51 research outputs found
Corticomedullary differentiation and maturational arrest in thymomas
No full textAimsMorphological complexity hampers the histological classification of thymomas. Our aim was to determine whether the use of novel differentiation and maturation markers of cortical and medullary thymic epithelial cells (cTECs and mTECs) might provide an approach to understanding the underlying biology of these tumours. Methods and resultsFifty-seven thymomas were studied by immunohistochemistry. The cortical markers used were B5T, PRSS16, and cathepsin V. The medullary markers used were CD40, claudin-4, AIRE, and desmin. Involucrin and cytokeratin 10 were used to study terminal mTEC maturation. Irrespective of histological subtype, most thymomas contained distinct areas with cortical and medullary differentiation. Type B1, type B2 and type AB thymomas showed marked bi-lineage differentiation, with lack of terminal mTEC maturation in type AB. Type AB thymomas were unique in showing areas where cells with either cortical or medullary differentiation were intimately mixed' at the single-cell level. Type B3 and type A thymomas showed only abortive lineage differentiation and maturation. ConclusionsThymomas show highly characteristic patterns of bi-lineage TEC differentiation that reflect the histological subtypes recognized by the WHO classification. We hypothesize that thymomas arise from thymic precursor cells with different cortical and/or medullary maturation defects
Primary Multi-Systemic Metastases in Osteosarcoma: Presentation, Treatment, and Survival of 83 Patients of the Cooperative Osteosarcoma Study Group
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The European Society of Thoracic Surgeons Lung Metastasectomy Project
No full textAbstractResection of metastases in the lung from a wide range of primary sites has become a routine part of the daily clinical practice of a thoracic surgeon. The European Society of Thoracic Surgeons brought together an international group of surgeons in 2006. The initial intention for this Lung Metastasectomy Working Group was to evaluate the evidence and to generate guidance. It rapidly became clear that although there was great experience in performing this surgery, the belief in its benefit relied on clinical case series and registry reports. Evidence fell well short of Evidence Based Medicine standards and robust guidance could not be produced on this basis. This supplement of the Journal of Thoracic Oncology brings together the findings and conclusions of the group under three headings. The first section covers generic issues such as imaging and the technical aspects of pulmonary metastasectomy. The second deals with specific cancer types in which pulmonary metastasectomy is more frequently performed. The third addresses the way forward to get better evidence for this practice
Abstract 1224: Combination of rapamycin and crizotinib induces partial remission of pleural mesothelioma in a patient-derived xenograft model
No full textAbstract
Introduction: Malignant pleural mesothelioma (MPM) is a neoplasm with inferior prognosis and notorious chemotherapeutic resistance. New treatment approaches may be based on specific inhibitors against kinases that are overexpressed in MPM, such as mTOR and MET. Here we examined the tyrosine kinase ALK as a potential therapeutic target and the combinatorial efficacy of the ALK/MET inhibitor crizotinib and the mTOR inhibitor rapamycin.
Methods: We investigated the ALK status and the expression of mTOR and MET in 145 primary MPM and 8 murine patient-derived xenograft models. ALK overexpression, rearrangement and mutation were studied by qRT-PCR, FISH, immunohistochemistry and sequence analysis. Expression of mTOR and MET was analyzed by qRT-PCR and immunohistochemistry. The combined anti-tumor effect of crizotinib and rapamycin was evaluated in a patient derived xenograft model. Effects of single drug vs. combination treatment on proliferation, apoptosis and autophagy were assessed using Ki-67 immunohistochemistry, TUNEL assay and LC3B immunofluorescence, respectively.
Results: Overexpression of ALK transcripts was detected in 25 (19.5%) of 128 interpretable primary MPM and two xenograft tumors and was neither associated with ALK rearrangement nor with mutation of the kinase domain. ALK protein was expressed in 8.3% MPM and the two xenograft tumors expressing ALK transcript. mTOR protein expression was detected in 28.7% MPM, co-expressed with ALK and/or MET in 17.8% MPM. Applied to a patient derived MPM xenograft model that co-expressed ALK, MET and mTOR, crizotinib alone did not exert anti-tumor growth activity, but enhanced the anti-tumor effect of rapamycin: Rapamycin was effective in 3 of 5 tumors (pathological partial remission in 1, stable tumor in 2 cases). Combination treatment was active in all 5 tumors (partial remission in 4, stable tumor in 1 case). Simultaneous treatment with rapamycin and crizotinib, however, significantly suppressed tumor proliferation compared to rapamycin-single treatment. Autophagy was induced by both single drug treatments and distinctly enhanced by combination treatment, while apoptosis was not promoted.
Conclusion: Dual combinatory treatment of rapamycin and crizotinib is more effective than rapamycin as single agent in suppressing MPM tumor growth and therefore merits further investigation.
