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author:("weber, Walter")
1.  Supplementary Prognostic Variables for Pleural Mesothelioma 
Journal of Thoracic Oncology  2014;9(6):856-864.
The staging system for malignant pleural mesothelioma is controversial. To revise this system, the International Association for the Study of Lung Cancer Staging Committee developed an international database. This report analyzes prognostic variables in a surgical population, which are supplementary to previously published CORE variables (stage, histology, sex, age, and type of procedure).
Supplementary prognostic variables were studied in three scenarios: (1) all data available, that is, patient pathologically staged and other CORE variables available (2) only clinical staging available along with CORE variables, and (3) only age, sex, histology, and laboratory parameters are known. Survival was analyzed by Kaplan–Meier, prognostic factors by log rank and stepwise Cox regression modeling after elimination of nonsignificant variables. p value less than 0.05 was significant.
A total of 2141 patients with best tumor, node, metastasis (TNM) stages (pathologic with/without clinical staging) had nonmissing age, sex, histology, and type of surgical procedure. Three prognostic models were defined. Scenario A (all parameters): best pathologic stage, histology, sex, age, type of surgery, adjuvant treatment, white blood cell count (WBC) (≥15.5 or not), and platelets (≥400 k or not) (n = 550). Scenario B (no surgical staging): clinical stage, histology, sex, age, type of surgery, adjuvant treatment, WBC, hemoglobin (<14.6 or not), and platelets (n = 627). Scenario C (limited data): histology, sex, age, WBC, hemoglobin, and platelets (n = 906).
Refinement of these models could define not only the appropriate patient preoperatively for best outcomes after cytoreductive surgery but also stratify surgically treated patients after clinical and pathologic staging who do or do not receive adjuvant therapy.
PMCID: PMC4132031  PMID: 24807157
Mesothelioma; Surgery; Prognosis; Registry; Staging
2.  Determinants of outcome of solitary fibrous tumors of the pleura: an observational cohort study 
BMC Pulmonary Medicine  2014;14:138.
Solitary fibrous tumors of the pleura (SFTP) are rare and their long-term outcome is difficult to predict, as there are insufficient data which allow accurate characterization of the malignant variant. Thus the aim of this study was to describe the outcome and possible determinants of malignant behavior of SFTPs.
Data were collected retrospectively from medical records of patients treated at the University Hospital Zurich from 1992 to 2012. Kaplan-Meier and Cox regression analysis were performed to define disease-free survival time (defined as survival without tumor-recurrence or tumor-related death) using the classical histo-morphological criteria (tumor size, localization, pedunculation, tumor necrosis or hemorrhage, mitotic activity and nuclear pleomorphism) and immunohistochemical parameters.
42 patients (20 males) with SFTP (median (IQR) age 62 (56–71) years) could be identified. SFTP were associated with symptoms in 50% of all cases. Complete resection was achieved by video-assisted thoracic surgery or thoracotomy in 20 and 22 patients, respectively. Three SFTP-related deaths (7.1%) and four tumor recurrences (9.5%) were observed. Mean disease-free survival time was 136.2 (±13.1) months, and 2-, 5- and 10-year disease-free survival was 91%, 84%, and 67%, respectively. Mean disease-free survival inversely correlated with the mean tumor diameter, number of mitotic figures and proliferation rate (Ki-67 expression). Other criteria (tumor necrosis, atypical localization, sessile tumor, and pleomorphism) were not statistically significant prognostic parameters.
Patients with large SFTP with a high mitotic index and high proliferation rate should be followed-up closely and over a prolonged time period in order to recognize recurrence of the SFTP early and at a treatable stage. Future research on this topic should focus on the prognostic role of immunohistochemistry including Ki-67 expression and molecular parameters.
PMCID: PMC4134113  PMID: 25115286
Solitary fibrous tumor; Pleura; Immunohistochemistry; Outcome; Proliferation rate
3.  Cytokine Complex–expanded Natural Killer Cells Improve Allogeneic Lung Transplant Function via Depletion of Donor Dendritic Cells 
Rationale: Natural killer (NK) cells are innate lymphocytes that target virus-infected and tumor cells. Much less is known about their ability to limit adaptive immune responses.
