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Background & Aims: The HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome is a life-threatening complication during pregnancy. The associated liver disease may be severe, and maternal hepatic complications may progress to the point that transplantation becomes necessary. CD95 (APO-1, Fas)-mediated apoptosis of liver cells is one of the major pathogenic mechanisms during liver disease. The interaction of CD95 with its ligand, CD95L(FasL), induces apoptosis and thus the source of the death-inducing ligand is critical for understanding the pathomechanism of liver damage involving the CD95-system. Methods: Sera from HELLP patients were analyzed and used in cell culture experiments to study CD95-mediated apoptosis. We established a mouse model for placenta-induced liver damage and used a new therapeutical agent, LY498919, to block CD95 apoptosis. Results: We describe apoptosis in the liver of HELLP patients and cytotoxic activity for primary human hepatocytes in HELLP serum. Blocking of CD95 signaling reduced the cytotoxic activity of HELLP serum. In addition, cytotoxic activity increased as HELLP syndrome developed. Furthermore, CD95L was found to be produced in the placenta and extracts of placenta were cytotoxic for human hepatocytes. Injection of mouse placenta extract in mice induces liver damage that could be prevented by blocking CD95L. Conclusions: Taken together, these data suggest that CD95L derived from the placenta acts systemically and is a primary cause of liver damage in HELLP syndrome. Our results also show that blocking of CD95L can reduce liver cell apoptosis, indicating that such a strategy may have therapeutic advantages.

Aim of the study. Preoperative chemotherapy (pCHT) changes established prognostic markers. This study evaluated the prognostic value of pathological complete response (pCR) in comparison to other prognostic factors (PF) after a follow up of 6 years. Material and methods. One hundred and fifty-six patients with locally advanced breast cancer (clinically T2 or T3-tumors, M0) obtained pCHT with Epirubicin/Cyclophosphamid (3–4 cycles, 90/600 mg/m2every 3 weeks). Results. Seventy seven percentage of patients showed a remission of greater than 50% (n= 120) and a pCR in 6.4% (n= 10). Breast conserving surgery was performed in 68% (n= 106) of patients. Metastasis was seen in 38.4% (n= 60) of patients but only in two of patients with pCR (p= 0.146). Significant prognostic factors for DFS (disease-free survival) were the clinically assessed tumor size before pCHT (p= 0.009), the clinical nodal status before pCHT (p= 0.041), grading (p= 0.005), the histological tumor size after pCHT (p= 0.001), the histological axillary lymph node status after pCHT (p= 0.001) and the clinical response of the tumor to pCHT (p= 0.032). Regarding OAS (overall survival) only the grading and the pathological lymph node status proved to be statistically significant. Occurrence of pathological complete response did not prove to be a statistically significant marker. Regarding DFS grading (p< 0.001, RR = 2.49), histological tumor size after pCHT (p< 0.001, RR = 2.49) and the histological lymph node status (p< 0.001, RR = 2.11) proved to be independent prognostic factors in multivariate regression analysis. Looking at OAS histological lymph node status (p= 0.008, RR = 1.79) as well as grading (p= 0.001, RR = 3.48) remained independent prognostic factors. Summary. The most important prognostic factors after 6 years of follow up are the pathological lymph node status and the grading. Occurrence of pathological complete response was no statistically significant prognostic factor. Kind of pCHT and number of cycles could be responsible for this finding.