Marcus Nils Scherer

Background: Infections of the biliary tract are found frequently in pathologically or surgically altered bile ducts. Mostly these infections result from the ascent of bacteria or fungi from the small bowel, although hematogeneous infections of the biliary system may also occur. The biliary sphincter and the continuous flow of bile are thought to prevent or limit ascending infections. Obstructive alterations in the biliary system are the most frequent indication of endoscopic retrograde cholangiography (ERC). The aim of this study was to analyze the spectrum and frequency of microbes within the bile, and discover the influence of earlier sphincterotomy. Methods: In our department, we routinely aspirate bile for microbiologic culture during ERC. For this study, all ERC performed in 2014–2018 were retrospectively analyzed, including all microbiological reports. Indications for the endoscopic examination were also recorded. In addition, the findings were correlated with whether or not a sphincterotomy had been previously performed, and whether or not there had been antibiotic treatment prior to the examination. Results: A total of 2253 successful standard ERC procedures were performed between 2014 and 2016. In 486 cases, bile was aspirated and sent for microbiologic culture. In total, 1220 bile samples were analyzed, and bacteria or fungi were found in 1029 (86.0%). Enterococci and Enterobacter were found most commonly, but E. coli, streptococci, klebsiella, and staphylococci were also found. In 11.2% of positive cultures, multiresistant pathogens were identified. In up to 29% Candida spp., most commonly, Candida albicans (68%) were also found, either alone or in conjunction with bacteria. Neither prior sphincterotomy nor the use of peri-interventional antibiotics had a major influence on the frequency with which positive bile cultures were detected. Conclusions: Aspiration of bile during ERC is of high clinical relevance, because microbiological analysis reveals the frequent presence of bacteria and fungi, knowledge of which may be useful for deciding on anti-infective treatment.

Liver transplantation (LTx) is often the only possible therapy for many end-stage liver diseases, but successful long-term transplant outcomes are limited by multiple factors, including ischemia reperfusion injury (IRI). This situation is aggravated by a shortage of transplantable organs, thus encouraging the use of inferior quality organs. Here, we have investigated early hepatic IRI in a retrospective, exploratory, monocentric case-control study considering organ marginality. We analyzed standard LTx biopsies from 46 patients taken at the end of cold organ preparation and two hours after reperfusion, and we showed that early IRI was present after two hours in 63% of cases. Looking at our data in general, in accordance with Eurotransplant criteria, a marginal transplant was allocated at our institution in about 54% of cases. We found that patients with a marginal-organ LTx showing evidence of IRI had a significantly worse one-year survival rate (51% vs. 75%). As we saw in our study cohort, the marginality of these livers was almost entirely due to steatosis. In contrast, survival rates in patients receiving a non-marginal transplant were not influenced by the presence or absence of IRI. Poorer outcomes in marginal organs prompted us to examine pre- and post-reperfusion biopsies, and it was revealed that transplants with IRI demonstrated significantly greater T cell infiltration. Molecular analyses showed that higher mRNA expression levels of CXCL-1, CD3 and TCRγ locus genes were found in IRI livers. We therefore conclude that the marginality of an organ, namely steatosis, exacerbates early IRI by enhancing effector immune cell infiltration. Preemptive strategies targeting immune pathways could increase the safety of using marginal organs for LTx.

Therapy-refractory persistent hypoparathyroidism after extensive neck surgery is a rare but severe complication. Parathyroid allotransplantation may represent a definitive treatment option. A 32-year old female was referred to our hospital with intractable persistent hypocalcemia after neck surgery for papillary thyroid cancer. Despite optimal medical treatment including calcium and vitamin D supplementation and even hormonal replacement therapy hypocalcemic symptoms failed to improve. The quality of life was considered very low. In light of the unsuccessful medical therapy and the young age of the patient parathyroid allotransplantation seemed an attractive treatment option to restore normal calcium homeostasis despite of the need for immunosuppressive therapy after the procedure. Therefore, we performed living-donor allotransplantation of two healthy parathyroid glands to the recipient’s left forearm. The surgical intervention was successful. Neither the donor nor the recipient showed any complications. In the postoperative course clinical symptoms of hypocalcemia significantly improved whereas serum calcium and parathyroid hormone (PTH) levels progressively increased into the normal range. Former intense replacement therapy could be discontinued completely in a stepwise fashion. To date, nearly three years after transplantation, the patient remains asymptomatic with normal serum levels of calcium and PTH. Successful living-donor parathyroid allotransplantation for postsurgical hypoparathyroidism represents an innovative therapeutic strategy that could provide the definitive treatment in those patients in which the disease is therapy-refractory. The procedure can be justified even in nontransplant recipients. Retrieval of parathyroid glands from healthy donors is feasible and safe.

