Abstract: Objective: To evaluate a new 2-step technique for obtaining adequate but short-term parenchymal hypertrophy in oncologic patients requiring extended right hepatic resection with limited functional reserve.
Background: Patients presenting with primary or metastatic liver tumors often face the dilemma that the remaining liver tissue may not be sufficient. Preoperative portal vein embolization has thus far been established as the standard procedure for achieving resectability.
Methods: Two-staged hepatectomy was performed in patients who preoperatively appeared to be marginally resectable but had a tumor-free left lateral lobe. Marginal respectability was defined as a left lateral lobe to body weight ratio of less than 0.5. In the first step, surgical exploration, right portal vein ligation (PVL), and in situ splitting (ISS) of the liver parenchyma along the falciform ligament were performed. Computed tomographic volumetry was performed before ISS and before completion surgery.
Results: The study included 25 patients with primary liver tumors (hepatocellular carcinoma: n = 3, intrahepatic cholangiocarcinoma: n = 2, extrahepatic cholangiocarcinoma: n = 2, malignant epithelioid hemangioendothelioma: n = 1, gallbladder cancer: n = 1 or metastatic disease [colorectal liver metastasis]: n = 14, ovarian cancer: n = 1, gastric cancer: n = 1). Preoperative CT volumetry of the left lateral lobe showed 310 mL in median (range = 197â444 mL). After a median waiting period of 9 days (range = 5â28 days), the volume of the left lateral lobe had increased to 536 mL (range = 273â881 mL), representing a median volume increase of 74% (range = 21%â192%) (P < 0.001). The median left lateral liver lobe to body weight ratio was increased from 0.38% (range = 0.25%â0.49%) to 0.61% (range = 0.35â0.95). Ten of 25 patients (40%) required biliary reconstruction with hepaticojejunostomy. Rapid perioperative recovery was reflected by normalization of International normalized ratio (INR) (80% of patients), creatinine (84% of patients), nearly normal bilirubin (56% of patients), and albumin (64% of patients) values by day 14 after completion surgery. Perioperative morbidity was classified according to the Dindo-Clavien classification of surgical complications: grade I (12 events), grade II (13 events), grade III (14 events, III a: 6 events, III b: 8 events), grade IV (8 events, IV a: 3 events, IV b: 5 events), and grade V (3 events). Sixteen patients (68%) experienced perioperative complications. Follow-up was 180 days in median (range: 60â776 days) with an estimated overall survival of 86% at 6 months after resection.
Conclusions: Two-step hepatic resection performing surgical exploration, PVL, and ISS results in a marked and rapid hypertrophy of functional liver tissue and enables curative resection of marginally resectable liver tumors or metastases in patients that might otherwise be regarded as palliative.
Abstract: BACKGROUND
Primary hepatic carcinoid tumors (PHCT) are rare entities; they are even rarer than extrahepatic neuroendocrine gastrointestinal tumors with only about 95 cases reported in the literature. An extrahepatic primary tumor must be excluded to confirm the diagnosis of PHCT.
CASE PRESENTATION
We report a case of a 42-year-old male patient with a primary hepatic neuroendocrine carcinoma, who successfully underwent living donor liver transplantation from his 70 years old mother with 10 years follow-up. Both donor and recipient are still alive and in the good health.
CONCLUSION
Living liver donation from elderly donors for the patients with irresectable neuroendocrine liver malignancies can be as safe as deceased donation or liver donation from young donors (age < 50). Living donation from elderly donors might significantly expand the donor pool for patients with liver neuroendocrine tumors (NET) and potentially reduce waiting list mortality. Especially young patients with irresectable NET can benefit from this option. However, caseâcontrol studies are needed to verify the advantage of living liver transplantation (LDLT) for the patients with irresectable liver NET and to define selection criteria for these patients.
