Transcriptome changes in renal allograft protocol biopsies at 3 months precede the onset of interstitial fibrosis/tubular atrophy (IF/TA) at 6 months.

BACKGROUND: Interstitial fibrosis and tubular atrophy (IF/TA) in renal transplants are the major morphological correlates of progressive graft deterioration. Early diagnosis of IF/TA is a pre-requisite for a timely therapeutic intervention in patients at risk. To evaluate events occurring before the overt onset of IF/TA, gene expression profiling of 3-month protocol biopsies from patients with IF/TA was performed in a patient group (n = 8) who developed mild IF/TA [chronic allograft nephropathy (CAN) grade I, by the Banff scoring system] in the subsequent 6-month protocol biopsy ('progressors'), and in 12 patients without IF/TA at 6 months ('non-progressors'). METHODS: RNA was extracted, labelled and hybridized to human specific genome wide DNA microarrays. Normalized data were subjected to gene-centric and pathway-centric statistical methods. RESULTS: Compared to the non-progressors, the 3-month biopsies of the progressor group showed overexpression of several genes that are important in the T- and B-cell activation and immune response. Genes involved in pro-fibrotic processes were identified in the biopsies of the progressors that preceded the observed IF/TA at 6 months. Furthermore, several genes with transporter and metabolic functions were underrepresented in the progressors in the 3-month biopsies. CONCLUSION: Gene expression profiling of early protocol biopsies identified changes in the transcriptome of grafts, which may be important for the development of IF/TA. Such early detection of transcriptome changes can facilitate the identification of patients at risk shifting the intervention time point well before the histological diagnosis of irreversible IF/TA.

Tabebuia avellanedae extracts inhibit IL-2-independent T-lymphocyte activation and proliferation.

In order to identify new, immune modulating compounds, aqueous extracts of plants pre-selected on ethno-pharmacological knowledge were screened for inhibitory effects in an anti-CD3 driven lymphocyte proliferation assay (MTT-assay). We found for the extract of the inner bark of Tabebuia avellanedae (Tabebuia) dose dependent and reproducible inhibitory effects on lymphocyte proliferation. We further analyzed Tabebuia in flow cytometry based whole blood T-cell function assays. We found that Tabebuia inhibited dose dependent ConA stimulated T-cell proliferation. Decreased T-lymphocyte proliferation was associated with dose dependent reduction of CD25 and CD71 expression on T-lymphocytes. In contrast Tabebuia exerted no effects on cytokine expression (Il-2 and TNF-alpha) by PMA/Ionomycin stimulated T-lymphocytes. Concentrations of Tabebuia used were not toxic for lymphocytes as verified by trypan blue exclusion assay. Further experiments showed that the immune inhibitory effects by Tabebuia were not mediated by its pharmacological lead compound beta-lapachone and only observed in aqueous but not in ethanol plant extracts.

Validation of immunological biomarkers for the pharmacodynamic monitoring of immunosuppressive drugs in humans.

Pharmacodynamic monitoring (PD) can evaluate the efficacy of immunosuppressive drug therapies. In this study, the expressions of PD biomarkers [lymphocyte proliferation, CD25 and CD71 expression, interleukin-2 (IL-2), and tumor necrosis factor-alpha (TNF-alpha) synthesis] were determined in whole-blood assays and were validated for their application in PD of immune modulators in future clinical trials. Initially, the assay conditions were re-evaluated. The measurement of T-lymphocyte proliferation and activation marker expression in whole-blood cultures resulted in optimized stimulation for 72 hours with 7.5 microg/mL concavalin A. Intracellular cytokine expression of CD3+ T-cells received optimized stimulation for 4 hours with 15 ng/mL phorbol 12-myristate 13-acetate and 0.75 microg/mL ionomycin. Statistical assay parameters (intra-assay, intra-individual, and interindividual variabilities) were determined. It was found that blood storage for up to 24 hours is possible without any change in biomarker expression. Dosage effects of immunosuppressive drugs (tacrolimus, cyclosporin A, sirolimus, mycophenolic acid, and methylprednisolone) were evaluated in vitro and the assay was applied successfully to dialysis, renal transplant, and liver transplant patients. We conclude that these biomarkers used in whole-blood assays are suitable for PD of immune modulators in clinical trials.

