The importance of MHC class II in allogeneic bone marrow transplantation and chimerism-based solid organ tolerance in a rat model.

Mixed hematopoietic chimerism enables donor-specific tolerance for solid organ grafts. This study evaluated the influence of different serological major histocompatibility complex disparities on chimerism development, graft-versus-host disease incidence and subsequently on solid organ tolerance in a rat model. For bone marrow transplantation conditioning total body irradiation was titrated using 10, 8 or 6 Gray. Bone marrow transplantation was performed across following major histocompatibility complex mismatched barriers: complete disparity, MHC class II, MHC class I or non-MHC mismatch. Recipients were clinically monitored for graft-versus-host disease and analyzed for chimerism using flow cytometry. After a reconstitution of 100 days, composition of peripheral leukocytes was determined. Mixed chimeras were challenged with heart grafts from allogeneic donor strains to define the impact of donor MHC class disparities on solid organ tolerance on the basis of stable chimerism. After myeloablation with 10 Gray of total body irradiation, chimerism after bone marrow transplantation was induced independent of MHC disparity. MHC class II disparity increased the incidence of graft-versus-host disease and reduced induction of stable chimerism upon myelosuppressive total body irradiation with 8 and 6 Gray, respectively. Stable mixed chimeras showed tolerance towards heart grafts from donors with MHC matched to either bone marrow donors or recipients. Isolated matching of MHC class II with bone marrow donors likewise led to stable tolerance as opposed to matching of MHC class I. In summary, MHC class II disparity was critically associated with the onset of graft-versus host disease and was identified as obstacle for successful development of chimerism after bone marrow transplantation and subsequent donor-specific solid organ tolerance.

Associating Liver Partition and Portal vein ligation for Staged hepatectomy after pre-operative chemotherapy.

BACKGROUND: Recently a procedure termed 'Associating Liver Partition and Portal vein ligation for Staged hepatectomy' (ALPPS) was developed to increase the resectability of marginally resectable or locally unresectable liver tumours. This study focused on the application of ALPPS in patients with advanced colorectal liver metastases (CRLM) and pre-operative chemotherapy, with the aim to investigate whether the latter still allows for sufficient hypertrophy of the future liver remnant (FLR) following the first step of ALPPS. METHODS: Retrospective analysis was performed on six patients suffering from advanced CRLM. Analyses comprised demographical and basic clinical data, the perioperative courses as well as short- and long-term outcomes. RESULTS: All patients presented with bilobular CRLM and pre-operative chemotherapy of at least 6 months. Extended right hemihepatectomy was performed in all cases, four patients additionally received atypical resections in segments II/III. Mean FLR prior to step 1 of ALPPS was 397.9 cm3 (121-753 cm3 ), on average representing 20.9% of the total liver volume (13.2-27.1%). A mean hypertrophy of the FLR of 67.9% (32.5-94.1%) was achieved. Overall, severe morbidity (Dindo Clavien >3a) occurred in two patients. Following completion of ALPPS, mean post-operative disease-free survival was 5.7 months (2.6-8.9 months). CONCLUSION: Despite pre-operative chemotherapy, ALPPS seems to result in adequate liver hypertrophy, preventing post-operative small-for-size syndrome. However, there might be a high risk of tumour recurrence in patients with an aggressive tumour biology.

Timing of parathyroidectomy in kidney transplant candidates with secondary hyperparathryroidism: effect of pretransplant versus early or late post-transplant parathyroidectomy.

BACKGROUND: The timing of parathyroidectomy in kidney transplant candidates suffering from secondary hyperparathyroidism before versus early or late after transplantation remains controversial. METHODS: The short-term follow-up cohort comprised 66 patients with 1-year post-transplant follow-up, while the long-term follow-up cohort contained 123 patients. Risk-adjusted identification of independent risk factors for compromised renal graft function (KDIGO stage ≥ IV) was performed using multivariable regression analysis adjusted for propensity score logits for parathyroidectomy before versus after renal transplantation. Intra-individual matched-pairs analyses were used to identify significant effects of post-transplant parathyroidectomy on graft function as assessed by estimated glomerular filtration rate (eGFR) and paired t tests. RESULTS: Donor kidney function KDIGO stage III (P = .030; OR = 5.191, 95% CI: 1.100-24.508), donor blood group 0 (P = .005; OR = 0.176, 95% CI: 0.048-0.642), and post-transplant parathyroidectomy (P = .032; OR = 17.849, 95% CI: 1.086-293.268) were revealed as independent significant risk factors for compromised renal graft function in the short-term follow-up cohort using propensity score risk adjustment while post-transplant parathyroidectomy had no independent influence in the long-term follow-up cohort (P = .651). Parathyroidectomy after renal transplantation compromised graft function early after parathyroidectomy and at last follow-up in all post-transplant parathyroidectomy cases (P ≤ .004). Parathyroidectomy within the first post-transplant year was associated with compromised renal graft function until last follow-up (P = .004), while parathyroidectomy late post-transplant was not. CONCLUSION: Parathyroidectomy should be conducted before transplantation or, if this is not possible, preferably after the first post-transplant year.