Abstract: Interleukin 2 receptor antagonists (IL-2Ra) are frequently used as induction therapy in liver transplant recipients to decrease the risk of acute rejection while allowing the reduction of concomitant immunosuppression. We conducted a systematic review of prospective, controlled studies to test the hypothesis that the use of IL-2Ra is associated with a decrease in acute rejection and/or a decrease in the side-effects of concomitant medication. We performed a search of all major databases and secondary sources from inception to December 2010. Random effects models were used to assess the incidence of acute rejection, graft loss, patient death and adverse side-effects, with or without IL-2Ra. Subgroup analysis and meta-regression were used to explore differences in effect and sources of heterogeneity. Eighteen studies (13 randomized and 5 non-randomized) met the inclusion and exclusion criteria. Acute rejection at 12 months or later favored the use of IL-2Ra (relative risk (RR) 0.83; 95%-confidence interval (CI) 0.76 to 0.94) and steroid-resistant rejection was also less frequent in patients receiving IL-2Ra (RR 0.66; CI 0.48 to 0.91). Graft loss and patient death did not differ significantly between treatments. Patients who received IL-2Ra in addition to reduced or delayed calcineurin inhibitors (CNI) had better renal function (mean difference of estimated glomerular filtration rate: 6.29 mL/min; CI 1.66 to 10.91) and a lower incidence of renal dysfunction (RR 0.46; CI 0.27 to 0.78). The use of IL-2Ra was also associated with a lower incidence of post-transplant diabetes mellitus, whereas the incidence of other adverse events was similar. Conclusion: The use of IL-2Ra is associated with a lower incidence of acute rejection after transplantation. Concomitant immunosuppression can be reduced, avoiding long-term side-effects of immunosuppression.
Abstract: Purpose
A common and serious problem after living donor liver transplantation (LDLT) of small grafts is small-for-size syndrome (SFSS). Although hyperdynamic portal inflow and portal hypertension are cornerstones in the development of SFSS, inadequate outflow may aggravate SFSS. Therefore, enlargement of the portal outflow tract by incision of the anterior rim of the orifice of the right hepatic vein (RHV) has been advocated for right lobe LDLT. But backwards tilt of a small graft into a large abdominal cavity may lead to a choking of the otherwise large anastomosis and thus we propose posterior enlargement of the orifice of the RHV.
Method
In this test-of-concept study, we evaluated portal vein pressure (PVP), clinical parameters, and laboratory measurements in 22 patients that underwent right lobe LDLT and either received standard end-to-end anastomosis of the RHV or posterior cavoplasty.
Results
In patients that underwent posterior cavoplasty, we observed significantly lower PVP and less hyperbilirubinemia. There was a non-significant trend to lower incidence of SFSS. Other laboratory measurements and clinical parameters were not significantly different.
Conclusion
We recommend posterior cavoplasty for enlargement of the hepatic venous outflow tract in right lobe LDLT as a method to avoid portal hypertension, hyperbilirubinemia, and possibly SFSS, especially in patients that receive small grafts.
Abstract: Patients with chronic liver disease are at high risk for severe infection due to increased bacterial translocation and immune suppression associated with liver dysfunction. Patients presenting with severe pneumonia and acute decompensation of cirrhosis are generally not considered for liver transplantation because it is unknown if these patients can recover from infection while under immunosuppression.
We performed an observational study where patients with cirrhosis of the liver remained on the waiting list although suffering from active pneumonia.
Nine patients were included, but only six patients improved under goal-directed therapy and subsequently underwent liver transplantation. All six patients recovered quickly from infection; five patients recovered without sequalae, and one patient died due to late complications.
We propose that in patients with chronic liver disease and active pneumonia transplantation is a treatment option that should not hastily be abandoned.
Abstract: Aim of this study was to collect information about oral health of patients before and after SOT as well as information about center-based recommendations for dental care. In a single center cross-sectional study, the oral situation of 20 patients before and 20 after SOT were examined including dental (DMF-T), periodontal (PSR(®) /PSI), and oral hygiene findings (modified QHI). In a second project, a survey among 50 transplant centers in Germany was questioned regarding their recommendations for dental care of SOT recipients. Patients before and after SOT showed similar quality of dental findings (DMF-T), but worse compared to the general population. In addition, most patients in both groups showed pronounced periodontal treatment need (PSR(®) /PSI score 3 or 4). Oral hygiene findings (modified QHI) after SOT were significantly worse than in patients on the waiting list (Pâ=â0.032). In a second project, the questionnaire was returned by 28 of 50 centers. Interpretation of data showed that 89% carry out a dental examination before SOT and 67% contacted the patients' dentists. After SOT, 83% of the transplant centers recommend antibiotic cover before dental measures. The results of our study revealed lacks in the dental care of SOT recipients. Consistent recommendations regarding the dental care of patients before and after SOT should be determined.
Abstract: Background and Aims: The standard treatment regimen for chronic HCV genotype 3 (HCV-G3) hepatitis consists of PEGylated interferon-α (IFN-α) and ribavirin at varying doses ranging from 400 to 1,200 mg and results in response rates of 80%. However, this therapy has substantial side-effects including anemia, is teratogenic, and costly. To reduce the side-effects of therapy, the role of monotherapy consisting of only IFN-α was investigated.