Objectives: Thus, we investigated to what extent NK cells can influence mouse lung allograft rejection.
Methods: For this purpose, we employed an orthotopic lung transplantation model in mice.
Measurements and Main Results: We demonstrate here that NK cells infiltrate mouse lung allografts before T cells and thereby diminished allograft inflammation, and that NK-cell deficiency enhanced allograft rejection. In contrast, expansion of recipient NK cells through IL-15/IL-15Rα complex treatment resulted in decreased T-cell infiltration and alloreactive T-cell priming as well as improved function of the allogeneic lung transplant. Only perforin-competent, but not perforin-deficient, NK cells were able to transfer these beneficial effects into transplanted NK cell–deficient IL-15Rα−/− mice. These NK cells killed allogeneic dendritic cells (DCs) in vitro and significantly decreased the number of allogeneic DCs in transplanted lungs in vivo. Furthermore, DC-depleted lung allografts presented decreased signs of rejection.
Conclusions: These results suggest that NK cells favor allograft acceptance by depleting donor-derived DCs, which otherwise would prime alloreactive T-cell responses. Thus, conditioning regimens that augment NK-cell reactivity should be clinically explored to prepare lung allograft recipients.
PMCID: PMC3734612  PMID: 23590269
natural killer cells; dendritic cells; lung; mouse transplantation; acute rejection
4.  Re-directed T cells for the treatment of fibroblast activation protein (FAP)-positive malignant pleural mesothelioma (FAPME-1) 
BMC Cancer  2012;12:615.
Asbestos is the main cause of MPM in industrialized countries. Even since asbestos is banned in most developed countries, the peak wave of MPM incidence is anticipated for the next years due to the long latency of asbestos induced MPM. MPM patients not eligible for surgical procedures like decortication or pleuro-pneumectomie have a median survival of 12 months with palliative chemotherapy. Therefore, new therapeutic approaches are of crucial need in this clinical situation.
This is a phase I trial for patients with malignant pleural mesothelioma with pleural effusion testing the safety of a fixed single dose of 1x106 adoptively transferred FAP-specific re-directed T cells given directly in the pleural effusion. Lymphocytes will be taken 21 days before transfer from peripheral blood. CD8 positive T cells will be isolated and re-programmed by retroviral transfer of a chimeric antigen receptor recognizing FAP which serves as target structure in MPM. At day 0 of the protocol, re-directed T cells will be injected in the pleural effusion and patients will be monitored for 48h under intermediate care conditions. AE, SAE, SADR and SUSAR will be monitored for 35 days and evaluated by an independent safety board to define any dose limiting toxicity (DLT). No further patient can be treated before the previous patient passed day 14 after T cell transfer. The protocol will be judged as save when no DLT occurred in the first 3 patients, or 1 DLT in 6 patients. Secondary objectives are feasibility and immune monitoring.
Adoptive T cell transfer is a new and rapidly expanding branch of immunotherapies focusing on cancer treatment. Recently, objective responses could be observed in patients with chronic lymphatic leukemia treated with adoptively transferred CD19-specific re-directed T cells. The choice of the target antigen determines the possible on-target off-tissue toxicity of such approaches. There are reports of severe toxicity in patients who received T cells intravenously due to unexpected expression of the target antigen (on-target) in other tissues than the tumor (off-tissue). To minimize the risk of on-target off-tissue toxicity and to maximize the on-target anti-tumor effect we propose a clinical protocol with loco-regional administration of re-directed T cells. FAP-specific T cells will be directly injected in the pleural effusion of patients with MPM.
Trial registration (NCT01722149)
PMCID: PMC3585825  PMID: 23259649
5.  Multimodality therapy for malignant pleural mesothelioma 
Annals of Cardiothoracic Surgery  2012;1(4):502-507.
PMCID: PMC3741801  PMID: 23977544
6.  L1CAM protein expression is associated with poor prognosis in non-small cell lung cancer 
Molecular Cancer  2011;10:127.
The L1 cell adhesion molecule (L1CAM) is potentially involved in epithelial-mesenchymal transition (EMT). EMT marker expression is of prognostic significance in non-small cell lung cancer (NSCLC). The relevance of L1CAM for NSCLC is unclear. We investigated the protein expression of L1CAM in a cohort of NSCLC patients. L1CAM protein expression was correlated with clinico-pathological parameters including survival and markers of epithelial-mesenchymal transition.