Risk-factors for nodular hyperplasia of parathyroid glands in sHPT patients.

INTRODUCTION: Nodular hyperplasia of parathyroid glands (PG) is the most probable cause of medical treatment failure in secondary hyperparathyroidism (sHPT). This prospective cohort study is located at the interface of medical and surgical consideration of sHPT treatment options and identifies risk-factors for nodular hyperplasia of PG. MATERIAL AND METHODS: One-hundred-eight resected PG of 27 patients with a broad spectrum of sHPT severity were classified according to the degree of hyperplasia by histopathology. Twenty routinely gathered parameters from medical history, ultrasound findings of PG and laboratory results were analyzed for their influence on nodular hyperplasia of PG by risk-adjusted multivariable binary regression. A prognostic model for non-invasive assessment of PG was developed and used to weight the individual impact of identified risk-factors on the probability of nodular hyperplasia of single PG. RESULTS: Independent risk-factors for nodular hyperplasia of single PG were duration of dialysis in years, PG volume in mm3 determined by ultrasound and serum level of parathyroid hormone in pg/mL. Multivariable analyses computed a model with an Area Under the Receiver Operative Curve of 0.857 (95%-CI:0.773-0.941) when predicting nodular hyperplasia of PG. Theoretical assessment of risk-factor interaction revealed that the duration of dialysis had the strongest influence on the probability of nodular hyperplasia of single PG. CONCLUSIONS: The three identified risk-factors (duration of dialysis, PG volume determined by ultrasound and serum level of parathyroid hormone) can be easily gathered in daily routine and could be used to non-invasively assess the probability of nodular hyperplasia of PG. This assessment would benefit from periodically collected data sets of PG changes during the course of sHPT, so that the choice of medical or surgical sHPT treatment could be adjusted more to the naturally changing type of histological PG lesion on an individually adopted basis in the future.

Ultrasound-based scores as predictors for nodular hyperplasia in patients with secondary hyperparathyroidism: a prospective validation study.

PURPOSE: Former studies evaluated echostructural and vascular patterns in ultrasound of the parathyroid gland to identify nodular hyperplasia in patients with secondary hyperparathyroidism due to chronic kidney disease. This prospective study aims to externally validate suggested ultrasound classifications. METHODS: Parathyroid glands of 27 patients with secondary hyperparathyroidism undergoing parathyroidectomy were prospectively analyzed. Ultrasound including Doppler imaging was performed 1 day prior to surgery. Ultrasound data were available for 70 parathyroid glands. Echostructural and vascular scores according to previous studies were applied calculating the area under the receiver operating characteristic curve (AUROC). Overall correctness, sensitivity, and specificity of the investigated scores were assessed with the Youden index method. RESULTS: The Doppler score introduced by Vulpio and colleagues based on characteristic blood flow patterns in parathyroid glands showed an AUROC of 0.749 for the prediction of nodular hyperplasia with an overall correctness of 72.8%. Other ultrasound classifications based on blood flow patterns, as well as echostructure of the parathyroid gland displayed AUROCs of <0.700, thus, lacking sufficient capability as a prognostic model. Overall correctness of prediction varied from 53.8 to 55.9%. CONCLUSIONS: The Vulpio Doppler score for the prediction of nodular hyperplasia in patients with secondary hyperparathyroidism was externally validated for the first time. Other ultrasound scores fail as prognostic models in this study population. Doppler sonography of the parathyroid gland has prognostic capability to identify nodular hyperplasia as surrogate marker for patients with secondary hyperparathyroidism indicating the need for ablative or surgical treatment when failing conservative therapy.