Background: Critical organ shortage results in the utilization of extended donor criteria (EDC) liver grafts. These marginal liver grafts are prone to increased ischemia reperfusion injury (IRI) which may contribute to deteriorated graft function and survival. Experimental data have shown that the calcineurin inhibitor tacrolimus exerts protective effects on hepatic IRI when applied intravenously or directly as a hepatic rinse. Therefore, the aim of the present study is to examine the effects of an ex vivo tacrolimus perfusion on IRI in transplantation of EDC liver grafts. Methods/Design: The TOP-Study (tacrolimus organ perfusion) is a randomized multicenter trial comparing the ex vivo tacrolimus perfusion of marginal liver grafts with placebo. We hypothesize that a tacrolimus rinse reduces IRI, potentially improving organ survival following transplantation of EDC livers. The study includes livers with two or more EDC, according to Eurotransplant International Foundation’s definition of EDC livers. Prior to implantation, livers randomized to the treatment group are rinsed with tacrolimus at a concentration of 20 ng/ml in 1000 ml Custodiol solution and in the placebo group with Custodiol alone. The primary endpoint is the maximum serum alanine transamninase (ALT) level within the first 48 hours after surgery; however, the study design also includes a 1-year observation period following transplantation. The TOP-Study is an investigator-initiated trial sponsored by the University of Munich Hospital. Seven other German transplant centers are participating (Berlin, Frankfurt, Heidelberg, Mainz, Münster, Regensburg, Tübingen) and aim to include a total of 86 patients. Discussion: Tacrolimus organ perfusion represents a promising strategy to reduce hepatic IRI following the transplantation of marginal liver grafts. This treatment may help to improve the function of EDC grafts and therefore safely expand the donor pool in light of critical organ shortage. Trial register: EudraCT number: 2010-021333-31, ClinicalTrials.gov identifier: NCT01564095

Background: Cellular therapy after organ transplantation is emerging as an intriguing strategy to achieve dose reduction of classical immunosuppressive pharmacotherapy. Here, we introduce a new scoring system to assess treatment-emergent adverse events (TEAEs) of adherent stem cell therapies in the clinical setting of allogeneic liver transplantation (for example, the MiSOT-I trial Eudract CT: 2009-017795-25). Methods: The score consists of three independent modalities (set of parameters) that focus on clinically relevant events early after intravenous or intraportal stem cell infusion: pulmonary toxicity, intraportal-infusional toxicity and systemic toxicity. For each modality, values between 0 (no TEAE) and 3 (severe TEAE) were defined. The score was validated retrospectively on a cohort of n=187 recipients of liver allografts not receiving investigational cell therapy between July 2004 and December 2010. These patients represent a control population for further trials. Score values were calculated for days 1, 4, and 10 after liver transplantation. Results: Grade 3 events were most commonly related to the pulmonary system (3.5% of study cohort on day 4). Almost no systemic-related TEAEs were observed during the study period. The relative frequency of grade 3 events never exceeded 5% over all modalities and time points. A subgroup analysis for grade 3 patients provided no descriptors associated with severe TEAEs. Conclusion: The MiSOT-I score provides an assessment tool to score specific adverse events that may occur after adherent stem cell therapy in the clinical setting of organ transplantation and is thus a helpful tool to conduct a safety study.

Background: Most patients with high MELD scores have impaired renal function prior to transplantation. Patient and Methods: A retrospective case control study was conducted with initial low immunosuppression, which was increased when patients rejected or were clinically stable beyond day 30 (‘bottom-up’). Results: Thirty patients with impaired renal function were included. Fifteen were treated with de novo cyclosporine A (CsA; group A), and 15 had ‘bottom-up’ immunosuppression (group B). Baseline renal function was similar: serum creatinine (SCr) median 1.8 mg/dl (range: 1.5–4.0 mg/dl; group A) versus 2.4 mg/dl (range: 1.5–4.0 mg/dl; group B; p = 0.24). The requirement for renal replacement therapy was significantly lower in group B (p = 0.032). Ten received ‘bottom-up’ immunosuppression [4 CsA/1 sirolimus (Sir) ‘on demand’ after rejection, 5 Sir (stable)] beyond day 30. By months 6 and 12 (1.6 mg/dl vs. 1.2 mg/dl), SCr values were significantly better in group B (p = 0.006). Renal function in group B did not differ between patients receiving CsA or Sir. Overall complication rates, survival and biopsy-proven acute rejection were similar, although BANFF scores were higher in group B (p = 0.004). Conclusion: Successful implementation of ‘bottom-up’ immunosuppression in liver transplant recipients with high lab-MELD scores and renal dysfunction at the time of transplantation has the potential to substantially improve short- and long-term outcomes.