L1CAM protein expression was found in 25% of squamous cell carcinomas and 24% of adenocarcinomas and correlated with blood vessel invasion and metastasis (p < 0.05). L1CAM was an independent predictor of survival in a multivariate analysis including pT, pN, and pM category, and tumor differentiation grade. L1CAM expression positively correlated with vimentin, beta-catenin, and slug, but inversely with E-cadherin (all p-values < 0.05). E-cadherin expression was higher in the tumor center than in the tumor periphery, whereas L1CAM and vimentin were expressed at the tumor-stroma interface. In L1CAM-negative A549 cells the L1CAM expression was upregulated and matrigel invasion was increased after stimulation with TGF-beta1. In L1CAM-positive SK-LU-1 and SK-LC-LL cells matrigel invasion was decreased after L1CAM siRNA knockdown.
A subset of NSCLCs with vessel tropism and increased metastasis aberrantly expresses L1CAM. L1CAM is a novel prognostic marker for NSCLCs that is upregulated by EMT induction and appears to be instrumental for enhanced cell invasion.
PMCID: PMC3198986  PMID: 21985405
L1 cell adhesion molecule; epithelial-mesenchymal transition; tumor-stroma interface; prognostic marker; non-small cell lung cancer; tissue microarray
7.  Clinical review: Practical recommendations on the management of perioperative heart failure in cardiac surgery 
Critical Care  2010;14(2):201.
Acute cardiovascular dysfunction occurs perioperatively in more than 20% of cardiosurgical patients, yet current acute heart failure (HF) classification is not applicable to this period. Indicators of major perioperative risk include unstable coronary syndromes, decompensated HF, significant arrhythmias and valvular disease. Clinical risk factors include history of heart disease, compensated HF, cerebrovascular disease, presence of diabetes mellitus, renal insufficiency and high-risk surgery. EuroSCORE reliably predicts perioperative cardiovascular alteration in patients aged less than 80 years. Preoperative B-type natriuretic peptide level is an additional risk stratification factor. Aggressively preserving heart function during cardiosurgery is a major goal. Volatile anaesthetics and levosimendan seem to be promising cardioprotective agents, but large trials are still needed to assess the best cardioprotective agent(s) and optimal protocol(s). The aim of monitoring is early detection and assessment of mechanisms of perioperative cardiovascular dysfunction. Ideally, volume status should be assessed by 'dynamic' measurement of haemodynamic parameters. Assess heart function first by echocardiography, then using a pulmonary artery catheter (especially in right heart dysfunction). If volaemia and heart function are in the normal range, cardiovascular dysfunction is very likely related to vascular dysfunction. In treating myocardial dysfunction, consider the following options, either alone or in combination: low-to-moderate doses of dobutamine and epinephrine, milrinone or levosimendan. In vasoplegia-induced hypotension, use norepinephrine to maintain adequate perfusion pressure. Exclude hypovolaemia in patients under vasopressors, through repeated volume assessments. Optimal perioperative use of inotropes/vasopressors in cardiosurgery remains controversial, and further large multinational studies are needed. Cardiosurgical perioperative classification of cardiac impairment should be based on time of occurrence (precardiotomy, failure to wean, postcardiotomy) and haemodynamic severity of the patient's condition (crash and burn, deteriorating fast, stable but inotrope dependent). In heart dysfunction with suspected coronary hypoperfusion, an intra-aortic balloon pump is highly recommended. A ventricular assist device should be considered before end organ dysfunction becomes evident. Extra-corporeal membrane oxygenation is an elegant solution as a bridge to recovery and/or decision making. This paper offers practical recommendations for management of perioperative HF in cardiosurgery based on European experts' opinion. It also emphasizes the need for large surveys and studies to assess the optimal way to manage perioperative HF in cardiac surgery.