Monitoring of liver function in a 73-year old patient undergoing 'Associating Liver Partition and Portal vein ligation for Staged hepatectomy': case report applying the novel liver maximum function capacity test.

BACKGROUND: The two-stage liver resection combining in situ liver transection with portal vein ligation, also referred to as ALPPS (Associating Liver Partition and Portal vein ligation for Staged hepatectomy), has been described as a promising method to increase the resectability of liver tumors. However, one of the most important issues regarding the safety of this procedure is the optimal timing of the second stage at the point of sufficient hypertrophy of the future liver remnant. The recently developed liver maximum function capacity test (LiMAx) can be applied to monitor the liver function postoperatively and hence could be a useful tool for decision-making regarding the timing of the second stage of ALPPS. CASE PRESENTATION: A 73-year-old female patient presented with metachronous colorectal liver metastasis comprising the complete right liver lobe as well as segment IV. Due to an insufficient future liver remnant (19.3 %; segments II and III of the liver) and a low future liver remnant:body weight ratio (0.28 %) the decision was made to perform an ALPPS-procedure in order to avoid development of postoperative small-for-size syndrome. Despite a formally sufficient increase of the FLR to 30.8 % within 7 days after the first step of ALPPS, the liver function was seen to only slowly increase as expressed by a LiMAx value of 245 µg/h/kg (baseline of 282 µg/h/kg prior to surgery). By means of the LiMAx test, sufficient increase of liver function eventually was detected by postoperative day 11 (LiMAx value of 371 µg/h/kg; FLR 35.2 %) so that the second step of ALPPS (completion of hepatectomy) was performed with no signs of liver failure during further clinical course. CONCLUSION: Performing ALPPS we have observed a significant difference between the increase in future liver remnant volume and function applying the LiMAx test. The latter tool thus might proof valuable for application in two-stage liver resection to avoid postoperative small-for-size syndrome.

A Depleting Anti-CD45 Monoclonal Antibody as Isolated Conditioning for Bone Marrow Transplantation in the Rat.

OBJECTIVE: A monoclonal antibody (mAb) against the leukocyte common antigen CD45 (RT7 in rats) could facilitate bone marrow transplantation (BMT). This study in rats evaluates a depletive rat anti-RT7a mAb as isolated tool for BMT conditioning without using irradiation or any chemotherapeutic / immunosuppressive agent. METHODS: The model used a CD45 di-allelic polymorphism (RT7a/RT7b). The anti-RT7a mAb was intravenously administered to LEW.1W rats (RT1uRT7a) at 5, 10 and 15 mg/kg. 1x10(8) BM cells of MHC syngeneic (RT1u), MHC disparate (RT1l) or MHC haploidentical (RT1u/l) donors were transplanted. All BM donor strains carried the RT7b allele so that their CD45+ cells were not affected by the anti-RT7a mAb. Recipients were monitored for reconstitution and donor-chimerism in blood leukocytes. RESULTS: mAb dosages of 5 or 10 mg/kg were myelosuppressive, whereas 15 mg/kg was myeloablative. Multi-lineage donor-chimerism at day 100 indicated engraftment of MHC syngeneic BM after any used mAb dosage (5 mg/kg: 46+/-7%; 10 mg/kg: 62+/-5%; 15 mg/kg: 80+/-4%). MHC disparate BM resulted in autologous reconstitution after conditioning by 10 mg/kg of the mAb and caused transient chimerism ending up in death associated with aplasia after conditioning by 15 mg/kg of the mAb. MHC haploidentical BM (F1 to parental) engrafted only after conditioning by 15 mg/kg (chimerism at day 100: 78+/-7%). Abandonment of α/ß TCR+ cell depletion from BM grafts impaired the engraftment process after conditioning using 15 mg/kg of the mAb in the MHC syngeneic setting (2 of 6 recipients failed to engraft) and the MHC haploidentical setting (3 of 6 recipients failed). CONCLUSION: This depletive anti-RT7a mAb is myelosuppressive and conditions for engraftment of MHC syngeneic BM. The mAb also facilitates engraftment of MHC haploidentical BM, if a myeloablative dose is used. RT7b expressing, BM-seeded α/ß TCR+ cells seem to impair the engraftment process after myeloablative mAb conditioning.

