Liver metastases (HCRM)
Importance of histological tumor response assessment in predicting the outcome in patients with colorectal liver metastases treated with neoadjuvant chemotherapy followed by liver surgery b) Morphological characterization and study on pathogenesis of the secondary effects of neoadjuvant chemotherapy on non tumoral liver"
Liver metastases (HCRM) are the most common colorectal cancer (CRC) complication and contribute greatly to CRC mortality. However the liver is often the initial metastatic site, HCRM surgical resection is currently accepted as the main treatment for a longer-term survival. Unfortunately, most patients are, at time of diagnosis, bad candidates for a liver surgery, due to tumor number, size or location. Thus new medico-surgical strategy emerge, associating preoperative chemotherapy followed by hepatic surgery. By reducing the size of metastases, several regimens allow the resection of HCRM previously deemed unresectable and provide information on the in vivo chemosensitivity of the tumor. The establishment of adapted procedures for each patient implies to possess of reliable criteria of judgment of the efficacy of the chemotherapy and knowledge of its secondary effects. One of the our main objectives is to identify the histological and molecular criteria to response to the neoadjuvant chemotherapy of HCRM, correlated to the probability of survival without relapse after hepatectomy. The definition of histological criteria to chemotherapy corresponds to a real need for the clinician for the assumption of metastatic colorectal disease on daily ' based practice and for the development of new therapeutic weapons. Our other main objective is to analyze the histological lesions of preoperative systemic chemotherapy on the non-tumoral hepatic parenchyma and to understand its pathogenesis. The identification and characterization of the lesions are clinically important in respect to the potential impairement of liver regeneration after extended resection, the potential increase for operative bleeding and the risk of evolution, particularly for that patient who has to receive multiple chemotherapy cycles to induce better tumor responses. We have recently shown that sinusoidal obstruction syndrome (SOS) related to rupture of the hepatic sinusoidal barrier developed, notably with the use of oxaliplatin. Since our publication, we have become aware of several patients developing major complications after neoadjuvant chemotherapy because of delay caused by poor liver function after hepatectomies or development of acute fatal portal hypertension. These pathological alteration of the liver surrounding the metastases have conducted several experts to publish recently a cautionary note regarding the used of chemotherapy before surgical resection Without discussing the fact that oxaliplatin yields excellent responses in HCRM, identification of new markers correlated to the presence of severe SOS could represent a great clinical interest. As a probable human susceptibility to this toxicity exists, the development of such markers could influence the extension of the surgical resection and participate to the surveillance of patients under adjuvant chemotherapy. Taking advantage of the availability of liver tissues, our project is to carry out a gene expression analysis of liver with or without SOS by cDNA microarray. This study could permit to identify genes differentially expressed permitting not only to progress in the knowledge but also in the characterization of potential new diagnostic serum markers of the disease. Our second project is to development of an animal model