating LVEPC numbers correlated with poor overall survival (P < 0.01). Although we observed significantly elevated VEGF-C concentrations in patients (versus controls; P < 0.01), there was no significant correlation between VEGF-C and LVEPC levels. Moreover, no significant differences in peripheral blood VEGF-C levels were seen between patients subgrouped by clinicopathologic variables including tumor and lymph node stages and survival.CONCLUSIONS: Peripheral blood levels of bone marrow-derived LVEPCs are significantly increased in patients with SCLC and correlate with lymphatic involvement and prognosis. This is the first study that shows evidence of increased numbers of circulating LVEPC in patients with a malignant tumor.
  • Combined cervicothoracic approaches for complex mediastinal masses.

    Clemens Aigner, Mir Ali Reza Hoda, Walter Klepetko

    Thoracic surgery clinics. 03/2009; 19(1):107-12.

    Tumors or masses occurring in the cervicothoracic region show a broad variety in their histologic origin. Accordingly, the indication for surgical resection varies, and especially in malignant lesions, surgery frequently is part of a multimodality treatment. Adequate access is important for any oper... [more] Tumors or masses occurring in the cervicothoracic region show a broad variety in their histologic origin. Accordingly, the indication for surgical resection varies, and especially in malignant lesions, surgery frequently is part of a multimodality treatment. Adequate access is important for any operation in a critical region such as the cervicothoracic junction. The anatomic location of the mass to be resected usually dictates either an anterior or posterior approach. The need for appropriate exposure is in addition paralleled by the need to preserve a maximum of important functional structures, to maintain their diligent functional interaction. Careful interdisciplinary preoperative treatment planning is necessary to achieve optimal results.
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    Pulmonary Vascular Reactivity and Prognosis in Patients With Chronic Thromboembolic Pulmonary Hypertension. A Pilot Study.

    Nika Skoro-Sajer, Niklas Hack, Roela Sadushi-Koliçi, Diana Bonderman, Johannes Jakowitsch, Walter Klepetko, Mir Ali Reza Hoda, Meinhard P Kneussl, Peter Fedullo, Irene M Lang

    Circulation. 01/2009;

    BACKGROUND: -Surgical pulmonary endarterectomy is the preferred treatment for chronic thromboembolic pulmonary hypertension. Persistent pulmonary hypertension after pulmonary endarterectomy has been recognized as a major determinant of poor outcome. We tested whether acute vasoreactivity identifies ... [more] BACKGROUND: -Surgical pulmonary endarterectomy is the preferred treatment for chronic thromboembolic pulmonary hypertension. Persistent pulmonary hypertension after pulmonary endarterectomy has been recognized as a major determinant of poor outcome. We tested whether acute vasoreactivity identifies chronic thromboembolic pulmonary hypertension patients prone to develop persistent/recurrent pulmonary hypertension after pulmonary endarterectomy and whether the degree of acute vasoreactivity affects survival or freedom from lung transplantation. Methods and Results-Right-sided heart catheterization at baseline and after inhalation of 40 ppm nitric oxide for 20 minutes was performed in 103 patients (56.3+/-15.3 years old, 53 women). Reductions in mean pulmonary arterial pressure (DeltamPAP; -8.8+/-12.6%; P<0.0001) and pulmonary vascular resistance (-16.1+/-18.1%; P<0.0001) and an increase in mixed venous saturation during inhaled nitric oxide (9.1+/-11.6%; P<0.0001) were observed. Sixty-two patients underwent pulmonary endarterectomy after a median of 49 days (25th and 75th percentiles: 24 and 123 days). Operated patients were followed up for a median of 70.9 months (25th and 75th percentiles: 14 and 97 months). Change in mPAP during inhaled NO was identified as a predictor of persistent/recurrent pulmonary hypertension after pulmonary endarterectomy. Patients experiencing a reduction in mPAP >10.4% with nitric oxide inhalation had a better postoperative outcome. A significant correlation was found between DeltamPAP and immediate postoperative pulmonary vascular resistance (r=0.5, P<0.0001). Conclusions-A total of 80 (77.7%) of 103 patients demonstrated acute pulmonary vascular reactivity of some degree. A decrease in mPAP >10.4% under inhaled nitric oxide is a predictor of long-term survival and freedom from lung transplantation in adult patients with chronic thromboembolic pulmonary hypertension who are undergoing pulmonary endarterectomy.
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    The Non-canonical WNT-pathway Is Operative in Idiopathic Pulmonary Arterial Hypertension.

