MDM2 is an important prognostic and predictive factor for platin-pemetrexed therapy in malignant pleural mesotheliomas and deregulation of P14/ARF (encoded by CDKN2A) seems to contribute to an MDM2-driven inactivation of P53.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a highly aggressive tumour that is first-line treated with a combination of cisplatin and pemetrexed. Until now, predictive and prognostic biomarkers are lacking, making it a non-tailored therapy regimen with unknown outcome. P53 is frequently inactivated in MPM, but mutations are extremely rare. MDM2 and P14/ARF are upstream regulators of P53 that may contribute to P53 inactivation. METHODS: A total of 72 MPM patients were investigated. MDM2 immunoexpression was assessed in 65 patients. MDM2 and P14/ARF mRNA expression was analysed in 48 patients of the overall collective. The expression results were correlated to overall survival (OS) and progression-free survival (PFS). RESULTS: OS and PFS correlated highly significantly with MDM2 mRNA and protein expression, showing a dismal prognosis for patients with elevated MDM2 expression (for OS: Score (logrank) test: P⩽0.002, and for PFS: Score (logrank) test; P<0.007). MDM2 was identified as robust prognostic and predictive biomarker for MPM on the mRNA and protein level. P14/ARF mRNA expression reached no statistical significance, but Kaplan-Meier curves distinguished patients with low P14/ARF expression and hence shorter survival from patients with higher expression and prolonged survival. CONCLUSIONS: MDM2 is a prognostic and predictive marker for a platin-pemetrexed therapy of patients with MPMs. Downregulation of P14/ARF expression seems to contribute to MDM2-overexpression-mediated P53 inactivation in MPM patients.

[Molecular pathology of the lungs. New perspectives by next generation sequencing]. / Molekularpathologie der Lunge. Perspektiven durch neue Sequenzierformen.

Lung cancer is one of the most frequent malignancies in the western world. Its frequent association with a wide spectrum of mutations in genes encoding various signal transducers that are often linked to therapy response, emphasizes the obvious need for improved, fast and highly efficient approaches in molecular pathology. Comprehensive analyses of the mutation status of progression and therapy relevant genes can be performed by the novel sequencing forms named next generation sequencing (NGS) providing extremely high capacities for ultra-deep sequence analyses. The 454 pyrosequencing method, the sequencing by synthesis and the semiconductor sequencing platform are now available for parallel sequencing approaches of multitudinous target genes linked to multiple tumor DNA applications. The "one molecule, one clone, one read" principle by the NGS approaches supplies not only information on allele frequencies and mutation rates but also has the advantage of a very sensitive detection of low frequency variants.

[Indications and limitations of fresh frozen sections in the pulmonary apparatus]. / Indikation und Grenzen des intraoperativen Schnellschnitts im Organbereich Lunge.

Recommendations for the diagnosis of lung tumors almost limit the use of fresh frozen sections to the evaluation of resection margins. In pathology pretherapeutic methods for assessment of clinically suspected lung cancer are favored over intraoperative frozen section diagnosis. For the interdisciplinary management of uncertain lung findings diagnostic methods, such as cytopathology and examination of biopsy material are available. The use of rapid on-site evaluation (ROSE) in cytopathology is limited due to the lack of necessary personnel. Diagnosis of unclear pulmonary lesions or distinction of metastases from primary lung tumors by intraoperative frozen sections is therefore limited to exceptional cases that were not resolved by preoperative biopsies. Such rare cases require a common consensus strategy between thoracic surgeons and pathologists in a preoperative tumor board.