Long-term oncological outcomes of endoscopic full-thickness resection after previous incomplete resection of low-risk T1 CRC (LOCAL-study): study protocol of a national prospective cohort study.

BACKGROUND: T1 colorectal cancer (CRC) without histological high-risk factors for lymph node metastasis (LNM) can potentially be cured by endoscopic resection, which is associated with significantly lower morbidity, mortality and costs compared to radical surgery. An important prerequisite for endoscopic resection as definite treatment is the histological confirmation of tumour-free resection margins. Incomplete resection with involved (R1) or indeterminate (Rx) margins is considered a strong risk factor for residual disease and local recurrence. Therefore, international guidelines recommend additional surgery in case of R1/Rx resection, even in absence of high-risk factors for LNM. Endoscopic full-thickness resection (eFTR) is a relatively new technique that allows transmural resection of colorectal lesions. Local scar excision after prior R1/Rx resection of low-risk T1 CRC could offer an attractive minimal invasive strategy to achieve confirmation about radicality of the previous resection or a second attempt for radical resection of residual luminal cancer. However, oncologic safety has not been established and long-term data are lacking. Besides, surveillance varies widely and requires standardization. METHODS/DESIGN: In this nationwide, multicenter, prospective cohort study we aim to assess feasibility and oncological safety of completion eFTR following incomplete resection of low-risk T1 CRC. The primary endpoint is to assess the 2 and 5 year luminal local tumor recurrence rate. Secondary study endpoints are to assess feasibility, percentage of curative eFTR-resections, presence of scar tissue and/or complete scar excision at histopathology, safety of eFTR compared to surgery, 2 and 5 year nodal and/or distant tumor recurrence rate and 5-year disease-specific and overall-survival rate. DISCUSSION: Since the implementation of CRC screening programs, the diagnostic rate of T1 CRC is steadily increasing. A significant proportion is not recognized as cancer before endoscopic resection and is therefore resected through conventional techniques primarily reserved for benign polyps. As such, precise histological assessment is often hampered due to cauterization and fragmentation and frequently leads to treatment dilemmas. This first prospective trial will potentially demonstrate the effectiveness and oncological safety of completion eFTR for patients who have undergone a previous incomplete T1 CRC resection. Hereby, substantial surgical overtreatment may be avoided, leading to treatment optimization and organ preservation. Trial registration Nederlands Trial Register, NL 7879, 16 July 2019 ( https://trialregister.nl/trial/7879 ).

[Young adult with psychotic disorders have problems relating to sexuality, intimacy and relationships. An explanatory study based on focus group]. / Jongeren met een psychotische kwetsbaarheid over seksualiteit, intimiteit en relaties.

BACKGROUND: Research has shown that young adults with psychotic disorders frequently have problems relating to sexuality, intimacy and relationships. Such problems are often neglected in clinical practice. AIM: To perform a study that explores, on the basis of focus groups, how issues such as sexuality, intimacy and relationships can be addressed as part of the treatment of adolescents suffering from a psychotic disorder. METHOD: We created eight focus groups consisting of clients attending the department of psychotic disorders and caregivers who worked there. The meetings of each focus group were fully transcribed and analysed by means of Nvivo. RESULTS: Clients indicated they wanted to address the topics of sexuality, intimacy and relationships in a group setting. They expressed the wish to have mixed gender groups and decided that in the group discussions the main focus should be on the exchange of personal experiences. CONCLUSION: In our view, it is desirable that psychiatry should pay more attention to the subject of sexuality. By giving adolescents suffering from psychotic disorders the opportunity to discuss their experiences, problems and feelings of insecurity in a group setting and in a low-threshold environment, psychiatrists can greatly improve the quality of care that they provide for their patients.

The mechanism of increased biliary lipid secretion in mice with genetic inactivation of bile salt export pump.

