Abstract
Cell based chemosensitivity and resistance testing is an attractive approach that offers functional measurement of drug response ex vivo with the ultimate goal to guide the choice of chemotherapy for various cancers. Thus, it has a great potential to select patients for the optimal treatment option, thereby offering a tool for personalized cancer therapy. Despite several decades of intensive scientific efforts ex-vivo tests are still not incorporated in the standard of care. Limited access to fresh tumor tissue, unsatisfactory models and single readout as endpoint constitute major hindrance. Thus, establishing and validating clinically useful and reliable model systems still remains a major challenge. Here we present malignant effusions as valuable sources for ex-vivo chemosensitivity and resistance testing. Accumulation of a malignant effusion in the pleura, peritoneum or pericardium is often the first diagnostic material for both primary malignant mesothelioma and a broad spectrum of metastatic adenocarcinoma originating from lung-, breast-, ovary- and gastro-intestinal organs as well as lymphoma. In contrast to biopsies, in these effusions malignant cells are easily accessible and often abundant. Effusion derived cells can occur dissociated or forming three-dimensional papillary structures that authentically recapitulate the biology of the corresponding tumor tissue and offer models for ex vivo testing. In addition, effusions have the advantage of being available prior to or concurrent with the pathological review, thus constituting an excellent source of viable cells for simultaneous molecular profiling, biomarker analysis and for establishing primary cells for studying tumor biology and resistance mechanisms. For a reliable test, however, a careful validation is needed, taking into account the inherited heterogeneity of malignant tumors, but also the complex interplay between malignant and benign cells, which are always present in this setting.
Highlights
Mechanisms of effusion formation and its clinical managementThe pleural and peritoneal cavity normally contains an evenly distributed thin layer of fluid that functions as a protective barrier and as lubricant to minimize friction between the serosal layers
In the present review we focus mainly on the most widely used methods for chemosensitivity and resistance testing, with particular relevance for malignant effusions
In a large scale cytotoxicity assay; the effect of 32 commonly used cytotoxic drugs was tested in primary MM cells compared to four benign mesothelial cell isolates obtained from tumor free pleural effusions [75]
Summary
The pleural and peritoneal cavity normally contains an evenly distributed thin layer of fluid that functions as a protective barrier and as lubricant to minimize friction between the serosal layers. Combining cisplatin with vinorelbine in a small phase II study presented interesting results with an average overall survival time of 16.8 months but these results need to be verified in a larger patient group [27] Another small phase II study, treating malignant pleural mesothelioma patients with gemcitabine in combination with oxaliplatin, produced results comparable with the standard treatment [28]. A rational and personalized drug selection ideally implies target identification and accurate prediction of sensitivity or resistance to an array of chemotherapeutic agents This is important for patients with advanced malignant tumors involving the serosal cavities as these patients often have chemotherapy as the only remaining treatment option and have a remarkably poor prognosis with a limited life expectancy. A greater and more detailed understanding of tumor characteristics, new drugs and drug combinations based on individual tumor features, can hopefully improve outcome for patients with malignant pleural effusions
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