Transplantation of an eight-organ multivisceral graft in a patient with frozen abdomen after complicated Crohn's disease.

To report an extended multivisceral transplantation (MVTx) including right kidney and ascending colon in a patient with complicated Crohn's disease (CD). A 36-year old female suffering from short bowel syndrome and frozen abdomen due to fistulizing CD after multiple abdominal operations underwent MVTx of eight organs including stomach, pancreatoduodenal complex, liver, intestine, ascending colon, right kidney, right adrenal gland, and greater omentum in November 2003. Immunosuppression consisted of alemtuzumab, tacrolimus and steroids. The patient was off parenteral nutrition by postoperative wk 3. She experienced one episode of pneumonia. The patient recovered completely and discharged 2.5 mo and was doing well 30 mo after MVTx. This is one of the very rare cases in which a complete mulitivisceral graft of eight abdominal organs was transplanted orthotopically.

Long-term results of mycophenolate mofetil as part of immunosuppressive induction therapy after liver transplantation.

BACKGROUND: The addition of mycophenolate mofetil (MMF) to the induction protocol resulted in a lower incidence of rejection episodes. However, the question whether MMF should be administered in combination with tacrolimus or cyclosporine has not been answered yet. In our study, we report on the long-term results of triple induction therapy after orthotopic liver transplantation (OLT), consisting of MMF and low-dose corticosteroids, in combination with either tacrolimus or cyclosporine. METHODS: Between March 1996 and April 1997, 120 consecutive patients, who underwent OLT at our institution, were enrolled in this study. Of these patients, 80 received triple induction therapy consisting of cyclosporine and MMF (40) or tacrolimus and MMF (40), in combination with low-dose corticosteroids, whereas the remaining 40 patients served as 'MMF-free' control group receiving dual induction therapy with tacrolimus and corticosteroids. Besides the eight-yr follow-up of patient and graft survival, clinical data were also reviewed for episodes of rejection and infection. Additionally, the early post-operative pharmacokinetics of mycophenolic acid (MPA, immunological active metabolite of MMF) were evaluated. RESULTS: Long-term results provided higher patient and graft survival after tacrolimus/MMF-based induction therapy than after cyclosporine/MMF-based induction therapy. However, the tacrolimus-based control protocol yielded similar results and, therefore, no significantly superior effect was observed when MMF was added. The same observation was made for incidence of rejection and infection episodes. AUC and C(max) of MPA increased in combination with tacrolimus compared with cyclosporine. CONCLUSIONS: Although pharmacological synergy between tacrolimus and MMF was observed, MMF showed no significant beneficial effects in the immunosuppressive induction protocol, neither in combination with tacrolimus nor with cyclosporine.

Long-term follow-up after recurrence of primary biliary cirrhosis after liver transplantation in 100 patients.