Human bile salt export pump (BSEP) mutations underlie progressive familial intrahepatic cholestasis type 2 (PFIC2). In the PFIC2 animal model, Bsep(-/-) mice, biliary secretion of bile salts (BS) is decreased, but that of phospholipids (PL) and cholesterol (CH) is increased. Under physiological conditions, the biliary secretion of PL and CH is positively related ("coupled") to that of BS. We aimed to elucidate the mechanism of increased biliary lipid secretion in Bsep(-/-) mice. The secretion of the BS tauro-ß-muricholic acid (TßMCA) is relatively preserved in Bsep(-/-) mice. We infused Bsep(-/-) and Bsep(+/+) (control) mice with TßMCA in stepwise increasing dosages (150-600 nmol/min) and determined biliary bile flow, BS, PL, and CH secretion. mRNA and protein expression of relevant canalicular transporters was analyzed in livers from noninfused Bsep(-/-) and control mice. TßMCA infusion increased BS secretion in both Bsep(-/-) and control mice. The secreted PL or CH amount per BS, i.e., the "coupling," was continuously two- to threefold higher in Bsep(-/-) mice (P < 0.05). Hepatic mRNA expression of canalicular lipid transporters Mdr2, Abcg5, and Abcg8 was 45-55% higher in Bsep(-/-) mice (Abcg5; P < 0.05), as was canalicular Mdr2 and Abcg5 protein expression. Potential other explanations for the increased coupling of the biliary secretion of PL and CH to that of BS in Bsep(-/-) mice could be excluded. We conclude that the mechanism of increased biliary lipid secretion in Bsep(-/-) mice is based on increased expression of the responsible canalicular transporter proteins.

[Advances, limitations and prospects of oncological liver surgery]. / Fortschritt, Limitationen und Zukunft der onkologischen Leberchirurgie.

Modern oncological liver surgery continues to push the limits of resectability by incorporating an array of new developments in the fields of surgery, anaesthesia and intensive care, oncology, radiology and transplantation medicine. New criteria for determining the resectability of primary and secondary liver tumours have been developed and introduced into national consensus guidelines. Modern tools for improving oncological outcome include the rapid induction of liver hypertrophy prior to major liver resection, downstaging of tumours with advanced chemotherapy protocols, minimally invasive local therapies like radiofrequency ablation and chemo- or radioembolisation, and liver transplantation for non-resectable hepatocellular carcinoma.

Conversion from cyclosporine to everolimus at 4.5 months posttransplant: 3-year results from the randomized ZEUS study.

The long-term effect of conversion from calcineurin inhibitor (CNI) therapy to an mTOR inhibitor requires clarification. Following completion of the 12-month, open-label, multicenter ZEUS study, in which 300 kidney transplant recipients were randomized to continue cyclosporine (CsA) or convert to everolimus at 4.5 months posttransplant, outcomes were assessed at month 36 (n = 284; 94.7%). CNI therapy was reintroduced in 28.4% of everolimus patients by month 36. The primary efficacy endpoint, estimated glomerular filtration rate (Nankivell, ANCOVA) was significantly higher with everolimus versus the CsA group at month 24 (7.6 mL/min/1.73 m(2) , 95%CI 4.3, 11.0 mL/min/1.73 m(2) ; p < 0.001) and month 36 (7.5 mL/min/1.73 m(2) , 95%CI 3.6, 11.4 mL/min/1.73 m(2) ; p < 0.001). The incidence of biopsy-proven acute rejection from randomization to month 36 was 13.0% in the everolimus arm and 4.8% in the CsA arm (p = 0.015). Patient and graft survival, as well as incidences of malignancy, severe infections and hospitalization, were similar between groups. Kidney transplant patients who are converted from CsA to everolimus at month 4.5 and who remain on everolimus thereafter may achieve a significant improvement in renal function that is maintained to 3 years. There was a significantly higher rate of rejection in the everolimus arm but this did not exert a deleterious effect by 3 years posttransplant.

A randomized, controlled study to assess the conversion from calcineurin-inhibitors to everolimus after liver transplantation--PROTECT.