Model of End-Stage Liver Disease Score and Derived Variants Lack Prognostic Ability after Liver Transplantation.

BACKGROUND The model of end-stage liver disease (MELD) score is currently used for donor liver allocation in many regions. The objective of this retrospective study was to assess the MELD score and its diverse variants as prognostic models for mortality after liver transplantation. MATERIAL AND METHODS An analysis of 454 consecutive adult liver transplants since the introduction of MELD-based donor liver allocation was conducted. Eight different MELD score variants were investigated. Receiver operating characteristic (ROC) curve analysis was performed to calculate the sensitivity, specificity, and overall model correctness of the investigated scores as a predictive model. The Brier score was used for the prediction of model accuracy and calculated as described before. Study endpoints were 90-day mortality and long-term patient mortality. RESULTS A 90-day mortality of 15.4% (n=69) and long-term mortality of 25% (n=112) were observed. All investigated models fail to reach relevant areas under the ROC curve greater than 0.700 for the prediction of mortality after liver transplantation. All calculated Brier scores were greater than 0.25, indicating a significant lack of model discrimination and calibration of the investigated scores. CONCLUSIONS A prognostic model for the prediction of outcome after transplantation still needs to be identified and should allow weighing urgency against utility in liver transplantation.

Application of allogeneic bone marrow cells in view of residual alloreactivity: sirolimus but not cyclosporine evolves tolerogenic properties.

BACKGROUND: Application of bone marrow cells (BMC) is a promising strategy for tolerance induction, but usually requires strong depletion of the host immune system. This study evaluates the ability of immunosuppressants to evolve tolerogenic properties of BMC in view of residual alloreactivity. METHODS: The rat model used a major histocompatibility complex (MHC) class II disparate bone marrow transplantation (BMT) setting (LEW.1AR1 (RT1auu) → LEW.1AR2 (RT1aau)). Heart grafts (LEW.1WR1 (RT1uua)) were disparate for the complete MHC to recipients and for MHC class I to BMC donors. Limited conditioning was performed by total body irradiation of 6 Gy. Cyclosporine (CsA) or Sirolimus (Srl) were administered for 14 or 28 days. Transplantation of heart grafts (HTx) was performed at day 16 or at day 100 after BMT. Chimerism and changes in the T cell pool were detected by flow cytometry. RESULTS: Mixed chimeras accepted HTx indefinitely, although the composition of the regenerated T cell pool was not changed to a basically donor MHC class II haplotype. Non-chimeric animals rejected HTx spontaneously. BMC recipients, who received HTx during T cell recovery at day 16, accepted HTx only after pre-treatment with Srl, although chimerism was lost. CsA pre-treatment led to accelerated HTx rejection as did isolated application of BMC. CONCLUSION: Srl evolves tolerogenic properties of allogeneic BMC to achieve indefinite acceptance of partly MHC disparate HTx despite residual alloreactivity and in particular loss of chimerism.

Preduodenal superior mesenteric vein and Whipple procedure with vascular reconstruction-A case report.

INTRODUCTION: Portal vein (PV) disorders are various, but rare. Here, we report a preduodenal superior mesenteric vein (PDSMV) in a patient who underwent a pancreaticoduodenectomy. PRESENTATION OF CASE: A 67-year old woman with familial adenomatosis polyposis was suspicious for cancer of the papilla of vater and scheduled for surgery. Pre-operative diagnostic revealed a PDSMV continuing into the left PV. The splenic vein (SV) continued directly into the right PV without forming ananatomic PV confluence. Eight centimetre of the PDSMV were resected during the pancreaticoduodenectomy and reconnected using a polytetrafluoroethylene prosthesis. On day 1, early graft thrombosis was treated by thrombectomy and change to a larger graft. Pathology confirmed a R0-resection of the adenocarcinoma of the papilla of vater (pTis pN0,G2). At three-month follow-up, the patient was cancer-free and clinically asymptomatic, although, a late graft thrombosis with accompanying newly build venous collaterals passing mesenteric blood to the SV were found. DISCUSSION: Rare PV disorders like a PDSMV do not contradict pancreatic surgery, but should be treated in experienced centres. Skills of SMV/PV reconstruction and its peri-operative management might be beneficial for successful outcome. Despite late graft thrombosis no clinical disadvantage occurred most likely due to preservation of the SV and of potential venous collateral pathways. CONCLUSION: Extended surgical procedures like a pancreaticoduodenectomy are realisable in patients with PV disorders, but require awareness, adequate radiological interpretation and specific surgical experience for secure treatment.

