Abstract Purpose: Fetal lung adenocarcinoma (FLAC) is an extremely rare subtype of pulmonary adenocarcinoma estimated to be the 0.5% of all lung cancers. Therefore a standardized model of FLAC primary cell culture and evidence-based treatment guidelines are not available. The aim of this study is to characterize FLAC primary cell culture, to evaluate the biological features of this uncommon tumor and the in vitro drug response. Methods: FLAC specimen was obtained from a 59-years-old female patient, cultured in vitro with DMEM-F12 medium supplemented with 5% FBS and maintained in culture for more than 6 passages. Primary cells from a lung adenocarcinoma specimen were as well cultured and used as control for all the in vitro experiments. Immunohistochemistry for β-catenin, TTF-1, Ki67, cKit, MDM2, p53, S-100, EGFR, E-cadherin, cytokeratin 7 and 8/18 was performed on paraffin-fixed specimen. Immunofluorescence on cells in culture was assessed for MDM2, p53, CD133. Specimen and cells in culture were analyzed by real time PCR for oncogenic mutations (KRAS, EGFR) and for a stem cells gene panel. In vitro tumorigenicity was tested by plating efficency and soft agar colony formation assays. Cell proliferation was determined and a cell viability test was performed after treatment of FLAC cells with tyrosine kinase inhibitors (erlotinib and gefitinib), temozolomide (TMZ), cisplatin, gemcitabine and cysplatin+gemcitabine by MTS assay. Results: A primary cell culture of human FLAC was characterized and standardized. FLAC histotype was confirmed by immunohistochemistry. Immunofluorescence showed a positivity for MDM2, but not for p53 and CD133. By molecular analysis, DNA from both specimen and cells in culture was found to harbor epidermal growth factor receptor (EGFR) kinase domain non-sense mutation in exon 20 and no mutations in the K-ras gene. Primary FLAC cells showed a colony formation activity and the soft agar assay revealed an anchorage-indipendent growth. At 48 hours FLAC cells proliferation was inhibited of 56% and 41% by erlotinib and gefitinib respectively, with an IC50 value of 10 μM, compared with the control proliferation (lung adenocarcinoma cells) inhibited of 25% and 60% by erlotinib and gefitinib respectively (p=0,17; p=0,005). However, FLAC cell viability at 48 hours after being treated with cisplatin 10 μM was 3%, compared with the control viability that was 16% (p=0,007). Conclusion: This well-characterized FLAC primary cell culture provide a unique model for future studies in lung cancer biology and drug response. Although chemosensitivity to cisplatin was determined, erlotinib and gefitinib were effective against FLAC cells and appear to represent a novel targeting approach for the treatment of this rare tumor.
Central MessageExtended resections including surrounding organs are justified for radical treatment of invasive thymoma and may allow remission of myasthenia crisis refractory to maximal medical therapy.See Article page 168. Extended resections including surrounding organs are justified for radical treatment of invasive thymoma and may allow remission of myasthenia crisis refractory to maximal medical therapy. See Article page 168. In their article in this issue of the Journal, Iqbal and colleagues1Iqbal F. Shokrzadeh C. Nawgiri R. Okereke I. Extrapleural pneumonectomy with en bloc myocardial resection for advanced thymoma.J Thorac Cardiovasc Surg Tech. 2020; 2: 168-170Google Scholar report an interesting case documenting a challenging radical resection of advanced-stage thymoma allowing resolution of the associated myasthenia gravis (MG) crisis refractory to maximal medical therapy. Surgical operation included extrapleural pneumonectomy and partial-thickness resection of the left ventricle without cardiopulmonary bypass (CPBP). The authors are to be congratulated for their excellent surgical and clinical results, and the scientific message arising from this article is certainly of great interest. The authors address some relevant issues in thymoma surgery. The first is that even extended and technically demanding operations can be justified for the treatment of advanced-stage large invasive thymic tumor. The biological behavior of this neoplasm, with long-term survival also in presence of recurrence, seems to support the rationale for such interventions. This is further confirmed by available results of surgery for advanced-stage thymic tumors that report survival rates comparable to those of patients with stage I and II disease when complete tumor removal is accomplished.2Fiorelli A. D'Andrilli A. Vanni C. Cascone R. Anile M. Diso D. et al.Iterative surgical treatment for repeated recurrences after complete resection of thymic tumors.Ann Thorac Surg. 2017; 103: 422-431Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 3Venuta F. Rendina E.A. Longo F. De Giacomo T. Anile M. Mercadante E. et al.Long-term outcome after multimodality treatment of stage III thymic tumors.Ann Thorac Surg. 2003; 76 (discussion 1872): 1866-1872Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 4Maurizi G. D'Andrilli A. Sommella L. Venuta F. Rendina E.A. Transsternal thymectomy.Thorac Cardiovasc Surg. 2015; 63: 178-186PubMed Google Scholar Completeness of resection has been reported as the main significant prognostic factor in many series.2Fiorelli A. D'Andrilli A. Vanni C. Cascone R. Anile M. Diso D. et al.Iterative surgical treatment for repeated recurrences after complete resection of thymic tumors.Ann Thorac Surg. 2017; 103: 422-431Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 3Venuta