Methods: A retrospective analysis of individual therapy courses of HCV-G3-infected patients who were treated with IFN-α2a monotherapy or a combination therapy with attention to the treatment outcome and the presence of IL28B rs12979860 and IL28B rs8099917 single-nucleotide polymorphism genotypes was performed. Conventional prognostic features in each case were assessed as well.
Results: In the study, 15/30 (50%) of patients treated with IFN-α2a monotherapy and 32/36 (89%) treated with combination therapy achieved a sustained virological response (SVR). In addition, 7/11 (64%) of those treated initially with monotherapy and subsequently with combination therapy achieved an SVR. An âultra-rapidâ virological response occurring within 2 weeks of initiation of therapy (p = 0.005), young age (<40; p < 0.001) and low initial γ-GT/ALT-ratio (p = 0.03) were associated with a SVR to IFN-α2a monotherapy. An SVR in those treated with combination therapy was found to be associated with a rapid virological response (RVR) (p = 0.03). The absence of histologic steatosis was associated with SVR in all patient groups (p = 0.01). Therapy duration (24 vs. 48 weeks) did not affect the SVR in either group. As expected, combination therapy resulted in more hematological side-effects than did monotherapy.
Conclusions: An âultra-rapidâ virological response, young age, low initial γ-GT/ALT-ratio and absence of steatosis were each associated with an SVR in those receiving IFN-α2a monotherapy. Therefore, monotherapy in these patients should still be discussed independently of the existence of the IL28B polymorphisms.
Abstract: Background/purpose:
For living-donor liver transplantation (LDLT) it is of paramount importance to preserve as much viable liver tissue as possible to avoid postoperative complications in the donor and recipient. The depth of tissue damage caused by common surgical techniques for liver resection has not been studied so far.
Methods:
Here we compared the depth of tissue damage and the immunohistochemical expression of heat shock protein (HSP) 70, a marker for tissue damage, in a porcine model of liver resection, to assess the effect of different surgical techniques, i.e., blunt dissection (BD), and dissection with an ultrasound aspirator (UA), an ultrasound scalpel (US), or a water-jet (WJ).
Results:
Analysis with linear mixed effects models (LME) showed significantly less tissue damage with BD and UA than with US and WJ (joint p value <0.001). Damage also increased within 6 h after surgery (p value = 0.004). Semiquantitative evaluation of HSP 70 showed increased expression after resection with US compared to all other resection methods (p value <0.001), indicating increased tissue damage with this method.
Conclusion:
We suggest that in cases of liver resection for LDLT surgeons should reevaluate using US and WJ because of possible excessive tissue damage compared to BD and UA. Overall we advocate the use of BD as it requires no special equipment and, hence, has considerably higher cost-effectiveness without compromising tissue preservation and clinical outcome and is readily available even in low-tech environments.
Abstract: We report on the successful regrafting of a transplanted kidney. The donor kidney was first transplanted into a 32-year-old patient with renal atrophy. More than 2 years later, he suffered from severe grand mal seizure with brain edema and the patient met the criteria for brain death. The well-functioning graft was recovered and subsequently transplanted into a 66-year-old woman with chronic glomerular nephritis. Neither the first nor the second recipient experienced any acute rejection. To date, more than 14 years later, she is in good health with excellent graft function. This case report implies that excellent long-term graft function is viable in a graft reused 2 years after the initial transplantation.
Abstract: In the article of Spriestersbach et al., it was stated that, in contrast to the box, the definition of the so-called âwhiskersâ in the box plot diagram is not uniform.
A diagram designated as a âbox and whiskers plotâ was first described by Tukey in 1977. In this plot, the whiskers extended to the greatest or to the smallest values within a limit, the so-called âinner fenceâ.
The width of the âinner fenceâ is defined as one and a half times the interquartile distance. An additional âouter fenceâ extends to three times the interquartile distance. Measured values outside these limits may be outliers and are designated with special symbols.
A similar diagram had already been described in 1952 by Spear and designated as a ârange barâ. This diagram corresponds to the description in the text.
On the other hand, Altman set the ends of the whiskers at the 2.5% and 97.5% quantiles. The box plot provided by statistics programs is likewise non-uniform. Whereas SAS presents the range bar as standard and only provides the original box and whiskers plot as an option, many other programs (S Plus, R, SPSS, Mathematica) use Tukeyâs algorithm as standard.