Surgical treatment for intrahepatic cholangiocarcinoma in Europe: a single center experience.

Intrahepatic cholangiocarcinoma is the second most common primary liver tumor. The aim of this study was to analyze retrospectively the outcome of surgical treatment and prognostic factors. Clinical, histopathological and treatment data of 221 patients treated from 1995 to 2010 at our institution were investigated. Univariate and multivariate analysis of the patient's data was performed. Patients after R0 and R1 resection presented an overall survival of 67% and 54.5% after 1 year and 40% and 36.4% after 3 years, respectively. The survival of patients without resection of the tumor was dismal with 26% and 3.4% after 1 and 3 years, respectively. Survival after resection was not statistically different in cases with R0 versus R1 resection (P = 0.639, log rank). Univariate Cox regression revealed that higher T stages are a significant hazard for survival (P = 0.048, hazard ratio (HR): 1.211, 95% confidence interval (CI): 1.002-2.465). Patients with tumor recurrence had a significantly inferior long-term survival when compared to patients without recurrence (P < 0.001, log rank). Presence of lymph node metastasis (N1) was an independent prognostic factor for survival after resection in risk-adjusted multivariate Cox regression (P < 0.001, HR: 2.577, 95% CI: 1.742-3.813). Adjuvant chemotherapy did not improve patient survival significantly (P = 0.550, log rank). Surgical resection is still the best treatment option for intrahepatic cholangiocarcinoma regarding the patient's long-term survival. R0 and R1 resection enable both better survival rates when compared to surgical exploration without resection. T status, N status, and tumor recurrence seem to be the most important prognostic factors after resection.

Explanted diseased livers - a possible source of metabolic competent primary human hepatocytes.

Being an integral part of basic, translational and clinical research, the demand for primary human hepatocytes (PHH) is continuously growing while the availability of tissue resection material for the isolation of metabolically competent PHH remains limited. To overcome current shortcomings, this study evaluated the use of explanted diseased organs from liver transplantation patients as a potential source of PHH. Therefore, PHH were isolated from resected surgical specimens (Rx-group; n = 60) and explanted diseased livers obtained from graft recipients with low labMELD-score (Ex-group; n = 5). Using established protocols PHH were subsequently cultured for a period of 7 days. The viability and metabolic competence of cultured PHH was assessed by the following parameters: morphology and cell count (CyQuant assay), albumin synthesis, urea production, AST-leakage, and phase I and II metabolism. Both groups were compared in terms of cell yield and metabolic function, and results were correlated with clinical parameters of tissue donors. Notably, cellular yields and viabilities were comparable between the Rx- and Ex-group and were 5.3±0.5 and 2.9±0.7×106 cells/g liver tissue with 84.3±1.3 and 76.0±8.6% viability, respectively. Moreover, PHH isolated from the Rx- or Ex-group did not differ in regards to loss of cell number in culture, albumin synthesis, urea production, AST-leakage, and phase I and II metabolism (measured by the 7-ethoxycoumarin-O-deethylase and uracil-5'-diphosphate-glucuronyltransferase activity). Likewise, basal transcript expressions of the CYP monooxygenases 1A1, 2C8 and 3A4 were comparable as was their induction when treated with a cocktail that consisted of 3-methylcholantren, rifampicin and phenobarbital, with increased expression of CYP 1A1 and 3A4 mRNA while transcript expression of CYP 2C8 was only marginally changed. In conclusion, the use of explanted diseased livers obtained from recipients with low labMELD-score might represent a valuable source of metabolically competent PHH which are comparable in viability and function to cells obtained from specimens following partial liver resection.

Inhibition of autophagic flux by salinomycin results in anti-cancer effect in hepatocellular carcinoma cells.