Orthotopic liver transplantation (OLT) is the only effective curative therapy for end-stage primary biliary cirrhosis (PBC). Survival after OLT is excellent, although recent data have shown a recurrence rate of PBC of up to 32% after transplantation. The aim of this study is to investigate the course after disease recurrence, particularly with regard to liver function and survival in a long-term follow-up. Between April 1989 and April 2003, 1,553 liver transplantations were performed in 1,415 patients at the Charité, Virchow Clinic. Protocol liver biopsies were taken after one, three, five, seven, 10 and 13 yr. One hundred (7%) patients suffered from histologically proven PBC. Primary immunosuppression consisted of cyclosporine (n = 54) or tacrolimus (Tac) (n = 46). Immediately after OLT, all patients received ursodeoxycholic acid. Corticosteroids were withdrawn three to six months after OLT. The median age of the 85 women and 15 men was 55 yr (range 25-66 yr). The median follow-up after liver transplantation was 118 months (range 16-187 months) and after recurrence 30 months (range 4-79 months). Actuarial patient survival after five, 10 and 15 yr was 87, 84 and 82% respectively. Ten patients (10%) died after a median survival time of 32 months. Two of these patients developed organ dysfunction owing to recurrence of PBC. Histological recurrence was found in 14 patients (14%) after a median time of 61 months (range 36-122 months). Patients with Tac immunosuppression developed PBC recurrence more often (p < 0.05) and also earlier (p < 0.05). Fifty-seven patients developed an acute rejection and two patients a chronic rejection episode. Liver function did not alter within the first five yr after histologically proven PBC recurrence. Multivariate analysis of the investigated patients showed that the recipient's age and Tac immunosuppression were significant risk factors for PBC recurrence. Long-term follow-up of up to 15 yr after liver transplantation, owing to PBC, in addition to maintenance of liver function, shows excellent organ and patient survival rates. Although protocol liver biopsies revealed histological recurrence in 14 (14%) patients, only two patients developed graft dysfunction. Tac-treated patients showed more frequently and also earlier histologically proven PBC recurrence; however, in our population we could not observe an impact on graft dysfunction and patient's survival.

Extended indications in living-donor liver transplantation: bile duct cancer.

The advantages of living donor liver transplantation are an individually available graft and a tremendously reduced waiting time until transplantation. One consequence is that many centers have extended the pretransplant selection criteria, especially for potential recipients suffering from hepatocellular carcinoma. In contrast, reports on living donor liver transplantation for cholangiocarcinoma are restricted to few case reports. We have analyzed our experience with seven patients suffering from cholangiocarcinoma (Klatskin tumors, n=5; intrahepatic cholangiocarcinoma, n=2). During a median follow-up of 20 months (range 2-46 months), all patients are alive except for one posttransplant death. Four patients suffering from Klatskin tumors are alive without recurrence; both patients suffering from intrahepatic cholangiocarcinoma are alive with bone and peritoneal metastases. Living donor liver transplantation may be beneficial in selected patients suffering from Klatskin tumors, whereas caution should prevail when considering intrahepatic cholangiocarcinoma.

Indications of mycophenolate mofetil in liver transplantation.

Mycophenolate mofetil (MMF) is approved for prophylaxis of acute rejection after kidney, heart, and liver transplantation as well as for pediatric patients after kidney transplantation. MMF, a noncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH), blocks de novo purine synthesis which leads to an effective inhibition of proliferation selectively in T and B lymphocytes, smooth muscle cells, and fibroblasts. MMF shows additional effects with inhibition of the expression of activating and adhesion molecules on the surface of lymphocytes. The beneficial safety profile with distinct side effects compared to calcineurin inhibitors (CNI) enable efficacious combination with ciclosporin or tacrolimus as de novo therapy after liver transplantation. Furthermore, recent studies show the possibility to reduce CNI induced toxicities by adding MMF to primary immunosuppression. MMF is also used to enable early steroid withdrawal after liver transplantation. MMF can increase efficacy of immunosuppressive therapy and thereby support the treatment of steroid resistant acute rejections, chronic rejections and chronic graft dysfunction.

Endocrine tumours of the gastrointestinal tract. Transplantation in the management of metastatic endocrine tumours.

