Ex-vivo activation of a liposomal prodrug of mitomycin C by human tumors.

PURPOSE: To examine the ex- vivo ability of explanted human tumors and normal tissue to activate liposomal mitomycin C lipidic prodrug (MLP) by releasing the active free drug form, mitomycin C (MMC). METHODS: We tested conversion of MLP to MMC in an ex vivo assay using explanted tissues obtained during routine surgery to remove primary tumors or metastases. Tumor and adjacent normal tissue were obtained from freshly explanted tumors and were immediately deep frozen at - 70 °C. On test day, the fragments were thawed, homogenized and incubated in the presence of a fixed amount of liposomal MLP at 37 °C for 1 h. We measured MLP and its rate of conversion to MMC by HPLC. Controls included plasma, malignant effusions, red blood cells, tumor cell lines, mouse liver, and buffer with dithiothreitol, a potent reducing agent. RESULTS: Most patients tested (16/20) were diagnosed with colo-rectal carcinoma. The average fraction of MLP cleaved per 100-mg tumor tissue (21.1%, SEM = 1.8) was greater than per 100-mg normal tissue (16.6%, SEM = 1.3). When the tumor and normal tissue samples were paired by patient, the difference was statistically significant (p = 0.022, paired t test). Biological fluids did not activate liposomal MLP, while normal liver tissue strongly does. Interestingly, the omental fatty tissue also greatly activated MLP. CONCLUSIONS: Tumor tissue homogenates activate MLP with greater efficiency than the surrounding normal tissues, but far less than liver and adipose tissue. These observations demonstrate the bioavailability of liposomal MLP in human tumors, and its pharmacologic potential in cancer therapy.

[Refractory ascites following liver transplantation caused by an anastomotic stricture of the portal vein].

We present a case of a 34-year-old woman who underwent liver transplantation and developed refractory ascites. Following a prolonged work-up she was diagnosed with anastomotic site stricture of the portal vein. The patient underwent percutaneous angioplasty with balloon dilatation and stent placement, with resolution of the ascites. We review the literature and discuss the etiology of posttransplant refractory ascites and its treatment.

Cryopreservation of whole murine and porcine livers.

Preservation of vascularized organs, such as the liver, is limited to 24 h before destructive processes disqualify them for transplantation. This narrow window of opportunity prevents the performance of optimal pathogen screening and matching tests and possibly results in the need for retransplantation. Numerous problems are associated with freezing and thawing a whole liver while preserving its viability upon thawing, including complicated geometry, poor heat transfer, release of latent heat, and the difficulty of generating a uniform cooling rate. On the basis of our past success with sheep ovaries, we have now applied our novel freezing technique to a larger solid organ, the liver. Whole rat and pig livers were frozen and thawed using directional solidification apparatus, and viability of these livers was tested by means of integrity and functionality in vitro and in auxiliary liver transplantation. The thawed rat and porcine livers were intact and demonstrated >80% viability. Histology revealed normal architecture. Bile production and blood flow following auxiliary transplantation were normal as well. Our encouraging results in applying this novel cryopreservation technique in rat and pig livers suggest that this method may enable better human organ donor-recipient matching in the future.

[Pancreas transplantation in insulin dependent diabetic patients].

Successful transplantation of the pancreas as a whole organ, or as isolated islet cells, is the only treatment that achieves a stable normoglycemia as a result of insulin secretion and renewal of serum glucose levels control systems. Nowadays, one year patient survival after pancreas transplantation is above 90%, while functioning grafts are observed in 84% of combined pancreas kidney and in 70% of isolated pancreas transplantations. Type I insulin dependent diabetic patients aged 45 or less with severe diabetic nephropathy, without immediate life saving cardiovascular risk, highly motivated and well informed achieve the best results. Namely, these results include euglycemia without exogenous insulin, improvement of secondary complications of diabetes, protection of the kidney graft, and longer life expectancy with better quality of life, as compared to dialyzed diabetic patients.

Social and utilitarian considerations for allocating organs within a national organ sharing system: a computerized simulation model for policy decision-making.

BACKGROUND: An organ-sharing system should achieve fairness and optimal graft longevity. Balancing between social and utilitarian considerations is a sensitive ethical, public and medical issue that requires a means to examine the consequences of any allocation policy or planned changes thereof. OBJECTIVE: To evaluate the performance and applicability of a computerized simulation model by examining the impact of two opposing organ allocation policies (social or utilitarian) on predicted organ distribution regarding age, waiting time, recipient sensitization measured by panel reactive antibody level, and overall donor-recipient tissue matching (measured by the number of HLA antigen mismatches). METHODS: Using a computerized simulation model, virtual donors and recipients were emulated and organs were allocated according to either social algorithms or utilitarian policies. The resulting number of HLA mismatches, PRA, age, and waiting time distributions were compared between allocation strategies. RESULTS: Simulating allocation of 7,000 organs to 17,000 candidate recipients and implementing social policies yielded donor-recipient compatibility comparable to utilitarian policies (0-1 mm: 19.4% vs. 28%) while allocating 66.7% of organs to long waiters (>48 months). CONCLUSION: This computerized simulation model is a valuable tool for decision-makers establishing or modifying organ allocation policies.