Salinomycin raised hope to be effective in anti-cancer therapies due to its capability to overcome apoptosis-resistance in several types of cancer cells. Recently, its effectiveness against human hepatocellular carcinoma (HCC) cells both in vitro and in vivo was demonstrated. However, the mechanism of action remained unclear. Latest studies implicated interference with the degradation pathway of autophagy. This study aimed to determine the impact of Salinomycin on HCC-autophagy and whether primary human hepatocytes (PHH) likewise are affected. Following exposure of HCC cell lines HepG2 and Huh7 to varying concentrations of Salinomycin (0-10 µM), comprehensive analysis of autophagic activity using western-blotting and flow-cytometry was performed. Drug effects were analyzed in the settings of autophagy stimulation by starvation or PP242-treatment and correlated with cell viability, proliferation, apoptosis induction, mitochondrial mass accumulation and reactive oxygen species (ROS) formation. Impact on apoptosis induction and cell function of PHH was analyzed. Constitutive and stimulated autophagic activities both were effectively suppressed in HCC by Salinomycin. This inhibition was associated with dysfunctional mitochondria accumulation, increased apoptosis and decreased proliferation and cell viability. Effects of Salinomycin were dose and time dependent and could readily be replicated by pharmacological and genetic inhibition of HCC-autophagy alone. Salinomycin exposure to PHH resulted in transient impairment of synthesis function and cell viability without apoptosis induction. In conclusion, our data suggest that Salinomycin suppresses late stages of HCC-autophagy, leading to impaired recycling and accumulation of dysfunctional mitochondria with increased ROS-production all of which are associated with induction of apoptosis.

Presence of small parathyroid glands in renal transplant patients supports less-than-total parathyroidectomy to treat hypercalcemic hyperparathyroidism.

BACKGROUND: Parathyroid glands (PG) are rarely analyzed in renal transplant (RTX) patients. This study analyzes comparatively PG of RTX and end-stage renal disease (ESRD) patients. The clinical part of the study evaluates if total parathyroidectomy with autotransplantation (TPT+AT) treats appropriately hypercalcemic hyperparathyroidism in RTX patients. METHODS: TPT+AT was performed in 15 of 23 RTX and 21 of 27 ESRD patients. Remaining patients underwent less-than-total PT. Volume and stage of hyperplasia were determined from 86 PG of RTX and 109 PG of ESRD patients. Patients were categorized according to the presence of small PG (volume < 100 mm(3)). Calcium homeostasis and hyperparathyroidism were evaluated 2 years after PT in RTX patients. RESULTS: PG of RTX patients were significantly smaller, but similar hyperplastic in comparison to PG of ESRD patients. Small PG were more frequent in RTX than in ESRD patients (19% vs 6%) and mainly graded normal or diffuse hyperplastic (94%). Forty-seven percent of RTX, but only 14% of ESRD, patients receiving a total PT possessed ≥1 small PG (P < .05). Overall, PT treated successfully hypercalcemic hyperparathyroidism. However, TPT+AT caused permanent hypocalcemia in 50% of RTX patients without small PG and even in 83% of RTX patients with small PG. All RTX patients receiving less-than-total PT were normocalcemic at 2-year follow-up. Logistic regression revealed a 10.7 times greater risk of permanent hypocalcemia in RTX patients with small PG receiving TPT+AT compared with RTX patients without small PG receiving TPT+AT or RTX patients undergoing less-than-total PT. CONCLUSION: Surgeons performing PT should be aware of the high frequency of small and less diseased PG in RTX patients. In this context, TPT+AT might overtreat hypercalcemic hyperparathyroidism in RTX patients, especially when small PG are present.

Effect of incomplete parathyroidectomy preserving entire parathyroid glands on renal graft function.

HYPOTHESIS: Parathyroidectomy (PT) corrects tertiary hyperparathyroidism in patients who have received renal grafts but can result in deterioration of renal function. OBJECTIVE: To compare different surgical procedures for their effect on renal function and efficacy to cure tertiary hyperparathyroidism. DESIGN: A retrospective cohort study. SETTING: University clinic. PATIENTS: Eighty-three patients with functioning renal grafts receiving PT for the first time. INTERVENTIONS: Group 1 received an incomplete PT, with at least 1 entire parathyroid gland (PG) remaining in situ (n = 12). Group 2 received an incomplete PT, with the most morphologically conserved PG partially resected (n = 22). Group 3 received a complete PT, with autotransplantation of PG tissue (n = 49). MAIN OUTCOMES MEASURES: The primary end point was the postoperative change in glomerular filtration rate. Secondary end points were rates of redialysis, hypercalcemia, and hyperparathyroidism within 5 years. RESULTS: A decrease in glomerular filtration rate occurred postoperatively in 75 patients (90%) and correlated significantly with the extent of PG resection. Recovery of renal function at month 6 was observed in group 1, but not in groups 2 and 3 (P < .001). Seven patients (8%) needed permanent dialysis (1 in group 2 and 6 in group 3). Hypercalcemia was abrogated in 78 patients (94%), without significant differences among the groups. Assessment of parathyroid hormone levels in accordance with target ranges from the Kidney Disease Outcomes Quality Initiative guidelines did not reveal significant differences in the rates of recurrent hyperparathyroidism. CONCLUSION: Incomplete PT preserving at least 1 entire PG does not cause deterioration of renal graft function and provides long-term correction of hypercalcemia and tertiary hyperparathyroidism.