Patients with neuroendocrine tumours often present with synchronous liver metastases or develop hepatic metastases in the course of their disease. A complete removal of liver metastases with an intention to cure may be accomplished by liver resection or, if hepatic disease is disseminated or hormonal symptoms and pain cannot be controlled medically, by total hepatectomy and transplantation. The indications for orthotopic liver transplantation for metastatic neuroendocrine tumour disease should be anchored in a multimodal and multidisciplinary therapeutic approach. Approximately, 120-130 cases of orthotopic liver transplantation for neuroendocrine tumours have been published so far, but follow-up after transplantation has been limited, and most reports comprise a small number of patients. After considering published studies and data, some recommendations may be given, although these are based on a low level of evidence. After excluding extrahepatic tumour manifestations by imaging procedures and diagnostic laparoscopy, the indication should be chosen restrictively. Few prognostic markers, for example age below 50 years and absence of concurrent extensive surgery, were identified by multivariate analysis in a large retrospective analysis. The prognostic impact of primary tumour localisation is still controversial. However, further indicators of favourable long-term prognosis are needed. Tumour biology characterised by Ki67 and E-cadherin expression may help to identify patients with a favourable outcome so that patient selection can be improved, but this needs further evaluation in larger patient cohorts. Orthotopic liver transplantation for patients with remission of disease or stable disease under medical treatment, and orthotopic liver transplantation for palliative reasons, should be restricted to selected individual cases.

Biologics in the treatment of transplant rejection and ischemia/reperfusion injury: new applications for TNFalpha inhibitors?

Tumor necrosis factor (TNF)-alpha inhibitors have proven efficacy in various autoimmune diseases such as Crohn disease, rheumatoid arthritis, psoriasis, and ankylosing spondylitis. Indeed, some TNFalpha inhibitors have already been approved for the management of the inflammatory manifestations associated with Crohn disease and rheumatoid arthritis. These agents are increasingly used for treatment of corticosteroid-resistant graft-versus-host disease after bone marrow transplantation, and case reports have documented their efficacy in treating corticosteroid- and muromonab-resistant rejection after intestinal transplantation. Thus, the potential role of TNFalpha inhibitors in transplantation of other vascularized solid organs is worthy of investigation. Experimental evidence indicates that TNFalpha plays a key role in mediating ischemia/reperfusion (IR) injury after liver, kidney, intestine, heart, lung, and pancreas transplantation. TNFalpha was also identified as a marker cytokine during organ rejection. Single-center studies evaluating the role of TNFalpha inhibitors in kidney transplantation have been initiated but the results are not yet available. TNFalpha is known to be a contributing factor in kidney allograft rejection, and may have value in predicting the onset of steroid-resistant acute rejection after liver transplantation. Experimental and preliminary clinical data have shown that circulating levels of TNFalpha are increased during cardiac graft rejection, and indicate that TNFalpha plays a role in the pathogenesis of acute cardiac allograft rejection. Anti-TNFalpha therapy was shown to prolong cardiac allograft survival when used alone or in combination with other drugs. TNFalpha genotype has been strongly associated with mortality in humans due to acute cell-mediated heart transplant rejection. In addition, there is evidence for a genetic predisposition toward acute rejection after kidney and simultaneous kidney-pancreas transplantation. TNFalpha inhibition has been used successfully as part of an induction therapy for pancreatic islet cell transplantation. Apart from IR injury and acute rejection after lung transplantation, TNFalpha was also found to be involved in the pathoimmunology of obliterative bronchiolitis. In conclusion, a substantial body of experimental evidence and preliminary clinical data suggest that TNFalpha inhibitors may play an important role in solid-organ transplantation, both in the amelioration of IR injury and in the treatment and prevention of acute rejection. Pharmacodynamic monitoring and pharmacogenetic screening may help to identify patients most likely to benefit from TNFalpha blockade. Randomized controlled trials in patients undergoing solid-organ transplantation are needed to further elucidate the clinical value of TNFalpha inhibition.

Hepatic resection in liver transplant recipients: single center experience and review of the literature.