PMCID: PMC2887098  PMID: 20497611
8.  Laser-Capture Microdissection Impairs Activity-Based Protein Profiles for Serine Hydrolase in Human Lung Adenocarcinoma 
Laser-capture microdissection (LCM) enables the selection of a specific and pure cell population from a heterogenous tissue such as tumors. Activity-based protein profiling/profile (ABPP) is a chemical technology using enzyme-specific active site-directed probes to read out the functional state of many enzymes directly in any proteome. The aim of this work was to assess the compatibility of LCM with downstream ABPP for serine hydrolase (SH) in human lung adenocarcinoma. Fresh frozen lung adenocarcinoma tissue was stained with hematoxylin, toluidine blue, or methyl green (MG). Proteome from stained tissue was labeled further with SH-directed probes, and ABPPs were determined on a one-dimensional gel-based approach. This allowed us to assess the impact of staining procedures on their ABPPs. The effect of the LCM process on ABPPs was assessed furthermore using MG-stained lung adenocarcinoma tissue. The staining procedures led to strong changes in ABPPs. However, MG staining seemed the most compatible with downstream ABPP. MG-stained, laser-captured, microdissected tissue showed additional change in profiles as a result of the denaturing property of extraction buffer but not to the microdissection process itself. LCM staining procedures but not microdissection per se interfered with downstream ABPP and led to a strong change in ABPPs of SHs in human lung adenocarcinoma.
PMCID: PMC2841994  PMID: 20357979
proteomics; staining
9.  Caveolin-1 Expression and Hemodynamics in COPD Patients 
Caveolin-1 is a regulator of both intracellular calcium homeostasis and endothelial nitric oxide synthase and may play a pathogenetic role in pulmonary hypertension. In the present study, we aimed to investigate the correlations between pulmonary hemodynamics and vessel morphology including the expression of Caveolin-1 in pulmonary arterioles from patients with chronic obstructive pulmonary disease (COPD) who underwent lung-volume reduction surgery. Staining and subsequent analysis was performed on paraffin-embedded lung tissue from COPD patients (n = 12). Pulmonary arteries with an external diameter of 100-500µm were analysed. Immunhistochemistry with antibodies against caveolin-1 was performed and intensity was assessed. Morphometric data were obtained by using computer-assisted imaging software. The findings were quantified and correlated to hemodynamic data obtained by right-heart catheterization. In COPD patients with pulmonary hypertension (n = 5), the expression of caveolin-1 within the medial smooth muscle cell layer was found to be increased, whereas the intimal caveolin-1 was more prominently expressed in COPD patients with normal pulmonary pressures (n = 7). The ratio between these expression patterns was positively correlated to the mean pulmonary artery pressure. Similar findings were observed for the ratio between intimal and medial thickness as well as for the expression of smooth muscle actin (SMA).
Taken together, the expression of caveolin-1 within medial smooth muscle cells of pulmonary arteries in patients with COPD is associated with pulmonary hypertension. Our results thus emphasize a potential novel player in the pathogenesis of COPD-associated pulmonary hypertension.
PMCID: PMC2703474  PMID: 19572028
Caveolin-1; chronic obstructive pulmonary disease (COPD); morphometry; pulmonary hypertension.
10.  EML4-ALK Fusion Lung Cancer: A Rare Acquired Event 
Neoplasia (New York, N.Y.)  2008;10(3):298-302.
A recurrent gene fusion between EML4 and ALK in 6.7% of non-small cell lung cancers (NSCLCs) and NKX2-1 (TTF1, TITF1) high-level amplifications in 12% of adenocarcinomas of the lung were independently reported recently. Because the EML4-ALK fusion was only shown by a reverse transcription-polymerase chain reaction approach, we developed fluorescent in situ hybridization assays to interrogate more than 600 NSCLCs using break-apart probes for EML4 and ALK. We found that EML4-ALK fusions occur in less than 3% of NSCLC samples and that EML4 and/or ALK amplifications also occur. We also observed that, in most cases in which an EML4/ALK alteration is detected, not all of the tumor cells harbor the lesion. By using a detailed multi-fluorescent in situ hybridization probe assay and reverse transcription-polymerase chain reaction, we have evidence that other, more common mechanisms besides gene inversion exist including the possibility of other fusion partners for ALK and EML4. Furthermore, we confirmed the NKX2-1 high-level amplification in a significant subset of NSCLC and found this amplification to be mutually exclusive to ALK and EML4 rearrangements.
PMCID: PMC2259458  PMID: 18320074

Results 1-10 (10)