    Isabel Pia Laumanns, Ludger Fink, Jochen Wilhelm, Jens C Wolff, Rita Mitnacht-Kraus, Sabine Graef-Hoechst, Maria M Stein, Rainer M Bohle, Walter Klepetko, Mir Ali Reza Hoda, Ralph Theo Schermuly, Friedrich Grimminger, Werner Seeger, Robert Voswinckel

    American journal of respiratory cell and molecular biology. 12/2008;

    Idiopathic pulmonary arterial hypertension (IPAH) is a fatal disease, which is comprised of sustained vasoconstriction, enhanced proliferation of pulmonary vascular cells and in situ thrombosis. The discovery of several contributing signaling pathways in recent years has resulted in an expanding arr... [more] Idiopathic pulmonary arterial hypertension (IPAH) is a fatal disease, which is comprised of sustained vasoconstriction, enhanced proliferation of pulmonary vascular cells and in situ thrombosis. The discovery of several contributing signaling pathways in recent years has resulted in an expanding array of novel therapies; however IPAH remains a progressive disease with poor outcome in most instances. To identify new regulatory pathways of vascular remodeling in IPAH, we performed transcriptome wide expression profiling in laser-microdissected pulmonary arterial resistance vessels derived from explanted IPAH and healthy human lungs. Statistical analysis of the data derived from six individuals in each group showed significant regulation of several mediators of the canonical and non-canonical wnt-pathway. As to the non-canonical wnt-pathway, the planar cell polarity (PCP) pathway, the ras homolog gene family member A (RHOA) and ras-related C3 botulinum toxin substrate-1 (RAC1) were strongly upregulated. Real-time PCR of laser-microdissected pulmonary arteries confirmed these array results and showed in addition significant upregulation of further PCP mediators wingless member 11 (WNT11), disheveled associated activator of morphogenesis-1 (DAAM1), disheveled (DSV), and rho-kinase (ROCK). Immunohistochemical staining and semiquantitative expression analysis confirmed the markedly enhanced expression of the PCP mediators in the pulmonary resistance vessels, in particular in the endothelial layer in IPAH. Therefore we propose the PCP pathway to be critically involved in the regulation of vascular remodeling in IPAH.
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    Outcome after extrapleural pneumonectomy for malignant pleural mesothelioma.

    Clemens Aigner, Mir Ali Reza Hoda, Gyoergy Lang, Shahrokh Taghavi, Gabriel Marta, Walter Klepetko

    European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. 08/2008; 34(1):204-7.