Biliary complications such as ischemic (type) biliary lesions frequently develop following liver transplantation, requiring costly medical and endoscopic treatment. If conservative approaches fail, re-transplantation is most often an inevitable sequel. Because of an increasing donor organ shortage and unfavorable outcomes in hepatic re-transplantation, efforts to prolong graft survival become of particular interest. From a series of 1685 liver transplants, we herein report on three patients who underwent partial hepatic graft resection for (ischemic type) biliary lesions. In all cases, left hepatectomy (Couinaud's segments II, III and IV) was performed without Pringle maneuver or mobilization of the right liver. All patients fully recovered postoperatively, but biliary leakage required surgical revision twice in one patient. At last follow-up, two patients presented alive and well. The other patient with persistent hepatic artery thrombosis (HAT), however, demonstrated progression of disease in the right liver remnant and required re-transplantation 13 months after hepatic graft resection. Including our own patients, review of the literature identified 24 adult patients who underwent hepatic graft resection. In conclusion, partial graft hepatectomy can be considered a safe and beneficial procedure in selected liver transplant recipients with anatomical limited biliary injury, thereby, preserving scarce donor organs.

Prevalence of thyroid nodules and carcinomas in patients operated on for renal hyperparathyroidism: experience with 339 consecutive patients and review of the literature.

The association between renal hyperparathyroidism (HPT) and differentiated thyroid carcinoma is discussed. To determine the prevalence and potential risk factors, we performed a retrospective analysis of our patients (1998-2004) and compared the data with the data from other surgical and autopsy studies. At our hospital, a total of 347 parathyroidectomies in 339 patients with renal HPT were performed. Most patients underwent preoperative ultrasound investigation of the thyroid gland and, if indicate, thyroid scintigraphy. Intraoperatively, both thyroid lobes were mobilized and palpated. Detected thyroid nodules were adequately resected and investigated histologically. A systematic analysis of the international literature was performed using the PubMed/MEDLINE system to identify publications on the prevalence of papillary thyroid carcinoma (PTC) in patients with renal HPT and in the overall population. Altogether, 133 patients (39.2%) underwent simultaneous thyroid surgery. The initial operation was hemithyroidectomy in 55 (16.2%), Dunhill operation in 36 (10.6%), unilateral subtotal resection in 17 (5.0%), bilateral subtotal resection in 5 (1.5%), and enucleation of a thyroid nodule in 18 (5.3%). A PTC was found in 8 of 339 patients (2.4%) and a follicular thyroid carcinoma in 1. Among 311 patients with primary cervical operation, 6 (1.9%) had a papillary thyroid carcinoma. All papillary tumors were classified as pT1 with a diameter of 1 to 12 mm; three were bifocal, and only one patient had positive lymph nodes. None of the analyzed factors showed a significant correlation with the occurrence of thyroid carcinoma. Depending on the screening method, the prevalence of occult PTC in European autopsy studies ranged from 5% to 9% and was markedly higher in almost all studies than in the present one. The prevalence of PTC in the present study makes an etiologic association between renal HPT and PTC unlikely. The clinical significance of these tumors remains unclear because all incidental tumors were small. However, if easily and safely feasible, relevant thyroid nodules should be removed during parathyroid surgery.

Coronary event rates in liver transplant recipients reflect the increased prevalence of cardiovascular risk-factors.

Increased prevalence of cardiovascular risk-factors in liver transplant recipients compared with pretransplant and standard population data has been acknowledged. The impact of risk-profiles on cardiovascular event rates or death, however, has not yet been established. Here we evaluate the development of risk-factors during a prospective follow-up of 10 years in 302 patients and compare numbers of coronary events with data from the German Prospective Cardiovascular Münster (PROCAM)-Score population. Prevalence of overweight (17% vs. 27%), hypertension (70% vs. 80%), and diabetes (21% vs. 25%) increased from early to late after transplantation, while elevated serum cholesterol (64% vs. 37%) and triglycerides (40% vs. 21%) became less frequent. Cardiovascular risk-profiles favoring tacrolimus over ciclosporin A based immunosuppression early after transplantation converged over time. Increased risk-scores in liver transplant recipients matched with score standardized event rates in the PROCAM population (ratio: 1.11, 95% CI: 0.53-2.03), nine events were predicted for the transplant population and oppose 10 events observed. Thus, indicating a reflection of increased cardiovascular risk-profiles in corresponding numbers of cardiovascular events.

