Development and validation of an UPLC-MS/MS method for the determination of irinotecan (CPT-11), SN-38 and SN-38 glucuronide in human plasma and peritoneal tumor tissue from patients with peritoneal carcinomatosis.

Irinotecan (CPT-11), an antineoplastic drug, is used for the treatment of colorectal and pancreatic cancer due to its topoisomerase I inhibitory activity. CPT-11 is a prodrug which is converted to its active metabolite SN-38 by carboxylesterases. SN-38 is further metabolized to its inactive metabolite SN-38 glucuronide. When evaluating the pharmacokinetic properties of CPT-11 and its metabolites, it is important to accurately assess the concentrations in both plasma as well as tumor tissues. Therefore, the aim of the current study was to develop and validate a robust and sensitive ultra-high performance liquid chromatography-tandem mass spectrometry method to quantify the concentration of CPT-11 and its metabolites (SN-38 and SN-38 glucuronide) in human plasma and peritoneal tumor tissue. The sample preparation of plasma and tumor tissue consisted of protein precipitation and enzymatic digestion/liquid-liquid extraction, respectively. Chromatographic separation was achieved with an Acquity UPLC BEH C18 column combined with a VanGuard pre-column. The mobile phases consisted of water +0.1 % formic acid (mobile phase A) and acetonitrile +0.1 % formic acid (mobile phase B). Mass analysis was performed using a Xevo TQS tandem mass spectrometer in the positive electrospray ionization mode. Method validation was successfully performed by assessing linearity, precision and accuracy, lower limit of quantification, carry over, selectivity, matrix effect and stability according to the following guidelines: "Committee for Medicinal Products for Human use, Guideline on Bioanalytical Method Validation". A cross-validation of the developed method was performed in a pilot pharmacokinetic study, demonstrating the usefulness of the current method to quantify CPT-11 and its metabolites in the different matrices.

The tumor immune microenvironment in peritoneal carcinomatosis.

One in four patients with colorectal cancer, 40% of gastric cancer patients, and 60% of ovarian cancer patients will develop peritoneal metastases (PM) in the course of their disease. The outcome of patients with widespread PM remains poor with currently available treatments. Despite the relatively common occurrence of PM, little is known on the pathophysiology that drives the peritoneal metastatic cascade. It is increasingly recognized that the stromal components of the peritoneal microenvironment play an essential role in tumor progression. However, little is known about the specific interactions and components of the peritoneal tumor microenvironment, particularly with respect the immune cell population. We summarize the current knowledge of the tumor immune microenvironment (TIME) in peritoneal metastases originating from the three most common origins: ovarian, gastric, and colorectal cancer. Clearly, the TIME is highly heterogeneous and its composition and functional activity differ according to tumor type and, within the same patient, according to anatomical location. The TIME in PM remains to be explored in detail, and further elucidation of their immune contexture may allow biology driven design of novel immune modulating or immune targeting therapies.