F. Rendina E.A. Longo F. De Giacomo T. Anile M. Mercadante E. et al.Long-term outcome after multimodality treatment of stage III thymic tumors.Ann Thorac Surg. 2003; 76 (discussion 1872): 1866-1872Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 4Maurizi G. D'Andrilli A. Sommella L. Venuta F. Rendina E.A. Transsternal thymectomy.Thorac Cardiovasc Surg. 2015; 63: 178-186PubMed Google Scholar Extrapleural pneumonectomy has been proposed as a viable option in selected cases with extended disease involving the lung and pleura, and precluding gross tumor removal with lesser resections.5Moser B. Fadel E. Fabre D. Keshavjee S. de Perrot M. Thomas P. et al.Surgical therapy of thymic tumor with pleural involvement: an ESTS thymic working group project.Eur J Cardiothorac Surg. 2017; 52: 346-355Crossref PubMed Scopus (23) Google Scholar Surgical treatment performed in the present case also included a partial-thickness resection of the left ventricle involved by the tumor. This proves that, as reported in other recent experiences, the heart is no longer an "off-limits zone" for the thoracic surgeon when performing surgical treatment of both thymic and lung tumors invading the cardiac chambers, with or without CPBP. Radical resection can be possible for deeper infiltration of the heart by thoracic malignancies as well. In our surgical practice over the last several years at the Sant'Andrea Hospital of the Sapienza University of Rome, we have shown that extended and full-thickness resection with prosthetic reconstruction of both the atrium and the ventricle infiltrated by the tumor also can be performed safely under CPBP with uneventful postoperative outcomes. Another interesting finding reported by Iqbal and colleagues is that complete removal of thymoma and thymic tissue can be the only effective therapeutic option in some cases of thymoma-associated MG crisis that have proven refractory to maximal medical therapy. However, it is well known that the efficacy of this surgical treatment for thymomatous myasthenia symptoms is not always assured, and that some patients do not achieve neurologic remission after thymoma resection.6Ströbel P. Helmreich M. Menioudakis G. Lewin S.R. Rüdiger T. Bauer A. et al.Paraneoplastic myasthenia gravis correlates with generation of mature naive CD4(+) T cells in thymomas.Blood. 2002; 100: 159-166Crossref PubMed Scopus (81) Google Scholar Moreover, MG outcome after thymectomy and thymomectomy has been reported to be significantly correlated with World Health Organization classification histotypes in some series, so the probability to obtain effective control of the neurologic disease with radical tumor resection can be partially predicted according to the histological characteristics.7Prokakis C. Koletsis E. Apostolakis E. Zolota V. Chroni E. Baltayiannis N. et al.Modified maximal thymectomy for thymic epithelial tumors: predictors of survival and neurological outcome in patients with thymomatous myasthenia gravis.World J Surg. 2009; 33: 1650-1658Crossref PubMed Scopus (3) Google Scholar All these aspects should be noted and considered when planning such a high-risk operation. Extrapleural pneumonectomy with en bloc myocardial resection for advanced thymomaJTCVS TechniquesVol. 2PreviewTreatment of patients with thymoma and myasthenia crisis can be challenging. After stabilization with medical management, surgical resection is recommended.1,2 Some patients will not significantly recover until the tumor is removed, however. We report a case of resolution of myasthenia crisis following extrapleural pneumonectomy in a young patient. Full-Text PDF Open Access
Twenty cases of macroscopically non‐neoplastic thymuses obtained from patients with myasthenia gravis have been studied histologically. Seven cases were characterized by lymphoid follicular hyperplasia and 13 by involutional changes of variable degree. In three cases (15%), one with lymphoid follicular hyperplasia and two with involutional changes, multiple microscopic epithelial lesions, 0.2–0.4 mm in diameter and consistent with foci of microscopic thymoma, were observed. Most of them were related to the thymic cortex and one, displaying a different histological pattern, was located in a medullary area. These observations provide morphological evidence of a possible multifocal origin of thymoma from distinct epithelial clones present in the different topographic areas of the human thymus.
The indications for the resort to sealants during thoracic surgery are still controversial w1x. The multiplicity of commercially available products, the lack of consistent, irrefutable evidence for their efficacy and the delicate relationship with industry call for a clarification of the status quo within the thoracic surgical community. The results of a survey conducted during the proceedings of a Satellite Symposium taking place during the last 2006 joint EACTS-ESTS meeting in Stockholm are hereafter reported. Two hundred and forty participants to a Satellite Symposium on the use of a specific, commercially available, sealant were asked to anonymously respond through a power-vote system to six multiple-choice questions aimed at establishing the current standards of practice. No additional demographic data nor information on professional experience were required to participate in the survey. The answers were collected via an electronic (‘power vote’) system and displayed by percentage at the end of the questionnaire (see Figures). The analysis of the results was as follows (Figs. 1–3).
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