Predictive value of intact parathyroid hormone measurement during surgery for renal hyperparathyroidism.

BACKGROUND AND AIMS: In contrast to that in patients with primary hyperparathyroidism, the value of intraoperative intact parathyroid hormone (iPTH) measurement is still unclear in patients with renal hyperparathyroidism and was, therefore, evaluated in a large cohort of patients. PATIENTS: Intraoperative iPTH measurement was performed in 153 patients with renal hyperparathyroidism (129 with terminal renal failure and 24 with functioning kidney graft). Subtotal and total parathyroidectomy were performed in 123 and 13 patients, respectively, during initial surgery. In patients with recurrent disease (17), the respective hyperfunctioning tissue was removed. Intraoperative blood samples were obtained by puncture of the internal jugular vein before preparation of the parathyroids (PTH0) and 15 min after parathyroidectomy (PTH15). iPTH was measured with the Elecsys 2010 system. Postoperative iPTH levels (PTH(post)) were determined at postoperative days 1 to 3 and at week 2. Patients were arbitrarily divided in four groups according to the postoperative iPTH values: 0-25 pg/ml (group 1), 26-65 pg/ml (group 2), 66-150 pg/ml (group 3) and more than 150 pg/ml (group 4). RESULTS: The mean PTH0 value was 869+/-57 pg/ml, which decreased to 167+/-15 pg/ml at PTH15. The mean relative PTH15 value was 21.6+/-1.7%. Postoperatively, iPTH decreased to 42+/-9 pg/ml. The postoperative iPTH value of the 129 patients with terminal renal failure was 25 pg/ml or less in 99 patients, 26-65 pg/ml in 11 patients, 66-150 pg/ml in eight patients and higher than 150 pg/ml in 11 patients. Two successive criteria of iPTH decrease were used: first, a PTH15 of < or =150 pg/ml or, second, a relative PTH15 of < or =30% less was used. Fifteen patients did not fulfil both criteria. In 13 of them (86.7%) iPTH(post) was higher than 65 pg (true failure to decline). Of 114 patients who fulfilled the criteria, 108 (94.7%) had normal postoperative iPTH values (true decline). Absolute PTH15 values of less than 150 pg/ml predicted normal postoperative iPTH levels in 77 of 78 patients. CONCLUSION: A PTH15 value of 150 pg/ml or less predicts operative success in patients with renal failure in 98.7% of cases, independently of the relative decay. In contrast, if the relative PTH15 is higher than 30%, high postoperative PTH values are predicted with a probability of 86.7%. Although there remain some borderline cases, intraoperative iPTH measurement is accurate and also can be useful in patients with renal hyperparathyroidism.

MMF and calcineurin taper in recurrent hepatitis C after liver transplantation: impact on histological course.

Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT) is almost universal. The optimal immunosuppression for these patients is still under discussion. We designed a retrospective case-control study to evaluate the effect of mycophenolate mofetil (MMF) treatment in patients with recurrent hepatitis C. Forty patients with histologically proven hepatitis C recurrence after OLT were treated with MMF and calcineurin inhibitor (CNI) taper for 24 months and matched with 40 non-MMF-treated positive liver transplant recipients. Liver biopsies were obtained prior to MMF treatment and after a mean follow-up of 24 months. Histological changes were evaluated utilizing the Metavir score. Comparison of fibrosis/inflammation showed no impairment of histological findings during MMF treatment. In contrast, histological findings of the 40 non-MMF patients showed a significant increase of severity for inflammation/fibrosis. Viral load was similar in both groups. The course of alanin amino transferase (ALT) levels measured during MMF treatment showed a significant decrease. MMF in combination with CNI taper showed a positive effect on fibrosis progression, graft inflammation and ALT levels and may improve the clinical course of HCV after OLT, however, the antiviral properties of MMF are still unconfirmed.