Posttransplant immunosuppression with calcineurin inhibitors (CNIs) is associated with impaired renal function, while mTor inhibitors such as everolimus may provide a renal-sparing alternative. In this randomized 1-year study in patients with liver transplantation (LTx), we sought to assess the effects of everolimus on glomerular filtration rate (GFR) after conversion from CNIs compared to continued CNI treatment. Eligible study patients received basiliximab induction, CNI with/without corticosteroids for 4 weeks post-LTx, and were then randomized (if GFR > 50 mL/min) to continued CNIs (N = 102) or subsequent conversion to EVR (N = 101). Mean calculated GFR 11 months postrandomization (ITT population) revealed no significant difference between treatments using the Cockcroft-Gault formula (-2.9 mL/min in favor of EVR, 95%-CI: [-10.659; 4.814], p = 0.46), whereas use of the MDRD formula showed superiority for EVR (-7.8 mL/min, 95%-CI: [-14.366; -1.191], p = 0.021). Rates of mortality (EVR: 4.2% vs. CNI: 4.1%), biopsy-proven acute rejection (17.7% vs. 15.3%), and efficacy failure (20.8% vs. 20.4%) were similar. Infections, leukocytopenia, hyperlipidemia and treatment discontinuations occurred more frequently in the EVR group. No hepatic artery thrombosis and no excess of wound healing impairment were noted. Conversion from CNI-based to EVR-based immunosuppression proved to be a safe alternative post-LTx that deserves further investigation in terms of nephroprotection.

Renal graft outcome in combined heart-kidney transplantation compared to kidney transplantation alone: a single-center, matched-control study.

BACKGROUND: Renal allograft outcome in heart-kidney transplantation (HKTx) might be affected by hemodynamic instability and high levels of calcineurin inhibitor-dependent immunosuppression. METHODS: From November 1999 to March 2008, 13 patients who received HKTx were compared with a matched control group of 13 kidney transplantation (KTx) recipients with similar cardiovascular risk factors. Graft function, rejection periods, and patient survival were analyzed. RESULTS: Renal allograft rejection was noted in three patients (23%) after HKTx and in four patients (31%) after KTx. Serum creatinine levels were comparable at 1 week, 1 month, 1, 2, and 3 years after transplantation. Patient survival rates at 1, 2, and 3 years were 100% for HKTx recipients and 100, 92, and 92% for isolated KTx patients. Graft survival was 92% at 1, 2, and 3 years after HKTx and 100% at 1 year and 92% at 2 and 3 years after isolated KTx. CONCLUSIONS: Our results with excellent long-term graft function and survival after combined HKTx indicate that this procedure is a valuable option for a growing number of patients suffering from coexistent cardiac and renal failure.

High detection rate of adenomas in familial colorectal cancer.

BACKGROUND AND AIMS: Subjects with one first-degree relative (FDR) with colorectal cancer (CRC) <50 years old or two FDRs with CRC have an increased risk for CRC (RR 4-6). Current guidelines recommend colonoscopic surveillance of such families. However, information about the yield of surveillance is limited. The aim of the present study was to evaluate the outcome of surveillance and to identify risk factors for the development of adenomas. PATIENTS AND METHODS: Subjects were included if they fulfilled the following criteria: asymptomatic subjects aged between 45 and 65 years, with one FDR with CRC <50 years old (group A) or two FDRs with CRC diagnosed at any age (group B). Subjects with a personal history of inflammatory bowel disease or colorectal surgery were excluded. RESULTS: A total of 551 subjects (242 male) met the selection criteria. Ninety-five subjects with a previous colonoscopy were excluded. Two of 456 remaining subjects (0.4%) were found to have a colorectal tumour (one CRC and one carcinoid). Adenomas were detected in 85 (18.6%) and adenomas with advanced pathology in 37 subjects (8.1%). 30 subjects (6.6%) had multiple (>1) adenomas. Men were more often found to have an adenoma than women (24% vs 14.3%; p=0.01). Adenomas were more frequent in group B compared with group A (22.0% vs 15.6%; p=0.09). CONCLUSION: The yield of colonoscopic surveillance in familial CRC is substantially higher than the yield of screening reported for the general population.

