3632 Background: Clinical trials may have a selection bias caused by an underrepresentation of pts older than 65 years (y) and of ECOG performance status > 1. Post-marketing NIS are a helpful tool to evaluate approved therapies in daily practice in the general patient population. The aim of this subgroup analysis of this german NIS was to evaluate the efficacy and safety profile of cetuximab in combination with chemotherapy in irinotecan pretreated mCRC patients aged > 65 y and < 65 y. Methods: Between 04/2005 and 11/2007 the data of 497 irinotecan-pretreated pts with mCRC (out of 657 pts documented) were entered in the database of this NIS. We analyzed both patient groups applying descriptive statistics and χ2- or Fishers exact test. Results: Median age was 66 y (30-88) with 247 and 250 pts of age < 65 and age > 65, respectively. 17.4% and 21.6% of pts in both groups showed an ECOG-Status of 2-3. Pts had 1-4 lines of previous chemotherapy: 26% and 17% 1 line, 43% and 43% 2 lines, 19% and 25% 3 lines, and 13% and 15% 4 lines (p = 0.55). Cetuximab was mainly combined with irinotecan in a weekly regimen (71% and 73%) and also combined with 5-FU in 20% and 19% of pts, respectively. Severe cetuximab-related toxicity occurred in 2% (6 and 4 pts, respectively). The median duration of any grade of skin reaction (35 d) was in pts age < 65 significantly longer (42 d), than in patients age > 65 (31 d); (p = 0.04). However, there was a trend towards higher grade (≥ 2) skin toxicity in pts age > 65. Skin toxicity led to discontinuation of therapy in 2.6% (6 pts in both groups), but in 22% and 31% to a dose modification and in 6% and 11% to a treatment pause. The objective response rates were similar for both groups: 38.1% for age < 65 vs. 36.4% for age > 65 (p = 0.57). The rates for secondary resectability of metastases after cetuximab-based therapy were 4.4% for both groups. Time to tumor progression was similar for both age groups: 4 months (range: 1.0-19.0) and 5 months (1.0-17.0) (p = 0.79). Conclusions: Cetuximab has a similar efficacy and safety profile for pts age > 65 and < 65 y. Therefore these results add valuable information to the clinical trials. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck Serono

Patients undergoing dialysis treatment have a high incidence of dyslipidemia. Rosuvastatin is a potent statin drug that improves overall lipid profiles in dyslipidemic patients. However, the pharmacokinetics of rosuvastatin has not been studied in patients with end-stage kidney disease undergoing chronic peritoneal dialysis (PD). The goals of this study are to determine the pharmacokinetics and tolerability of a single oral dose of rosuvastatin in patients undergoing continuous ambulatory PD (CAPD). This was a nonrandomized, open-label, 1-week trial. Ten stable PD patients were given a single oral dose of rosuvastatin (10 mg). Serial blood samples were obtained over the next 48 hours, and the patients were followed for 1 week while they underwent CAPD. Rosuvastatin plasma concentration peaked (Cmax) at 3.68 +/- 2.3 ng/ml (geometric mean), 4.5 hours (median; range 2 - 6 hours) after oral dosing. The plasma concentration of rosuvastatin was 0.44 +/- 0.23 ng/ml at 24 hours (C24) and 0.14 +/- 0.07 ng/ml, with levels below the detectable range in 5 of 10 subjects, at 48 hours (C48). The area under the plasma concentration-time from 0 to 48 hours (AUC0-48) was 32.6 +/- 1.6 ng/ml/h. These pharmacokinetic profiles of rosuvastatin in CAPD patients are very similar to those observed in healthy volunteers, but different from patients with Stages 4 - 5 chronic kidney disease. A single oral dose of rosuvastatin was well tolerated in this small number of patients. We conclude that pharmacokinetic profiles of rosuvastatin in patients undergoing CAPD are similar to those observed in healthy volunteers. These findings suggest that a lower dose of rosuvastatin (<<= 10 mg) may be administered in CAPD patients without dose adjustment.