Parathyroid hormone venous sampling before reoperative surgery in renal hyperparathyroidism: comparison with noninvasive localization procedures and review of the literature.

OBJECTIVES: To analyze the predictive values of selective venous sampling (SVS) in our own experience and in a systematic meta-analysis of the international literature and to compare them with the results of noninvasive localization studies before reoperative parathyroid surgery. DATA SOURCES: Twenty-one consecutive patients with persistent or recurrent renal hyperparathyroidism underwent preoperative SVS and noninvasive imaging. These data were added to a systematic review of the literature on localization studies before reoperative surgery. The literature search included localization studies, recurrent hyperparathyroidism, and reoperation. STUDY SELECTION Prospective and retrospective studies that provided at least the true-positive rate of 1 procedure were included. Data from initial surgery, hyperfunctioning autografts, and case reports were excluded. DATA EXTRACTION: Thirty-one publications reported on SVS (n = 22), technetium Tc 99m sestamibi scintigraphy (n = 17), thallium-technetium scintigraphy (n = 11), ultrasonography (n = 18), magnetic resonance imaging (n = 12), and computed tomography (n = 13). The overall analysis was performed by dividing the overall number of true- and false-positive results by the total number of patients. DATA SYNTHESIS: Localization by SVS was correct in 20 of 21 patients. In 1 patient with 2 localizations, only 1 was predicted correctly. Therefore, the sensitivity of SVS was at least 90%, with no false-positive results. Overall true- and false-positive rates, respectively, in 31 studies were 71% and 9% for SVS, 69% and 7% for technetium Tc 99m sestamibi scintigraphy, 54% and 16% for magnetic resonance imaging, 55% and 15% for thallium-technetium scintigraphy, 50% and 18% for ultrasonography, and 45% and 14% for computed tomography. CONCLUSIONS: With its high sensitivity, SVS is the gold standard in patients with persistent or recurrent renal hyperparathyroidism and negative results of noninvasive localization procedures. The noninvasive procedure of choice is now technetium Tc 99m sestamibi scintigraphy, with high sensitivity and a low rate of false-positive results.

Motivation for living-donor liver transplantation from the donor's perspective: an in-depth qualitative research study.

BACKGROUND: There has been a lack of systematic in-depth research on the motives of living liver donors before transplantation that could contribute to an advanced understanding of their situation and to a more precise psychosocial evaluation, to protect the autonomy for decision, and to prevent psychosocial complications. METHODS: Twenty-eight living liver donors were assessed preoperatively through a semistructured clinical interview. The taped and transcribed interviews were analyzed using a combination of grounded theory and empirically grounded type construction. RESULTS: Various factors contribute to the donor's motivation for donation: the relationship to the recipient, the personal attitude of the donor, his or her personal history, family dynamics, the donor's personal profit, and the exceptional situation of the recipient's life-threatening disease combined with the life-rescuing possibility of living-donor liver transplantation (LDLT). In reference to this, five "ideal types" of living donors emerged from the authors' data. CONCLUSIONS: A complete absence of coercion on the decision to donate seems unrealistic because of the dynamics initiated by the life-threatening condition of the recipient. It is important that donors feel they are gaining something by donation to be sufficiently motivated and that their profit is of an emotional or moral nature (i.e., the donation being set in an emotionally meaningful context). A mature relationship with the recipient usually provides such a context. The role of the clinician as a part of LDLT dynamics has a decisive influence.

Sustained suppression of peripheral blood immune functions by treatment with mycophenolate mofetil correlates with reduced severity of cardiac allograft rejection.