Pathologic interpretation of transbronchial biopsy for acute rejection of lung allograft is highly variable.

Despite the standardization of pathologic grading of acute rejection in transbronchial lung biopsies following lung transplantation, the reproducibility of pathologic diagnosis has not been adequately evaluated. To determine the interobserver variability for pathologic grading of acute rejection, 1566 biopsies from 845 subjects in the Lung Allograft Rejection Gene Expression Observational study were regraded by a pathology panel blinded to the original diagnosis and compared to the grade of acute rejection assigned by individual center pathologists. The study panel confirmed 49.1% of center pathologists' A0 grades, but upgraded 5.7% to A1 and 2.7% to grade ≥ A2 rejection; 42.5% were regraded as AX. Of 268 grade A1 samples, 21.2% were confirmed by the pathology panel; 18.7% were upgraded to ≥ A2 and 35.8% were downgraded to A0 with 24.3% being regraded as AX. Lastly, 53.5% of ≥ A2 cases were confirmed, but 15.7% were downgraded to grade A0 and 18.4% cases to A1, while 12.4% were regraded as AX. The kappa value for interobserver agreement was 0.183 (95%CI 0.147-0.220, p < 0.001). The results for B grade interpretation were similar. Suboptimal sampling is common and a high degree of variability exists in the pathologic interpretation of acute rejection in transbronchial biopsies.

Adenosine triphosphate-dependent taurocholate transport in human liver plasma membranes.

Transport systems involved in uptake and biliary secretion of bile salts have been extensively studied in rat liver; however, little is known about these systems in the human liver. In this study, we investigated taurocholate (TC) transport in canalicular and basolateral plasma membrane vesicles isolated from 15 human livers (donor age 6-64 yr). ATP stimulated the uptake of TC into both canalicular and basolateral human liver plasma membrane vesicles (cLPM and blLPM, respectively). Considerable interindividual variations in the transport velocity were observed in the different membrane preparations used: 9.0 +/- 1.3 (mean +/- SEM, n = 17; range 1.6-18.0) and 9.3 +/- 2.0 (range 1.1-29.8) pmol TC.mg protein-1.min-1 at 1.0 microM TC for cLPM and blLPM, respectively. TC transport was temperature sensitive and showed saturation kinetics with a high affinity for TC (Km 4.2 +/- 0.7 microM and 3.7 +/- 0.5 microM for cLPM and blLPM, respectively). Transport was dependent on the ATP concentration and saturable (Km 0.25 +/- 0.03 mM, n = 3). Neither nitrate, which reduces membrane potential, nor the protonophore FCCP strongly inhibited ATP-dependent TC transport, indicating that membrane potential and proton gradient are not involved in this process. TC transport was significantly inhibited by the classical anion transport inhibitor 4,4'-diisothiocyanostilbene-2,2'-disulfonate (250 microM) and the glutathione conjugate S-(2,4-dinitrophenyl)glutathione (100 microM). In conclusion, high affinity ATP-dependent TC transport is present in human liver at both the canalicular and the basolateral sides of the hepatocyte.

Dietary fish oil-induced changes in intrahepatic cholesterol transport and bile acid synthesis in rats.

Hepatic cholesterol metabolism was studied in rats fed purified diets supplemented (9% wt/wt) with either fish oil (FO) (n-3 fatty acids) or corn oil (CO) (n-6 fatty acids) for 4 wk. Rats were equipped with permanent catheters in heart, bile duct, and duodenum to allow studies under normal feeding conditions. [3H]-cholesteryl oleate-labeled small unilamellar liposomes, which are rapidly endocytosed by hepatocytes, were intravenously injected to label intrahepatic cholesterol pools, and plasma and bile were collected. FO as compared to CO induced a lowering of plasma cholesterol levels by 38% and of triglyceride levels by 69%. This reduction in plasma lipids in FO rats was accompanied by: (a) an increased bile acid pool size (28%); (b) a fourfold increase in the ratio cholic acid/chenodeoxycholic acid in bile; (c) increased biliary excretion of cholesterol (51%); (d) accelerated excretion of endocytosed free cholesterol into bile; (e) accelerated incorporation of endocytosed cholesterol in bile acids; (f) a significant increase in the bile acid-independent fraction of bile flow; and (g) a threefold increase in hepatic alkaline phosphatase activity. The results show that FO induces changes in transport and metabolic pathways of cholesterol in the rat liver, which result in a more rapid disposition of plasma-derived cholesterol into the bile.

