**5. Role of ascites in translational science**

treatment is the risk of significant morbidity associated with bowel perforation in patients with very advanced OC. Thus, the advantages of aflibercept over bevacizumab are unclear [53].

MMPs, mainly MMP9, play a role in the release of biologically active VEGF and, consequently, play a role in the formation of ascites. Batistamat, a potent reversible inhibitor of a broad spectrum of MMP, has been developed and has been shown to resolve ascites when given *i.p.* to mice ascites secondary to an ovarian carcinoma xenograft; treatment was accompanied by a 6.5-fold increase in survival [54]. Sixteen patients with OC (out of 23 patients) were included in a Phase I study of *i.p.* administration of batistamat after drainage of ascites. Patients acquired a predicted survival of 1 month or more. Of the 23 patients in the study, 16 did not require redrainage within 28 days of the initial treatment. Five of the 23 patients neither reaccumulated ascites nor died up to 112 days after dosing. Seven patients died without reaccumulating ascites. Adverse effects considered at least possibly related to the treatment occurred in 16 patients, the most common of which were fatigue, fever, vomiting and abdomi-

Intraperitoneal chemotherapy is an effective way to palliate malignant ascites. By destroying the surface cancer, it induces a progressive fibrotic process, which will prevent the formation of fluid. If the sclerotic process is not complete, it may produce fluid loculation, which will interfere with uniform drug distribution, may cause obstructions and makes subsequent paracentesis difficult and risky [29]. Intraperitoneal therapy with cisplatin has been evaluated for the first-line treatment of optimal debulked OC patients with FIGO stage III. Despite a 16-month survival advantage, the catheter-related complications rate was 34%, and only 42%

The procedure called intraperitoneal hyperthermic chemotherapy (HIPEC) is an attempt to increase the cytotoxicity of selected cytotoxic drugs by a hyperthermic medium (40.5–43°C), thereby improving tissue penetration and reducing drug resistance. The primary objective is an increase of PFS and OS, not the control of ascites itself [47]. Finally, aggressive cytoreductive surgery combined with laparoscopic installation of HIPEC is reserved for selected patients with malignant ascites. In well-selected patients, results are encouraging, and this

Laparoscopic installation of HIPEC has been recently reported as an option to treat resistant malignant ascites not suitable for surgery. The biggest series published, which also included patients with OC, was by Valle et al. [55], who achieved complete remission of ascites in 94% of 52 patients after 1 month of follow-up. There were no complications of the procedure, dem-

Some patients with liver metastasis and malignant ascites have raised plasma renin concentrations, and these patients showed a good response to aldosterone competitive antagonist

*4.2.5. Matrix metalloproteinase inhibitors (MMPIs)*

208 Ovarian Cancer - From Pathogenesis to Treatment

nal pain [46]. MMP inhibitors may warrant further study.

of women in the trial completed six cycles of chemotherapy [46].

onstrating the feasibility and safety of this technique [55].

*4.2.7. Diuretics*

procedure not only controls ascites, but prolongation of OS is possible [29].

*4.2.6. Intraperitoneal chemotherapy*

Ascites is often therapeutically removed from patients and is therefore an available source of valuable tumour material. Representing the local tumour environment, ascites is composed of cellular and acellular components. In addition to tumour cells present, either as single cells or as spheroids, the cellular component of ascites is composed of stromal cells, including fibroblasts, mesothelial cells, endothelial cells, adipocytes and inflammatory cells. Cells in ascites communicate with each other through acellular components, including cytokines, proteins, metabolites and exosomes. All these components work in coordination to create a tumour-friendly microenvironment. Better knowledge of the tumour microenvironment represented by ascites would thus certainly help to overcome the limitations of current anticancer treatments [23].

Targeting ascites components that cause immunosuppression of T-cells is an interesting future therapeutic option. T-cells present in ovarian tumour ascites do not respond properly to stimulation via the T-cell receptor. Since these T-cells were assayed in the absence of ascites, they gained their normal function, but when ascites was added to T-cells, this effect was rapidly reversed. This might explain why human tumours grow despite the presence of T-cells and other cells of immunological response [10].

In the study by Latifi et al. [57], it was demonstrated that cells in malignant ascites belong to two types of tumour cells, adherent cells (expressed mesenchymal features) and non-adherent cells with an epithelial phenotype, as expressed by EpCAM and cytokeratin 7. Patients with chemoresistant tumours had more tumorogenic, non-adherent cells in the ascites than non-tumorogenic adherent cells. Non-adherent cells featured increased mRNA expression of cancer stem cell-associated genes [10]. Since catumaxomab selectively kills epithelial tumour cells belonging to the non-adherent cell type, this might explain why it is beneficial for patients with OC.

Ascites is highly attractive as a source for biomarker discovery study. The concentrations of cancer-associated soluble factors are usually much higher in ascites than in serum [47, 58]. Moreover, investigation of the relationship between biomarker concentrations in ascites and serum in OC patients may help elucidate whether concentration changes in the local environment can be detected with a blood test [58].