    Background Malignant pleural mesothelioma is a mainly asbestos-related neoplasm that occurs with increasing frequency and is associated with a poor prognosis. Extrapleural pneumonectomy which was initially performed as a stand-alone treatment in patients with resectable disease is now currently almo... [more] Background Malignant pleural mesothelioma is a mainly asbestos-related neoplasm that occurs with increasing frequency and is associated with a poor prognosis. Extrapleural pneumonectomy which was initially performed as a stand-alone treatment in patients with resectable disease is now currently almost uniformly applied as part of a multi-modal approach. Its value and advantage over other therapeutic strategies remain points of discussion. We therefore analysed our experience with extrapleural pneumonectomy in the treatment of malignant pleural mesothelioma. Methods We retrospectively reviewed our institutional experience with all consecutive patients undergoing extrapleural pneumonectomy for malignant pleural mesothelioma from 1994 to 2005. Patients were analysed with regard to hospital mortality and morbidity and long-term outcome. Results Forty-nine patients (10 female/39 male, mean age 58+12 years) underwent extrapleural pneumonectomy during the observation period. Median ICU stay was 1 day, median postoperative length of hospital stay was 13 days. After a mean follow-up of 2573 days, median survival was 376 days (mean 672+121 days, range 9-3384). One-year survival was 53%, 3-year survival 27% and 5-year survival 19%. Conclusion Extrapleural pneumonectomy as part of a multi-modality treatment regimen is a good treatment option for selected patients with malignant pleural mesothelioma. The long-term results of this limited series compare favourably to non-surgical treatment regimens. Larger randomised prospective multi-centre trials are warranted to establish clear guidelines.
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    Haemodynamic complications after pneumonectomy: atrial inflow obstruction and reopening of the foramen ovale.

    Clemens Aigner, György Lang, Shahrokh Taghavi, Mir Ali Reza Hoda, Gabriel Marta, Helmut Baumgartner, Walter Klepetko

    European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery. 03/2008; 33(2):268-71.

    BACKGROUND: Haemodynamic impairments after pneumonectomy are rare complications and present in different forms. Due to a low awareness of these potential complications their diagnosis is difficult and often established late. The most important forms are: firstly reopening of a previously closed fora... [more] BACKGROUND: Haemodynamic impairments after pneumonectomy are rare complications and present in different forms. Due to a low awareness of these potential complications their diagnosis is difficult and often established late. The most important forms are: firstly reopening of a previously closed foramen ovale (PFO) caused by a combination of changed anatomic position of the left atrium and elevated pulmonary artery pressure leading to a significant right-left shunt; secondly diaphragmatic relaxation can lead to a dislocation of the liver into the right hemithorax, compressing the right atrium with subsequent inflow obstruction. METHODS: We retrospectively analysed our patient cohort from 1997 to 2006 for occurrence of haemodynamic complications requiring surgical intervention after pneumonectomy. RESULTS: Five hundred and forty-six pneumonectomies were performed in our centre during the observation period. Five patients (1 female, 4 male, age 59+/-9 years) with haemodynamic complications were identified. Two of those patients were referred with haemodynamic complications after pneumonectomy was performed in a peripheral centre. All patients had undergone right pneumonectomy for NSCLC (n=4) or atypical carcinoid (n=1). Two patients were readmitted 3 months and 2 years postoperatively due to increasing platypnoea and orthodeoxia. After closure of the reopened foramen ovale, which was found as the underlying pathological mechanism, respiratory symptoms were resolved. One patient required reintubation 2h postoperatively; after surgical closure of a PFO the respiratory situation significantly improved. One patient was readmitted due to right atrial inflow obstruction 17 months after right pneumonectomy. Underlying cause was a severe diaphragmatic relaxation with compression of the atrium by the liver. After diaphragmatic plication all symptoms resolved. However 1 year thereafter reoperation for recurrence of diaphragmatic elevation was required. One patient was readmitted 3 months after pneumonectomy and partial atrial resection for cyanosis and dyspnoea. Diagnostics revealed a PFO and a massive raise of the right diaphragm with compression of the right atrium. After surgical correction of the contorted foramen ovale and diaphragmatic plication, symptoms vanished. CONCLUSION: Haemodynamic alterations due to a reopened foramen ovale or right atrial inflow obstruction are rare, however they are severe complications after pneumonectomy. They occur at variable points in time after pneumonectomy. Diagnostic efforts are often made at a late stage due to a low awareness of the problem. Closure of the PFO either surgical or interventional and/or plication of the elevated diaphragm are mandatory. In our experience these complications occur only after right pneumonectomy.
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    Pulmonary retransplantation: is it worth the effort? A long-term analysis of 46 cases.