Kidney transplantation using donors with history of diabetes and hypertension.

PURPOSE: Due to the persistant organ shortage for kidney transplantation, donor selection has changed in the past years. Although hypertension and diabetes mellitus are known to be risk factors for renal insufficiency, kidneys from donors with these diagnoses in their history have been accepted for kidney transplantation even with an increased risk of poor graft function. Herein we have reported our experience with kidney transplantation using grafts from donors with both, a history of type II diabetes and hypertension. METHODS: Between 2000 and 2005, ten patients were grafted using donors with history of type II diabetes mellitus and hypertension. Mean donor age was 58 +/- 7.5 years and recipient age, 52.2 +/- 15.7 years. Mean HLA mismatch was 0.8 (A); 1.2 (B) and 0.9 (DR). Cold ischemia time was 17.4 +/- 4.1 hours. Immunosuppression was based on CyA (n = 7), tacrolimus (n = 2) or sirolimus (n = 1). RESULTS: Six patients (60%) showed good initial function, and four (40%) had delayed graft function (DGF). One patient died at ten weeks due to multiorgan failure. Two (20%) biopsy-proven rejections were diagnosed, one of which was resistant to therapy. Six months after kidney transplantation, 7 (77%, n = 9) showed good graft function (creatinine 1.3 to 2.4 mg/dL), but one patient displayed long-lasting DGF with poor function. CONCLUSION: Grafts from donors with a history of diabetes mellitus and hypertension are suitable for kidney transplantation. Elevated rate of DGF (40%) would justify allocation of these organs to local transplant centers to shorten ischemia time and thereby reduce DGF and achieve better long-term results. Identification and detailed evaluation of these donors prior to allocation (eg, HbAlc, biopsy) may help transplant centers to accept these kidneys.

Reconstruction of ureteral necrosis in kidney transplantation using an ileum interposition.

PURPOSE: Ureteral necrosis is a serious problem in kidney transplantation. Sometimes re-ureterocystostomy is possible, while other cases require an elaborate reconstruction to maintain kidney function. We report our experience with ileum interposition for ureteral reconstruction. METHODS: After 9 years of dialysis treatment a 58-year-old patient was grafted using the left kidney of a 59-year-old donor with a cold ischemic time of 9.5 hours. The early postoperative course was uneventful apart from delayed graft function. Immunosuppression consisted of an IL-2-receptor antibody, calcineurin inhibitor, mycophenolate mofetil, and corticosteroids. Discharge serum creatinine was 2.3 mg/dL. In month 4 the patient showed a pararenal urinoma; cystoscopy revealed necrosis of the distal ureter. Operative revision showed urine leakage from the renal pelvis through the urinoma into the bladder. As the whole ureter was necrotic, a re-ureterocystostomy was not possible. The patient's own ureter had been extirpated, and the bladder was too small to do a direct anastomosis between it and the kidney. Consequently, an ileum interposition was performed. RESULTS: The postoperative course was uneventful. Kidney function was stable with a nadir creatinine concentration of 2.0 mg/dL 18 months' posttransplantation, and 14 months' post ileal interposition the kidney function was still satisfactory, with a creatinine level of 2.0 mg/dL. CONCLUSION: Ureteral necrosis is a serious complication following kidney transplantation. Whenever a re-ureterocystostomy or an uretero-ureterostomy is not possible, the interposition of the ileal segment represented a safe procedure to deal with this problem.

Recurrent complicated colon diverticulitis in renal transplanted patient.

