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Patient-derived xenograft (PDX) models have been rediscovered as meaningful research tool. By using severely immunodeficient mice, high-engraftment rates can be theoretically achieved, permitting clinical stratification strategies. Apart from engraftment efficacy, tolerability towards certain cytostatic drugs varies among individual mouse strains thus impeding large-scale screenings. Here, we aimed at optimizing an in vivo treatment schedule using the widely applied cytostatic drug 5-fluoruracil (5-FU) for exemplary response prediction in colorectal cancer (CRC) PDX models. Four different individual CRC PDX models were engrafted into NOD.Cg-Prkdc scid Il2rg tm1 Wjl (NSG) mice. Mice with established PDX were allocated to different treatment groups, receiving 5-FU, the oral prodrug Capecitabine, or 5-FU/leucovorin (LV) at different doses. Body weight, tumor size, and general behavior were assessed during therapy. Ex vivo analyses were done from blood samples, liver, as well as tumor resection specimen. Engraftment efficacy was high as expected in NSG mice, yielding stable PDX growth for therapy stratification. However, overall tolerability towards 5-FU was unexpectedly low, whereas the prodrug Capecitabine as well as the combination of 5-FU/LV at low doses were well tolerated. Accompanying plasma level determination of DYPD, the rate-limiting enzyme for 5-FU-mediated toxicity, revealed reduced activity in NSG mice compared with other common laboratory mouse strains, offering a likely explanation for the drug incompatibility. Also, the De Ritis quotient was highly elevated in treated mice, reflecting overall organ injury even at low doses. Summarizing these findings, NSG mice are ideal hosts for in vivo engraftment studies. However, the complex immunodeficiency reduces tolerance to certain drugs, thus making those mice especially sensitive. Consequently, such dose finding and tolerance tests constitute a necessity for similar cancer precision medicine approaches.

Unlabelled: Fabry's disease is an X-linked inborn error of glycosphingolipid metabolism caused by a deficiency of the lysosomal hydrolase alpha-galactosidase A. Due to deficiency of this enzyme activity, a progressive lysosomal accumulation of glycosphingolipids, in particular globotriaosylceramide, takes place within endothelial cells and cells of the vascular and nervous systems, myocardial cells, endothelial, and mesangial and epithelial cells of the kidney, eventually leading to organ dysfunction. The degree of renal involvement generally correlates with the progression of glycosphingolipid accumulation and may lead to renal insufficiency and failure. Renal dysfunction can progress to end-stage renal failure, which usually occurs in the third to fifth decade of life. The prevalence of this disease among males on chronic hemodialysis is different in various countries. Screening for alpha-galactosidase A deficiency by blood spot tests was performed among 536 male dialysis patients in all 42 hemodialysis centers in Lithuania in the period of April-June, 2005. All tests, showed normal galactosidase A enzymatic activity., Conclusion: No patient with suspicion of Fabry's disease was found by this screening method.

The aim of our study was to evaluate the changes in hemodialysis service, main demographic characteristics of hemodialysis patients in Lithuania during 1996-2005, and their correlation with the number of recipients on the kidney waiting list. During the study period, we annually visited all hemodialysis centers in Lithuania and collected data about all hemodialysis patients. There was a sharp increase in the number of hemodialysis centers (from 17 to 43), hemodialysis stations (from 25 to 100 per million population, P<0.001), hemodialysis patients (from 60 to 312 per million population, P<0.001), and new hemodialysis patients (from 54.3 to 95 per million population, P<0.01). The mean age of hemodialysis patients increased from 47.2+/-16.1 years in 1996 to 58.8+/-15.6 years in 2005 (P<0.001). Hemodialysis population became older. The percentage of patients aged more than 60 years increased from 22.8% to 53.2% (P<0.001) and aged more than 70 years from 5.4% to 24.4% (P<0.001). The frequency of chronic glomerulonephritis as underlying disease of end-stage renal disease decreased from 54.5% in 1996 to 21.1% in 2005 (P<0.001). There was an increase in the percentage of patients in whom end-stage renal disease was caused by diabetic (from 7.1% to 19.2%, P<0.01) and hypertensive nephropathies (from 3.1% to 13.9%, P<0.05) and chronic pyelonephritis (from 11.2% to 17.9%, P<0.01). The percentage of recipients on the kidney waiting list decreased from 71.4% in 1996 to 21.1% in 2005. In summary, during the last 9 years, hemodialysis service in Lithuania significantly expanded. The number of hemodialysis patients was continuously rising with predominance of diabetic, hypertensive, and elderly patients. Diabetic nephropathy, chronic glomerulonephritis, and pyelonephritis were the main underlying diseases of end-stage renal disease in hemodialysis patients in 2005. The percentage of recipients on the kidney waiting list decreased probably because of the rise in the number of elderly patients and patients with diabetes mellitus in Lithuanian hemodialysis population.

The aim of our study was to evaluate the changes of hemodialysis (HD) service and main demographic characteristics of HD patients in Lithuania during seven years period. From 1996 to 2003 we visited annually all HD centers in Lithuania and collected data about all HD patients. There was a sharp increase in the number of HD centers (from 17 to 37), HD stations (from 25 p. m. p. (per million population) to 87 p.m.p.; p<0.001), HD patients (from 60 p.m.p. to 264 p.m.p.; p<0.001) and incidence of new HD patients (from 54.3 p.m.p. to 92 p.m.p.; p<0.01). In 1996 all 17 HD centers in Lithuania were public. Private HD centers appeared in 1998 and reached 43.2% of all HD centers (n=16) in 2003. 44.8% of HD patients were dialyzed in private HD centers. The mean age of HD patients increased from 47.2+/-16.1 years in 1996 to 57.5+/-14.9 years in 2003 (p<0.001). HD population became older. The percentage of patients over 60 years old increased from 22.8% to 49.7% (p<0.001) and over 70 years old--from 54% to 21.9% (p<0.001). The main underlying disease of end-stage renal disease was chronic glomerulonephritis but its rate had decreased from 54.5% in 1996 to 26.5% in 2003 (p<0.001). During this period there was a statistically significant increase in the incidence of end-stage renal disease due to diabetics (from 7.1% to 18.0%; p<0.01), hypertensive nephropathy (from 3.1% to 9.4%; p<0.05), and chronic pyelonephritis (from 11.2% to 18.6%; p<0.01). In summary during the last seven years HD service in Lithuania expanded significantly, and rapid development of private HD was observed. The number of HD patients was rising continuously with predominance of diabetic, hypertensive and elderly patients.