Surgery and radioablation therapy combined: introducing a 1-week-condensed procedure bonding total thyroidectomy and radioablation therapy with recombinant human TSH.

OBJECTIVE: The objective of this study was to determine whether the use of recombinant human TSH (rhTSH) to stimulate radioiodine uptake after thyroidectomy is as efficacious as a period of withholding thyroid hormones, while at the same time avoiding hypothyroidism, reducing sick leave time and shortening the hospital stay. DESIGN: Our aim was to compare the standard procedure of differentiated thyroid cancer treatment, which consists of thyroidectomy followed by 4 weeks of hypothyroidism and a conclusive ablative activity of (131)iodine, with a new shortened treatment in which l-thyroxine (T(4)) medication is initiated a day after thyroidectomy, followed by application of rhTSH stimulation and subsequent ablation a few days after surgery. We presumed our treatment to represent the most sophisticated strategy for the reduction in sick leave days overall without any reduction in safety or the efficacy of ablative therapy. METHODS: Patients (n=25) were randomized either for surgery and rhTSH stimulation or surgery and l-T(4) abstinence before the first application of radioiodine. Ablation success was determined by neck ultrasound and serum thyroglobulin during follow-up. RhTSH receivers were monitored for an average of 635 days (s.d.+/-289) and patients in l-T(4) abstinence for an average of 624 days (s.d.+/-205). Both groups were statistically compared for significant differences in treatment efficacy, safety and overall time of sick leave. RESULTS AND CONCLUSIONS: Our shortened treatment proved to be equally efficacious and safe in comparison with the conventional therapy regimen. At the same time, it showed economic advantages through the reduction in average sick leave time from approximately 29 days (l-T(4) abstinence) down to approximately 6 days (rhTSH stimulation) as well as sustaining the patient's quality of life by the complete avoidance of hypothyroidism.

Sirolimus promotes tolerance for donor and recipient antigens after MHC class II disparate bone marrow transplantation in rats.

OBJECTIVE: Mixed chimerism after allogeneic bone marrow transplantation (BMT) promotes immunologic tolerance. Graft-vs-host disease (GvHD) can occur when immunosuppressive control of the graft fails. Here we evaluate the influence of concurrent immunosuppression after irradiation-based induction therapy on development of tolerance and GvHD. METHODS: Conditioning was performed by different doses of total body irradiation (TBI) in a major histocompatibility complex (MHC) class II disparate rat BMT model. Animals received subsequent immunosuppression with either cyclosporine A (CsA) or sirolimus. Nonresponsiveness toward donor and recipient antigens was demonstrated by development of mixed chimerism and/or GvHD. RESULTS: Administration of 10 Gy of TBI prior to BMT alone was associated with severe GvHD. Induction therapy with 8 Gy of TBI alone led to graft rejection in the long-term. Two weeks of immunosuppression with CsA after 8 Gy of TBI resulted in transient chimerism, but was finally associated with a combination of fatal GvHD and graft rejection. Six gray of TBI with CsA treatment for 14 or 28 days caused only mild GvHD, but did not lead to stable chimerism. In contrast, treatment with sirolimus was associated with stable chimerism after 8 Gy of TBI (14-day course) and 6 Gy of TBI (28-day course) accompanied by a low incidence of GvHD. CONCLUSIONS: In contrast to CsA, sirolimus facilitates development of tolerance after MHC class II disparate BMT and irradiation-based conditioning, with a low risk of GvHD. Therefore, sirolimus has promising characteristics for inclusion in immunosuppressive protocols.