Citation Format: Dina Mönch, Sabine Bode-Erdmann, Jörg Kalla, Jörn Sträter, Carsten Schwänen, Roger-Fei Falkenstern-Ge, Martin Kimmich, Martin Kohlhäufl, Godehard Friedel, German Ott, Claudia Kalla. Combination of rapamycin and crizotinib induces partial remission of pleural mesothelioma in a patient-derived xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1224. doi:10.1158/1538-7445.AM2017-1224</jats:p
Alveolar inflammation in cystic fibrosis
No full textIn infected lungs of the cystic fibrosis (CF) patients, opportunistic pathogens and mutated cystic fibrosis transmembrane conductance regulator protein (CFTR) contribute to chronic airway inflammation that is characterized by neutrophil/macrophage infiltration, cytokine release and ceramide accumulation. We sought to investigate CF lung inflammation in the alveoli
Long-term results after 110 tracheal resections
No full textObjective: Among the many therapeutic options for treating tracheal stenosis (e.g. bouginage, laser resection and stenting), segmental resection and reconstruction with end-to-end anastomosis is the method of choice. We verified this in an analysis of clinical material. Patients and methods: We retrospectively evaluated 110 tracheal sleeve resections performed between 1985 and 2001. Data before and after resection were analyzed, and the patients were interviewed. Results: The aetiology of stenosis was mainly postintubation injury (n = 92) (83.6%), followed by goiter with malacia (n = 8) (7.3%) and tumor (n = 6) (5.5%). There were a few other causes (n = 3) (2.7%). 48 patients (43.6%) had undergone prior conservative or surgical treatment other than sleeve resection. A cervical approach was used in 93 (84.6%), a cervicomediastinal in 15 (13.6%), and a transthoracic in two. Healing of anastomosis was uncomplicated in 101 patients (91.8%). Major and minor complications occurred in 29 patients (26.4); there were 4 dehiscences (3.6%), 3 restenoses (2.7%), 2 suture line granulations (1.8%) and 4 vocal cord dysfunctions (3.6%). The 30-day mortality rate was 0.9%. 77 patients were interviewed after surgery (median 80.1 months); 93.5% (n = 72) were satisfied with the surgical treatment. Conclusions: Resection and reconstruction offer the best treatment for tracheal stenosis. Lethal complications were due to severe comorbidity. Many patients today still undergo unsuccessful conservative treatment before being referred to surgery
Host-integration of a tissue-engineered airway patch: Two-year follow-up in a single patient
No full textS.573-579Different bioengineering techniques have been applied repeatedly for the reconstruction of extensive airway defects in the last few years. While short-term surgical success is evident, there is a lack of long-term results in patients. Here, we report the case of a young male who received a 5×2cm bioartificial airway patch for tracheoesophageal reconstruction focusing on clinical defect healing and histomorphological tissue reorganization 2.5 years after surgery. We generated bioartificial airway tissue using a cell-free biological vascularized scaffold that was re-endothelialized and reseeded with the recipient's autologous primary cells and we implanted it into the recipient's left main bronchus. To investigate host-integration 2.5 years after the implantation, we obtained biopsies of the implant and adjacent tracheal tissue and processed these for histological and immunohistochemical analyses. The early postoperative course was uneventful and the transplanted airway t issue was integrated into the host. 2.5 years after transplantation, a bronchoscopy confirmed the scar-free reconstruction of the former airway defect. Histological work-up documented respiratory airway mucosa lining the bronchial reconstruction, making it indistinguishable from native airway mucosa. After transplantation, our bioartificial airway tissue provided perfect airway healing, with no histological evidence of tissue dedifferentiation.21Nr.3-
A Novel, Highly Sensitive ALK Antibody 1A4 Facilitates Effective Screening for ALK Rearrangements in Lung Adenocarcinomas by Standard Immunohistochemistry
No full textIntroductionSuccessful treatment of lung cancer patients with crizotinib depends on the accurate diagnosis of anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements. The approved fluorescence in-situ hybridization test is complex and difficult to use in daily diagnostic practice. Immunohistochemical assays—rapid and perfectly adapted for routine pathology practice—have been proposed as alternatives. We evaluated the novel high affinity ALK 1A4 antibody for routine diagnostics in formalin fixed, paraffin-embedded tumor specimens.MethodsDetection of ALK protein expression was investigated by comparing the new 1A4 antibody and the established D5F3 antibody/Ventana system in 218 lung cancer specimens with known ALK status preanalyzed by quantitative reverse transcription-polymerase chain reaction and fluorescence in-situ hybridization (20 ALK-positive cases, 198 ALK-negative cases).ResultsThe accuracy of both immunohistochemical assays for the detection of ALK rearrangements was high. Using a conventional staining procedure without signal enhancement, the 1A4 antibody assay identified all 20 ALK-rearranged tumors (100% sensitivity) and correctly characterized 196 of 198 negative cases (99.1% specificity). The D5F3/Ventana assay detected 19 ALK-rearranged tumors and typed 217 of 218 tumors correctly (95% sensitivity, 99.5 % specificity).ConclusionsThe novel 1A4 antibody represents a promising candidate for screening lung tumors for the presence of ALK rearrangements
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