Colon perforation due to diverticulitis is a life-threatening complication in the postoperative course of kidney transplantation. In the immunocompromised patient a diagnosis of diverticulitis is difficult to make. We report a 53-year-old woman being kidney transplanted 14 years ago with known diverticulosis. She was admitted with acute severe pain in the lower left abdomen. Abdominal computed tomography (CT) scan indicated a diagnosis of intestinal abscess in the small pelvis. Laparotomy showed a covered sigma perforation with abscess located in the small pelvis (Hinchey-I). Because of the immunocompromised situation of the patient we performed a Hartmann procedure. Her postoperative course was uneventful. In a 6-month interval the intestinal continuity restoration was performed. Twelve days after discharge the patient was readmitted with reduced renal function and increased infection parameters. During physical examination the abdomen was tender. The patient complained of abdominal pain in the left upper abdomen and additional pain in the left shoulder. An antibiotic therapy using ciprofloxacin was already initiated owing to a urinary tract infection. An abdominal CT scan was performed and indicated an intestinal abscess in the left upper abdomen. Laparotomy showed an abscess involving transverse colon, distal jejunum, and proximal ileum (Hinchey-II). Segmental resection of the left colonic flexure, proximal jejunum, and ileum was performed. The postoperative course was uneventful and the patient was discharged on the 8th postoperative day. The present casuistry emphasizes that the immunocompromised patient can undergo diverticulitis twice, and that primary anastomosis is a feasible option for patients with localized peritonitis due to complicated diverticulitis.

Living donor kidney transplantation from the elderly donor.

PURPOSE: The organ shortage has led to increasing acceptance of living donation in all transplant centers. Although the risk of impaired long-term outcome seems to be greater using elderly donors, these organs are not generally refused for transplantation. We report our experience with 25 living donor kidney transplantations from donors older than 60 years. METHODS: Between 1995 and 2004, 124 living donor procedures were performed in our center from 83 related and 41 unrelated donors. Twenty-five donors (19 female, 6 male) were 60 years or older (mean, 65.3 +/- 3.9 years). The recipient included (10 females and 15 males) showed a higher degree of variance in age (46.1 +/- 14.6 years). The immunosuppressive protocol was cyclosporine (CyA)-based regimen in related cases and tacrolimus-based in unrelated cases. RESULTS: We transplanted 16 left and 9 right kidneys from older donors. The mean cold ischemia time was 171 +/- 64 minutes with a second warm ischemia time of 24 +/- 6 minutes. Severe arteriosclerosis made vascular reconstruction by graft interposition necessary in two recipients. The acute rejection rate was 20%. Two patients (8%) required dialysis in the early postoperative course, whereas initial function was excellent in 22 patients (88%). The mean serum creatinine concentration after 12 months was 1.6 +/- 0.3 mg/dL (n = 24) and 2.0 +/- 0.7 mg/dL (n = 16) at 4 years. In comparison, the mean creatinine concentration after 4 years in donors under 60 years was 1.6 +/- 0.9 mg/dL. Our analysis showed no significant difference in long-term graft function comparing young versus old donors in the setting of living donor transplants. CONCLUSION: Using living donors older than 60 years for transplantation is a feasible and safe option. The difference in long-term creatinine between young and old donors was not significant.

Isolation and characterization of canalicular and basolateral plasma membrane fractions from human liver.