1. The expression of liver-specific transcription factors and cytochrome P450 (CYP) enzymes have been studied in three new hepatocyte-like cell lines derived from SV Delta 202 transgenic mice: AMH-Delta 202 (adult mouse hepatocytes), TAMH-Delta 202 (tumour-derived adult mouse hepatocytes) and NMH-Delta 202 (newborn mouse hepatocytes). 2. mRNA levels of liver-enriched transcription factors such as D-element binding protein (DBP), liver-enriched transcription activating protein (LAP) and the hepatic nuclear factors (HNF) 1, 2 and 3 in all Delta 202 transgenic hepatocyte lines were similar to those in the wild-type liver and in primary mouse hepatocytes. 3. Analysis of basal CYP activities and testosterone metabolism revealed that Delta 202 cells showed higher similarities to mouse hepatocytes than Hepa 1c1c7 hepatoma cells. All three Delta 202 cell lines exhibited substantial active CYP1A1/2, CYP2A4/5 and CYP3A11 activities and lower levels of CYP2B, CYP2C and CYP2E1 activities. 4. The Delta 202 cells also responded to model inducers. 3-Methylcholanthrene induced CYP1A1/2 (7-ethoxyresorufin O-deethylation); phenobarbital induced CYP2B (7-benzoxyresorufin O-debenzylation), CYP2A4/5 (testosterone 7alpha -hydroxylation) and CYP3A11 (testosterone 6beta -hydroxylation); and rifampicin and dexamethasone induced CYP3A11 activities in the three Delta 202 cell lines, whereas only AMH-Delta 202 cells reproduced to a limited extent the response of CYP2E1 to ethanol observed in hepatocytes. 5. The results suggest that generation of hepatocyte lines from transgenic animals constitutes a successful approach to obtain in vitro models alternative to primary hepatocytes for drug metabolism and CYP inducibility studies.

Several obstacles have hindered the successful transplantation of islets of Langerhans to human patients in efforts to cure type I diabetes mellitus. One problem is the necessity for short- and long-term storage of islets after isolation and before transplantation. Current long-term storage methods, such as incubation in a physiological medium and cryopreservation, are suboptimal, resulting in significant loss of viable islet mass or function. Better storage methods are needed, In this study we examined the long-term storage of rat islets in macrobeads composed of agarose and collagen, Islets isolated from Wistar-Furth rats were placed into macrobeads (1000 islets/macrobead) and maintained in culture for periods of up to 189 days at 37 degrees C. Insulin released from the cultured macrobeads remained constant for periods of at least 154 days. In one group, insulin release was 1050 mU/24 hr/4 beads on day 3 and 1040 mU/24hr/4 beads on day 154. In another group, insulin release was 1305 mU/24 hr/5 beads on day 17 and 1580 mU/24 hr/5 beads on day 112. Xenotransplantation of Wistar Furth islet macrobeads, stored for 10 to 112 days at 37 degrees C, into 42 B6AF/1 mice with streptozotocin-induced diabetes resulted in a return to euglycemia in the recipients within 24 hr. Thereafter, euglycemia was maintained for more than 100 days in 32/42 of the recipients, and removal of the macrobeads caused a return to hyperglycemia within 48 hr in all animals. In addition, a group of 7 mice receiving macrobeads containing 1000 islets stored for 84 days had normal glucose tolerance tests (compared with those of 7 nontreated, nontransplanted mice with streptozotocin-induced diabetes and 7 normal mice), demonstrating that the islets in the macrobeads were functioning as they would in an intact pancreas. Finally, 5 macrobeads transplanted after initial storage of 112 days, removed from the first recipient after 100 days or more, stored again for 4 days in vitro, and retransplanted into 5 other diabetic mice also restored and maintained euglycemia for at least 45 days. Our results indicate that collagen-agarose macrobeads are capable of preserving rat pancreatic islets for extended periods without loss of in vitro insulin release capability or ability to achieve and maintain euglycemia in vivo, As such they should be useful for human islet transplantation efforts.

Prevention of rejection and prolongation of graft survival are critical to achieving successful islet cell transplantation. Various techniques have been utilized to prolong graft survival. Recently, protection of pancreatic islets from host immune mechanisms by isolating the islets in artificial membranes has emerged as an attractive alternative to the use of immunosuppression. In this Rapid Communication, we describe a novel method for macroencapsulation of rat islets in hydrophilic macrobeads made with various combinations of agarose, collagen, and Gelfoam. Encapsulated xenotypic islets were placed intraperitoneally in mice in which diabetes was induced by streptozotocin. The encapsulated xenografts maintained normoglycemia > 170 days. Recipients mice had normal glucose tolerance tests, which indicates that the islets in the macrobeads were functioning as they would in an intact pancreas. Macrobeads retrieved up to 103 days after transplantation showed no evidence of tissue reaction or local inflammation. These retrieved macrobeads could also be retransplanted and replaced. Our studies indicate that the agarose-collagen/Gelfoam macrobeads we have developed serve both to protect islet xenografts from rejection and to provide a microenvironment in which the islets maintain and support their normal function in vivo. Because they may be retrieved after implantation and replaced, these macrobeads may be suitable for human clinical islet cell xenotransplantation.