Volume 1, Issue 3 -

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.

Mesothelial cells line the surface of the pleura, pericardium, peritoneum and internal reproductive organs. One of their main functions is to act as a non-adhesive barrier to protect against physical damage, however, over the past decades their physiological and pathological properties have been revealed in association with a variety of conditions and diseases. Mesothelium has been used in surgical operations in clinical settings, such as omental patching for perforated peptic ulcers and in glutaraldehyde-treated autologous pericardium for aortic valve reconstruction. Various methods for mesothelial cell transplantation have also been established and developed, particularly within the area of tissue engineering, including scaffold and non-scaffold cell sheet technologies. However, the use of mesothelial cell transplantation in patients remains challenging, as it requires additional operations under general anesthesia in order to obtain enough intact cells for culture. Moreover, the current methods of mesothelial cell transplantation are expensive and are not yet available in clinical practice. This review firstly summarizes the history of the use of mesothelial cell transplantation in tissue engineering, and then critically discusses the barriers for the clinical application of mesothelial cell transplantation. Finally, the recent developments in xenotransplantation technologies are discussed to evaluate other feasible alternatives to mesothelial cell transplantation.

The peritoneum consists of a layer of mesothelial cells on a connective tissue base which is perfused with circulatory and lymphatic vessels. Total effective blood flow to the human peritoneum is estimated between 60 and 100 mL/min, representing 1–2 % of the cardiac outflow. The parietal peritoneum accounts for about 30 % of the peritoneal surface (anterior abdominal wall 4 %) and is vascularized from the circumflex, iliac, lumbar, intercostal, and epigastric arteries, giving rise to a quadrangular network of large, parallel blood vessels and their perpendicular offshoots. Parietal vessels drain into the inferior vena cava. The visceral peritoneum accounts for 70 % of the peritoneal surface and derives its blood supply from the three major arteries that supply the splanchnic organs, celiac and superior and inferior mesenteric. These vessels give rise to smaller arteries that anastomose extensively. The visceral peritoneum drains into the portal vein. Drugs absorbed are subject to first-pass hepatic metabolism. Peritoneal inflammation and cancer invasion induce neoangiogenesis, leading to the development of an important microvascular network. Anatomy of neovessels is abnormal and characterized by large size, varying diameter, convolution and blood extravasation. Neovessels have a defective ultrastructure: formation of large “mother vessels” requires degradation of venular and capillary basement membranes. Mother vessels give birth to numerous “daughter vessels”. Diffuse neoangiogenesis can be observed before appearance of macroscopic peritoneal metastasis. Multiplication of the peritoneal capillary surface by neoangiogenesis surface increases the part of cardiac outflow directed to the peritoneum.

Background Peritoneal metastasis (PM) develop in more than 50 % of gastric cancer (GC) patients. Median survival without treatment is not more than 3–7 months, and 8–12 months after modern combination chemotherapy. Innovative therapeutic approaches are urgently needed. Methods Phase-2, open label prospective clinical trial assessing safety and efficacy of bidirectional chemotherapy for treating peritoneal metastasis of gastric cancer (PMGC). Treatment protocol included initial staging laparoscopy or laparotomy, 3–4 courses of systemic chemotherapy (XELOX) followed by Pressurized IntraPeritoneal Aerosol Chemotherapy (PIPAC) procedures every 6 weeks until progression of disease or death. Primary endpoints were overall survival and histological peritoneal regression grading score after rebiopsy. Results 31 patients were included (9 men, 22 women, mean age 52 years), 24 with synchronous PM at diagnosis, 7 with metachronous PM after previous chemotherapy. Mean PCI was 13.8 (min-max 6–34). XELOX was administered in all patients and combined with 56 PIPAC procedures. Complete and partial pathological response was found in 60 % of the 15 patients eligible for tumor response assessment (4 and 5 patients, respectively). Median survival was 13 months. Conclusions Bidirectional chemotherapy combining XELOX with PIPAC with cisplatin and doxororubicin is well tolerated, can induce objective tumor regression and is associated with a promising survival in PMGC.