    Clemens Aigner, Peter Jaksch, Shahrokh Taghavi, Gyoergy Lang, Mir Ali Reza Hoda, Wilfried Wisser, Walter Klepetko

    The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation. 02/2008; 27(1):60-5.

    BACKGROUND: Pulmonary retransplantation remains the only therapeutic option in some cases of severe primary graft dysfunction (PGD), advanced bronchiolitis obliterans syndrome (BOS), and in some cases of severe airway problems (AWP), mainly cicatriceal stenosis. However, its value has been questione... [more] BACKGROUND: Pulmonary retransplantation remains the only therapeutic option in some cases of severe primary graft dysfunction (PGD), advanced bronchiolitis obliterans syndrome (BOS), and in some cases of severe airway problems (AWP), mainly cicatriceal stenosis. However, its value has been questioned due to the overall scarcity of donor organs and reports indicating unsatisfactory outcome. We analyzed our institutional experience with pulmonary retransplantation to evaluate its value for different indications. METHODS: We retrospectively analyzed all 46 patients undergoing pulmonary retransplantation from the 567 consecutive primary lung or heart-lung transplantations performed in our department from August 1995 to August 2006. We stratified patients according to indication for retransplantation and analyzed the outcome. RESULTS: Forty-six patients (mean age 41 +/- 16 years, 18 men and 28 women) underwent pulmonary retransplantation (14 bilateral lung transplantations, 32 single-lung transplantations) for primary graft dysfunction (n = 23), bronchiolitis obliterans syndrome (n = 19) and airway problems (n = 4). Mean time to retransplantation was 26 +/- 27 days in the PGD group, 1,069 +/- 757 days in the BOS group and 220 +/- 321 days in the AWP group. Thirty-day, 1-year and 5-year survival rates after retransplantation were 52.2%, 34.8% and 29.0% in the PGD group and 89.2%, 72.5% and 61.3% in the BOS group, respectively. All 4 patients in the AWP group are presently alive (BOS vs PGD: p = 0.02; BOS vs AWP: p = 0.27; PGD vs AWP: p = 0.06). CONCLUSIONS: Pulmonary retransplantation for bronchiolitis obliterans offers long-term survival rates in the range of primary lung transplantation for selected patients. Long-term survival rates for retransplantation due to PGD are significantly lower, warranting restrictive use in this setting. In our experience with a limited number of patients, retransplantation for airway problems has shown excellent results. Pulmonary retransplantation for chronic problems is a plausible approach, provided that patients are carefully selected. Retransplantation for PGD should be avoided.
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    Hypoxia-dependent regulation of nonphagocytic NADPH oxidase subunit NOX4 in the pulmonary vasculature.

    Manish Mittal, Markus Roth, Peter König, Simone Hofmann, Eva Dony, Parag Goyal, Anne-Christin Selbitz, Ralph Theo Schermuly, Hossein Ardeschir Ghofrani, Grazyna Kwapiszewska, Wolfgang Kummer, Walter Klepetko, Mir Ali Reza Hoda, Ludger Fink, Jörg Hänze, Werner Seeger, Friedrich Grimminger, Harald H H W Schmidt, Norbert Weissmann

    Circulation research. 09/2007; 101(3):258-67.