Abstract: Background
Hepatic artery thrombosis is a devastating complication after orthotopic liver transplantation often requiring revascularization or re-transplantation. It is associated with considerably increased morbidity and mortality. Acute cognitive dysfunction such as delirium or acute psychosis may occur after major surgery and may be associated with the advent of surgical complications.
Case presentation
Here we describe a case of hepatic artery thrombosis after living-donor liver transplantation which was not preceded by signs of liver failure but rather by an episode of acute psychosis. After re-transplantation the patient recovered without sequelae.
Conclusion
This case highlights the need to remain cautious when psychiatric disorders occur in patients after liver transplantation. The diagnostic procedures should not be restricted to medical or neurological causes of psychosis alone but should also focus vascular complications related to orthotopic liver transplantation.
Abstract: Background: Immunosuppression with calcineurin inhibitors (CNI) increases the risk of renal dysfunction after orthotopic liver transplantation (OLT). Controlled trials have shown improvement of renal function in patients that received delayed and/or reduced-dose CNI after OLT. Delaying immunosuppression with CNI in combination with induction therapy does not increase the risk of acute rejection but reduces the incidence of acute renal dysfunction. Based on this clinical data this study protocol was designed to assess the efficacy and safety of calcineurin-inhibitor-free de-novo immunosuppression after liver transplantation. Methods / Design: A prospective therapeutic exploratory, non-placebo controlled, two stage monocenter trial in a total of 29 liver transplant patients was designed to assess the safety and efficacy of de-novo CNI-free immunosuppression with basiliximab, mycophenolate sodium, prednisolone and everolimus. The primary endpoint is the rate of steroid resistant rejections. Secondary endpoints are the incidence of acute rejection, kidney function (assessed by incidence and duration of renal replacement therapy, incidence of chronic renal failure, and measurement glomerular filtration rate), liver allograft function (assessed by measurement of AST, ALT, total bilirubin, AP, GGT), treatment failure, (i. e., re-introduction of CNI), incidence of adverse events, and mortality up to one year after OLT.
Discussion: This prospective, two-stage, single-group pilot study represents an intermediate element of the research chain. If the data of the phase I I study corroborates safety of de-novo CNI-free immunosuppressive regimen this should be confirmed in a randomized, prospective, controlled double-blinded clinical trial. The exploratory data from this trial may then also facilitate the design (e. g. sample size calculation) of this phase III trial. Trial registration number: NCT00890253 (clinicaltrials.gov)
Abstract: Adult living donor liver transplantations (ALDLTs) across the ABO blood group barrier have been reported in Asia, North Americas, and Europe, but not yet in Germany. Several strategies have been established to overcome the detrimental effects that are attached with such a disparity between donor and host, but no gold standard has yet emerged. Here, we present the first experiences with three ABO-incompatible adult living donor liver transplantations in Germany applying different immunosuppressive strategies. Four patient-donor couples were considered for ABO-incompatible ALDLT. In these patients, resident ABO blood group antibodies (isoagglutinins) were depleted by plasmapheresis or immunoadsorption and replenishment was inhibited by splenectomy and/or B-cell-targeted immunosuppression. Despite different treatments ALDLT could safely be performed in three patients and all patients had good initial graft function without signs for antibody-mediated rejection (AMR). Two patients had long-term graft survival with stable graft function. We thus propose the feasibility of ABO-incompatible ALDLT with these protocols and advocate further expansion of ABO incompatible ALDLT in multicenter trials to improve efficacy and safety.
Abstract: BACKGROUND AND AIMS: Patients with bilobular colorectal liver metastases (CRLM) experience poor prognosis, especially when curative resection cannot be achieved. However, resectability in these patients is often limited by low future remnant liver volume (FRLV). The latter can be enhanced by a two-stage liver resection, using portal vein ligation to induce liver hypertrophy. The aim of this prospective pilot study was to evaluate safety, secondary resectability, and time to recurrence of two-stage hepatectomy with portal vein ligation (PVL) and complete surgical clearance of the FRLV in patients with bilobular CRLM. MATERIALS AND METHODS: Out of 24 patients (63 +/- 8.26 years) with extended bilobular CRLM (metachronous n = 10, synchronous n = 14), 18 received preoperative 5-FU-based chemotherapy combined with oxaliplatin or irinotecan. Staging included thoracoabdominal computed tomography and (18)F-fluorodeoxyglucose-positron emission tomography scans. First-stage procedure consisted of PVL, resection of all CRLM in the FRLV, and radiofrequency ablation (RFA) of CRLM situated near the future resection plane. RESULTS: During first-stage procedure, 7x RFA, 4x non-anatomical resections, and 4x bisegmentectomies were performed additionally to PVL. FRLV/body-weight ratio increased from 0.4% to 0.6% within 55 days (median) after PVL. Second-stage hepatectomy was performed in 19 patients without tumor progression. R0 resection was possible in 14 patients. During a median follow-up of 17 months, intrahepatic recurrence occurred in two, and extrahepatic recurrence in nine out of 14 patients. CONCLUSION: Two-stage hepatectomy with PVL and complete surgical clearance of FRLV is safe even after intensified systemic chemotherapy resulting in a curative resection rate of 58.3% (73.7% of re-explored cases).
