Budde, K; Nolting, J; Glander, P; Gauer, N; Naik, M; Sefrin, A; Mai, M; Klupp, J; Neumayer, H- H.; Reinke, P Author Information

Background: T-cell activation markers in peripheral blood are helpful to detect acute rejection in liver transplantation (LTX) patients with immunosuppression by Cyclosporin A or Tacrolimus. Immunosuppression including basiliximab may influence the diagnostic value of T-cell markers.Methods: In the present study, 80 LTX patients receiving immunosuppressive treatment based on induction with basiliximab were monitored as well as clinical examination with conventional (liver enzymes, cholesterol, bilirubin, prothrombin time, leukocyte count and differentiation) and immunologic markers [soluble interleukin (IL)-2 receptor, IL-8, lymphocyte subpopulations] during the first 3 weeks after transplantation. In total, 15 patients suffered from acute rejection, 34 patients had no complications, and 31 patients suffered from other complications including infections, poor graft function or renal failure.Results: Cholesterol, prothrombin time and CD3+/CD4-/CD8- lymphocytes allowed for discrimination between the group with acute rejection and patients suffering from other complications. Furthermore, significant time-dependent changes between both groups were found for alanine amino transferase (ALT), soluble IL-2 receptor (slL-2R), eosinophils, lymphocytes and CD3+/CD4-/CD8- lymphocytes. In contrast, receiver operating characteristic (ROC) curve analysis for diagnostic relevance revealed only a Youden index > 0.5 for prothrombin. When combining cholesterol, lymphocyte count, sIL-2R and time courses of ALT, eosinophils and sIL-2R, diagnostic efficacy could be maximized to a Youden index of 1.0.Conclusion: Despite significant differences between several single parameters, diagnostic application of the laboratory results requires a combination of a broad panel including the analysis of time courses to distinguish groups suffering from acute rejection or other complications. The complexity of this approach may limit its application in clinical practice.

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.

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.

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.

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.

Tumor necrosis factor (TNF)-α inhibitors have proven efficacy in various autoimmune diseases such as Crohn disease, rheumatoid arthritis, psoriasis, and ankylosing spondylitis. Indeed, some TNFα 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 TNFα inhibitors in transplantation of other vascularized solid organs is worthy of investigation.

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.

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 becauses all incidental tumors were small. However, if easily and safely feasible, relevant thyroid nodules should be removed during parathyroid surgery.

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.

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.