A method is described for the isolation of subfractions from human liver plasma membranes, enriched in canalicular domains (cLPM) and basolateral domains (blLPM), respectively, and the results are compared to those obtained with rat liver. The studies were performed in 18 human livers. The cLPM (isolated at densities 1.103-1.127 for human and 1.036-1.127 for rat cLPM) from human as well as rat liver showed a lower density than the blLPM (1.141-1.161 for human and 1.151-1.172 for rat blLPM). Human and rat blLPM were characterized by increased levels of (Na+/K+)-ATPase (relative enrichment 33 and 21, respectively). Both human and rat cLPM showed high specific activities of leucine aminopeptidase; relative enrichment factors were 42 and 31, respectively. Mg(2+)-ATPase and alkaline phosphatase, specific canalicular enzymes in rat liver, were only slightly enriched in the cLPM of human liver, which indicates that these enzymes are not suitable as marker enzymes for human liver cLPM. Both cLPM and blLPM of human and rat origin were only slightly contaminated with mitochondria, lysosomes, Golgi membranes and endoplasmic reticulum. Total recoveries of cLPM and blLPM were 0.02 mg protein/g liver each for the human membrane preparations, compared to 0.07 and 0.16 mg protein/g liver for the membranes prepared from rat liver. Analysis of membrane fluidity revealed that the human liver cLPM were more rigid than blLPM (mean difference in fluorescence polarization PDPH 0.024). They contained more cholesterol (0.43 vs. 0.30 mumol/mg protein) and phospholipids (0.54 vs. 0.39 mumol/mg protein, respectively), which was compatible to rat liver plasma membrane fractions. This study shows that besides similarities, there are several differences between human and rat liver plasma membrane fractions.

Mice expressing only the mutant APOE3Leiden gene show impaired VLDL secretion.

Apolipoprotein E (apoE)-deficient mice develop hepatic steatosis and show impaired very low density lipoprotein (VLDL)-triglyceride (TG) secretion. These effects are normalized on the introduction of the human APOE3 gene. To assess whether this apoE effect is isoform specific, we studied hepatic lipid metabolism in mice expressing either APOE3 or the mutant APOE3Leiden on apoe-/- or apoe+/- backgrounds. The transgenes were expressed mainly in periportal hepatocytes, as revealed by in situ hybridization. Mice expressing APOE3Leiden, on the apoe-/- and apoe+/- backgrounds, had fatty livers, which were absent in APOE3/apoe-/- mice. APOE3Leiden/apoe-/- mice showed a strongly reduced VLDL-TG secretion compared with APOE3/apoe-/- mice (48+/-14 versus 82+/-10 micromol/kg per hour, respectively). The presence of a single mouse apoe allele increased VLDL-TG secretion in APOE3Leiden/apoe+/- mice (121+/-43 micromol/kg per hour) compared with APOE3Leiden/apoe-/- mice. These results show that APOE3Leiden does not prevent development of a fatty liver and does not normalize VLDL-TG secretion in mice with an apoE-deficient background. The presence of a single mouse apoe allele is sufficient to normalize the APOE3Leiden-associated reduction of VLDL-TG secretion but does not prevent steatosis. We conclude that apoE-mediated stimulation of VLDL secretion is isoform specific.

The cost-effectiveness of basiliximab induction in "old-to-old" kidney transplant programs: Bayesian estimation, simulation, and uncertainty analysis.

INTRODUCTION: Markov models are employed in economic analyses to evaluate all possible expectations in a dilemna. The introduction of a new clinical protocol (Basiliximab induction with calcineurin-sparing protocols) for a group of kidney transplant recipients receiving organs from marginal donors was validated with a Markov simulation model, demonstrating the usefulness of combining simulation with Bayesian estimation methods for analysis of cost-effectiveness data collected alongside a clinical trial. We sought to determine whether calcineurin-sparing protocols using anti-interleukin-2/antibody induction (Simulect) would show a beneficial effect on initial kidney function and reduce transplantation costs upon admission, clinical incidences, graft function, and complications during the first month after transplant. PATIENTS AND METHODS: A Markov Chain Monte Carlo (MCMC) was used to estimate a system of generalized linear models relating costs and outcomes to a kidney transplant process affected by treatment under alternative therapies. The Markov simulation model was established following three chains: a calcineurin-free regimen with Basiliximab induction (chain A); a calcineurin-sparing protocol with Basiliximab induction (chain B); and a conventional immunosuppressive regimen (chain C). The MCMC draws were used as parameters in simulations that yielded inferences about the relative cost-effectiveness of the novel therapy under a variety of scenarios. After designing the Markov chain and cohorts, 31 patients from the "old-to-old" program were assigned; eight to chain A; eight to chain B; and 15 to chain C. A year after transplantation a cost-benefit study was performed guided by the three branches of the Markov model. RESULTS: The Markov model showed a benefit of induction therapies in elderly patients. A cost-benefit model showed that after a year, there was a clear benefit from calcineurin-free plus Basiliximab induction therapies, with a slight benefit from calcineurin-sparing protocols. CONCLUSIONS: Markov models are extremely useful when introducing new clinical therapies. The approach allows flexibility in assessing treatment using various premises and quantifies the global effect of parametric uncertainty on a decision maker's confidence to adopt one therapy over another. In our transplant program, a cost-effective analysis of outcomes in old patients using the Markov model showed a clear benefit of calcineurin-sparing protocols with Basixilimab induction.