    Nonphagocytic NADPH oxidases have recently been suggested to play a major role in the regulation of physiological and pathophysiological processes, in particular, hypertrophy, remodeling, and angiogenesis in the systemic circulation. Moreover, NADPH oxidases have been suggested to serve as oxygen se... [more] Nonphagocytic NADPH oxidases have recently been suggested to play a major role in the regulation of physiological and pathophysiological processes, in particular, hypertrophy, remodeling, and angiogenesis in the systemic circulation. Moreover, NADPH oxidases have been suggested to serve as oxygen sensors in the lung. Chronic hypoxia induces vascular remodeling with medial hypertrophy leading to the development of pulmonary hypertension. We screened lung tissue for the expression of NADPH oxidase subunits. NOX1, NOXA1, NOXO1, p22phox, p47phox, p40phox, p67phox, NOX2, and NOX4 were present in mouse lung tissue. Comparing mice maintained for 21 days under hypoxic (10% O(2)) or normoxic (21% O(2)) conditions, an upregulation exclusively of NOX4 mRNA was observed under hypoxia in homogenized lung tissue, concomitant with increased levels in microdissected pulmonary arterial vessels. In situ hybridization and immunohistological staining for NOX4 in mouse lungs revealed a localization of NOX4 mRNA and protein predominantly in the media of small pulmonary arteries, with increased labeling intensities after chronic exposure to hypoxia. In isolated pulmonary arterial smooth muscle cells (PASMCs), NOX4 was localized primarily to the perinuclear space and its expression levels were increased after exposure to hypoxia. Treatment of PASMCs with siRNA directed against NOX4 decreased NOX4 mRNA levels and reduced PASMC proliferation as well as generation of reactive oxygen species. In lungs from patients with idiopathic pulmonary arterial hypertension (IPAH), expression levels of NOX4, which was localized in the vessel media, were 2.5-fold upregulated. These results support an important role for NOX4 in the vascular remodeling associated with development of pulmonary hypertension.
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    Does gastric dilatation limit the success of sleeve gastrectomy as a sole operation for morbid obesity?

    Felix B Langer, Arthur Bohdjalian, Franz X Felberbauer, Edith Fleischmann, Mir A Reza Hoda, Bernhard Ludvik, Johannes Zacherl, Raimund Jakesz, Gerhard Prager

    Obesity surgery. 02/2006; 16(2):166-71.

    BACKGROUND: Sleeve gastrectomy as the sole bariatric operation has been reported for high-risk super-obese patients or as first-step followed by Roux-en-Y gastric bypass (RYGBP) or duodenal switch (DS) in super-super obese patients. The efficacy of laparoscopic sleeve gastrectomy (LSG) for morbidly ... [more] BACKGROUND: Sleeve gastrectomy as the sole bariatric operation has been reported for high-risk super-obese patients or as first-step followed by Roux-en-Y gastric bypass (RYGBP) or duodenal switch (DS) in super-super obese patients. The efficacy of laparoscopic sleeve gastrectomy (LSG) for morbidly obese patients with a BMI of <50 kg/m2 and the incidence of gastric dilatation following LSG have not yet been investigated. METHODS: 23 patients (15 morbidly obese, 8 super-obese) were studied prospectively for weight loss following LSG. The incidence of sleeve dilatation was assessed by upper GI contrast studies in patients with a follow-up of >12 months. RESULTS: Patients who underwent LSG achieved a mean excess weight loss (EWL) at 6 and 12 months postoperatively of 46% and 56%, respectively. No significant differences were observed in %EWL comparing obese and super-obese patients. At a mean follow-up of 20 months, dilatation of the gastric sleeve was found in 1 patient and weight regain after initial successful weight loss in 3 of the 23 patients. CONCLUSION: LSG has been highly effective for weight reduction for morbid obesity even as the sole bariatric operation. Gastric dilatation was found in only 1 patient in this short-term follow-up. Weight regain following LSG may require conversion to RYGBP or DS. Follow-up will be necessary to evaluate long-term results.
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    Sleeve gastrectomy and gastric banding: effects on plasma ghrelin levels.

    F B Langer, M A Reza Hoda, A Bohdjalian, F X Felberbauer, J Zacherl, E Wenzl, K Schindler, A Luger, B Ludvik, G Prager

    Obesity surgery. 09/2005; 15(7):1024-9.