Haematopoietic stem cells improve cardiac function after infarction without permanent cardiac engraftment.

BACKGROUND: Transplantation of bone marrow derived adult stem cells (BMC) improves cardiac function after acute myocardial infarction (MI). However, the cell population mediating myocardial recovery and the fate of the transplanted cells are still controversial. AIMS: We determined the effects of Sca-1+ c-kit+ lin- haematopoietic BMC on cardiac function after MI and the cell fate after transplantation. METHODS: Sca-1+ c-kit+ lin- BMC of male donor C57BL/6 mice were transplanted by intravenous injection into syngenic females after permanent MI. LV dimensions and function were determined by echocardiography and cardiac magnetic resonance imaging, transplanted BMC were identified by Y chromosome DNA in situ hybridization. RESULTS: BMC treatment completely prevented LV dilation (LV end-diastolic volume BMC 70 +/- 16 microl vs. control 122 +/- 41 microl; p < 0.05) and improved fractional shortening (BMC 22.9 +/- 8% vs. control 15.4 +/- 8.4%; p < 0.05) and ejection fraction BMC 68.2 +/- 6.6% vs. control 52 +/- 14.3%; p < 0.05) as early as 3 days after transplantation, but did not decrease infarct size (BMC 27 +/- 6% vs. control 28 +/- 7%, p = n.s.). After 4 weeks, only sporadic cells of male origin were identified in infarcted hearts (< 0.01% of periinfarct cells). CONCLUSION: Intravenous injection of Sca-1+ c-kit+ lin- in BMC after MI improves LV dimensions and function without evidence for long term engraftment.

Quality of life following living donor nephrectomy comparing classical flank incision and anterior vertical mini-incision.

In this study we focused on the quality of life and satisfaction of living kidney donors comparing traditional lumbar (LDN) and mini-incision donor nephrectomy (MIDN). From May 1996 to December 2002, 174 donor nephrectomies including 127 cases of LDN and 47 cases of MIDN were performed. Donors were evaluated using the SF-36 quality-of-life survey as well as a questionnaire dealing with donors' attitude towards kidney donation, financial burdens, pain, cosmetic satisfaction and duration of sick leave. Our donors achieved comparable or even higher scores in all the SF-36 categories in comparison to the general US population. Following MIDN, quality of life tended to be superior compared to that of LDN donors; however, statistical significance was reached only in one of the eight categories. Duration of sick leave following surgery was in favor of MIDN compared to LDN donors. Statistically significant differences favoring MIDN were observed regarding postoperative hospital stay and cosmetic satisfaction. The procedure would be again undergone by 94 of LDN and 97% of MIDN donors. Open-donor nephrectomy is a safe and cost-effective procedure. Introduction of the here-described MIDN has led to comparable or even improved results compared to LDN.

Liver regeneration in a retrorsine/CCl4-induced acute liver failure model: do bone marrow-derived cells contribute?

BACKGROUND/AIMS: Adult bone marrow contains progenitors capable of generating hepatocytes. Here a new liver failure model is introduced to assess whether bone marrow-derived progeny contribute to liver regeneration after acute hepatotoxic liver failure. METHODS: Retrorsine was used to inhibit endogenous hepatocyte proliferation, before inducing acute liver failure by carbon tetrachloride. Bone marrow chimeras were generated before inducing liver failure to trace bone marrow-derived cells. Therefore, CD45 and major histocompatibility complex (MHC) class I dimorphic rat models were applied. RESULTS: Early after acute liver failure a multilineage inflammatory infiltrate was observed, mainly consisting of granulocytes. In long-term experiments small numbers of CD90+/CD45- cells of donor origin occurred in clusters associated with portal triads. Bone marrow cell infusion was not able to enhance liver regeneration. Cellular hypertrophy was the predominant way of liver mass regeneration in models applying retrorsine. CONCLUSIONS: Retrorsine pretreatment did not affect sensitivity for carbon tetrachloride. A multilineage inflammatory infiltrate was observed in rats whether pretreated with retrorsine or not. Few donor cells co-expressing CD90 (THY 1) were present in recipient livers, which may resemble donor-derived hematopoietic progenitors or oval cells. No other donor cells within liver parenchyma were detected. This is in contrast to other cell infusion models of acute cell death.