Therapy and prognosis of tumors of the genitourinary tract after kidney transplantation.

There is an increased incidence of tumors of the genitourinary tract among kidney graft recipients. From 1979 to 2001, all patients who received kidney transplants had records of both their underlying diseases and their initial immunosuppression. Patients who developed a genitourinary tract malignancy were evaluated for tumor type, location, stage, tumor therapy and clinical course. During this period, 1804 patients underwent 2068 kidney transplantations. Thirty-four patients had 39 tumors of genitourinary origin. One patient was lost to follow-up. There were 15 patients with 18 renal cell carcinomas (one of them multifocal): six had seven transitional cell carcinomas; six, prostatic carcinoma; six, tumor of the female genital tract (one also had a renal cell carcinoma); and two, a seminoma. Most tumors were diagnosed in their early stages (< or = pT3, N0, M0; n = 31 tumors) and thus accessible to curative therapy, achieving good long-term results: 1- and 5-year survival rates of 100% and 91%, which were better than those obtained in advanced stages (N+, M+; n = 7 tumors), namely both 1- and 5-year survival rates of 38% (P < .05). Death was caused by tumor growth in nine patients (27%) and by other causes in three patients (9%). With appropriate treatment genitourinary tumors at early stage show a good prognosis. New immunosuppressants with supposed antiproliferative effects may help to decrease the incidence of malignancies. The most important factor is risk-adapted screening to identify malignancies early and to initiate appropriate therapy.

Living donor kidney transplantation: impact of differentiated immunosuppressive regimen.

INTRODUCTION: Recipients of related (R) and unrelated (NR) living donor kidney transplantations (LDKTX) receive immunosuppressive (IS) therapy 5 days in advance in order to achieve low rates of acute rejection episodes. We herein report the different IS regimens for R and NR transplants as well as acute rejection and primary function rates. METHODS: Ninety-five LDKTX (69% R, 31% NR) were performed with mean cold ischemia time (CIT) of 145 +/- 32 minutes. In R-LDKTX mean age of recipients was 31 +/- 12.5 years. This cohort included 41 men and 25 women whose mean age was 50 +/- 11.1 years. The therapeutic regimen for R-LDKTX included CyA/MMF/prednisone; for NR-LDKTX, FK/MMF/prednisone. Among the recipients of NR grafts the mean recipient age was 51 +/- 8.5 years. This cohort included 23 men and 6 women whose donor mean age was 50 +/- 8.8 years. The mean HLA mismatch among R-LDKTX (2.3) was significantly less than that in the NR-LDKTX cohort (3.51). RESULTS: At a mean follow-up of 35 months, 94.7% of grafts were functioning. DGF was seen in only one recipient (1%). Three grafts were lost due to acute (R) or chronic (NR) rejection or to multiorgan failures. Two recipients died with functioning grafts. Biopsy-proven rejection episodes were observed in 17.2% of NR-LDKTX and 9% of R-LDKTX. In R-LDKTX 50% of rejection episodes were corticoid-sensitive, while 33% needed ATG, and 16% were treated by a switch to FK. In NR-LDKTX 20% of rejections were corticoid-sensitive, 40% needed ATG, and 40% were treated with rapamycin rescue therapy. CONCLUSION: Although HLA mismatching is significantly different between R- and NR-LDKTX, no difference in outcome was observed, which may be due to the specific therapeutic regimen and short CIT.