BACKGROUND: We tested the hypothesis that sustained suppression of immune functions by mycophenolate mofetil (MMF) throughout the dosing interval reduces the severity of rejection. METHODS: Four groups of rat heart allograft recipients were treated orally daily through Day 5 with either: "low-dose" MMF, 10 mg/kg once daily (QD) or 5 mg/kg twice daily (BID); or "high-dose" MMF, 20 mg/kg QD or 10 mg/kg BID. The following were determined for all animals on Day 6: pharmacokinetics (PK, using high-performance liquid chromatography) of mycophenolic acid (MPA); pharmacodynamics (PD, by flow cytometry quantitation of whole blood mitogen-stimulated lymphocyte proliferation and expression of diverse T-cell surface activation molecules); and histologic graft rejection scores (RS). RESULTS: RS correlated with PD for suppression of both lymphocyte proliferation and transferrin receptor expression (r2 = 0.85 and 0.81, respectively) more highly than with MPA plasma levels (r2 = 0.45), which shows the validity of PD as surrogate markers of MMF efficacy. MMF 5 mg/kg BID produced greater (p < 0.001) suppression of lymphocyte proliferation (area under the PD effect-time curve, AUE = 2,010% inhibition. hour) and sustained trough (E0) PD effect (86% suppression) than MMF 10 mg/kg QD (AUE = 1,436% inhibition. hour, E0 = 55%). RS did not differ between the 20 mg/kg QD and 10 mg/kg BID "high-dose" groups, because PD was maximally suppressed. CONCLUSIONS: PD were surrogate markers for MMF immunosuppressive efficacy. MMF 5 mg/kg BID produced more sustained suppression of both PD and rejection than MMF 10 mg/kg QD.

Microscopic tumor cell dissemination in gastric cancer.

PURPOSE: There is still much controversy surrounding the prognostic significance of microscopic tumor cell dissemination in gastric cancer and its correlation with histopathologic parameters. We herein investigate such dissemination, predominantly restricted to the subserosa, in patients with gastric cancer. METHODS: Intraoperative bone marrow aspiration was done in 26 patients undergoing resection of gastric carcinoma. Peritoneal lavage could not be done in 8 of these 26 patients. The R0-resection rate was 84% (n = 22). A cytokeratin-directed antibody and an antibody directed against carcinoembryonic antigen served for the immunocytochemical detection of tumor cells, and the alkaline phosphatase antialkaline phosphatase method was used for visualization. RESULTS: The bone marrow aspirate and peritoneal lavage fluid were immunocytochemically positive in 31% and 56% of the patients, respectively. There was a trend (P = 0.10) towards higher overall survival rates in patients with negative bone marrow samples than in those with tumor cells detected in bone marrow samples. Analyzing the results of peritoneal lavage did not reveal any significant differences. In the group of T1/2 cancers, survival was significantly worse if the bone marrow was positive for tumor cells, with 3-year survival rates of 25% vs 77%, respectively (P < 0.05). CONCLUSION: The rates of tumor cell dissemination into the bone marrow or into the peritoneal cavity were within the scope of previous reports. Dissemination into the bone marrow resulted in significantly impaired survival in patients with T1 and T2 gastric carcinoma, and it did not correlate with known prognostic parameters.

Successful infliximab treatment of steroid and OKT3 refractory acute cellular rejection in two patients after intestinal transplantation.

Acute rejection resistant to established immunosuppressive rescue protocols remains the most prominent risk factor after intestinal transplantation. In two patients presenting with steroid-resistant severe acute cellular rejection 9 months and 2 years after intestinal transplantation, complete resolution was not achieved despite 5 and 10 days of OKT3 treatment, respectively, and high-dose triple baseline immunosuppression with tacrolimus, rapamycin, and steroids. There was a dissociated course of rejection with persistent moderate to severe rejection in the terminal portion of the graft despite complete recovery from rejection in the proximal parts. Both patients were treated with four subsequent infusions of infliximab (3 mg/kg body weight), a chimeric anti-tumor necrosis factor-alpha antibody. There was an immediate response regarding macroscopic appearance, graft histology, and clinical symptoms. Both patients recovered. In conclusion, infliximab has proven to be an effective rescue therapy in a selected group of patients with steroid and OKT3 refractory severe acute rejection after intestinal transplantation.