    BACKGROUND: Different changes of plasma ghrelin levels have been reported following gastric banding, Roux-en-Y gastric bypass, and biliopancreatic diversion. METHODS: This prospective study compares plasma ghrelin levels and weight loss following laparoscopic sleeve gastrectomy (LSG) and laparoscopi... [more] BACKGROUND: Different changes of plasma ghrelin levels have been reported following gastric banding, Roux-en-Y gastric bypass, and biliopancreatic diversion. METHODS: This prospective study compares plasma ghrelin levels and weight loss following laparoscopic sleeve gastrectomy (LSG) and laparoscopic adjustable gastric banding (LAGB) in 20 patients. RESULTS: Patients who underwent LSG (n=10) showed a significant decrease of plasma ghrelin at day 1 compared to preoperative values (35.8 +/- 12.3 fmol/ml vs 109.6 +/- 32.6 fmol/ml, P=0.005). Plasma ghrelin remained low and stable at 1 and 6 months postoperatively. In contrast, no change of plasma ghrelin at day 1 (71.8 +/- 35.3 fmol/ml vs 73.7 +/- 24.8 fmol/ml, P=0.441) was found in patients after LAGB (n=10). Increased plasma ghrelin levels compared with the preoperative levels at 1 (101.9 +/- 30.3 fmol/ml vs 73.7 +/- 24.8 fmol/ml, P=0.028) and 6 months (104.9 +/- 51.1 fmol/ml vs 73.7 +/- 24.8 fmol/ml, P=0.012) after surgery were observed. Mean excess weight loss was higher in the LSG group at 1 (30 +/- 13% vs 17 +/- 7%, P=0.005) and 6 months (61 +/- 16% vs 29 +/- 11%, P=0.001) compared with the LAGB group. CONCLUSIONS: As a consequence of resection of the gastric fundus, the predominant area of human ghrelin production, ghrelin is significantly reduced after LSG but not after LAGB. This reduction remains stable at follow-up 6 months postoperatively, which may contribute to the superior weight loss when compared with LAGB.
  • [Surgical treatment of obesity]

    Arthur Bohdjalian, Felix Langer, Mir Ali Reza Hoda, Franz Felberbauer, Gerd Silberhumer, Johannes Zacherl, Karin Schindler, Anton Luger, Bernhard Ludvik, Gerhard Prager

    Wiener medizinische Wochenschrift (1946). 08/2004; 154(13-14):329-33.

    At the beginning of the 21st century, obesity has become an epidemic with the greatest prevalence in the western world. For morbidly obese patients, conservative treatment has yielded disappointing results: On the other hand, bariatric surgery offers a sustained substantial weight loss for these pat... [more] At the beginning of the 21st century, obesity has become an epidemic with the greatest prevalence in the western world. For morbidly obese patients, conservative treatment has yielded disappointing results: On the other hand, bariatric surgery offers a sustained substantial weight loss for these patients. Common bariatric procedures including results and complications are described. Different Bariatric procedures including Gastric Banding, Vertical Banded Gastroplasty, Gastric Bypass, Duodenal Switch and Gastric Pacing are introduced. Bariatric procedures can result in permanent excessive weight loss ranging from 25 to 78% and thus are an effective treatment for morbidly obese patients. Efficacy, morbidity and late term complications, however, should be considered in choosing the most effective bariatric approach.
  • Current treatment paradigms of superior sulcus tumours

    Masaya Tamura, Mir Alireza Hoda, Walter Klepetko

    European Journal of Cardio-Thoracic Surgery.

    Pancoast or superior pulmonary sulcus tumours are a rare subset of non-small-cell lung carcinomas (NSCLCs) which occur with an incidence of less than 5% of all lung cancers. Today, induction chemoradiation followed by surgical resection has become the established standard treatment approach for pati... [more] Pancoast or superior pulmonary sulcus tumours are a rare subset of non-small-cell lung carcinomas (NSCLCs) which occur with an incidence of less than 5% of all lung cancers. Today, induction chemoradiation followed by surgical resection has become the established standard treatment approach for patients with sulcus superior tumours in the absence of other contraindications. This review focusses on the historical change of the treatment strategy, the evolution of surgical and multimodality management of this disease and the most recent published clinical outcome data of patients suffering from superior pulmonary sulcus carcinoma.

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