Abstract: With regard to living-donor liver transplantation, it should be added that blood-group compatibility of the donor and the recipient, though always desirable, is not an absolute sine qua non. There have been many reports, mainly from Asia, of living-donor liver transplantation where the donor and the recipient had different blood types.
In the Göttingen Transplantation Center, three AB0-incompatible living-donor liver transplantations have been performed to date (report submitted for publication).
The data from Asia show a higher rate of biliary and vascular complications after such procedures, resulting in a lower rate of transplant survival. Under favorable conditions, however, a three-year patient survival of 70% can be achieved in adults, and 85% in children.
Intensive interdisciplinary collaboration and preparation of the recipient are essential for an optimal result of transplantation. Generally speaking, a special immunosuppression regimen is necessary, as well as a reduction of the serum titers of blood-group specific antibodies in the recipient. This can be achieved by plasmapheresis or by immunoadsorption.
Because of the lower rates of transplant and patient survival associated with AB0-incompatible living-donor liver transplantation, it remains a treatment option to be pursued only in individual cases in the face of the persisting donor shortage.
The recent, promising advances in immune suppression and the ever-improving safety of liver donation surgery nonetheless justify the use of AB0-incompatible living-donor liver transplantation as a treatment option of last resort.
Abstract: The synaptic long-term potentiation between primary afferent C-fibers and spinal lamina I projection neurons is a cellular model for hyperalgesia [Ikeda H, Heinke B, Ruscheweyh R, Sandkuhler J (2003) Synaptic plasticity in spinal lamina I projection neurons that mediate hyperalgesia. Science 299:1237-1240]. In lamina I neurons with a projection to the periaqueductal gray, this long-term potentiation is dependent on nitric oxide. In the present study, we used immunohistochemistry to detect possible sources and sites of action of the nitric oxide necessary for the long-term potentiation at lamina I spino-periaqueductal gray neurons in rats. None of the three isoforms of the nitric oxide synthase was expressed in a significant number of lamina I spino-periaqueductal gray neurons or primary afferent C-fibers (as evaluated by staining of their cell bodies in the dorsal root ganglia). However, endothelial and inducible nitric oxide synthase were found throughout the spinal cord vasculature and neuronal nitric oxide synthase was present in a number of neurons in laminae II and III. The nitric oxide target soluble guanylyl cyclase was detected in most lamina I spino-periaqueductal gray neurons and in approximately 12% of the dorsal root ganglion neurons, all of them nociceptive as evaluated by coexpression of substance P. Synthesis of cyclic 3â,5â-guanosine monophosphate upon stimulation by a nitric oxide donor confirmed the presence of active guanylyl cyclase in at least a portion of the spino-periaqueductal gray neuronal cell bodies. We therefore propose that nitric oxide generated in neighboring neurons or blood vessels acts on the spino-periaqueductal gray neuron and/or the primary afferent C-fiber to enable long-term potentiation. Lamina I spino-parabrachial neurons were stained for comparison and yielded similar results.
Abstract: Introduction: Acute renal dysfunction has been observed in up to 50% of all patients after orthotopic liver transplantation (OLT). More than 90% of patients receive calcineurin inhibitors (CNI) for immunosuppression after OLT, and nephrotoxicity of CNI contributes to renal impairment. Early renal dysfunction significantly increases the risk of chronic renal failure and subsequently the risk of premature death. Multiple trials investigated the effect of delayed CNI and reduced-dose CNI regimens or early withdrawal of CNI. Generally, avoidance of CNIs improves kidney function and does not result in higher rate of rejection when an adequate level of immunosuppression is maintained, e. g. by use of alternative, non-nephrotoxic agents such as mTOR- inhibitors and mycophenolate, or concomitant interleukin-2 receptor blockade by induction with anti- CD25 antibodies. Methods: Based on the aforementioned data we conducted a prospective, non-controlled, test-of-concept study to evaluate the efficacy and safety of CNI-free de-novo immunosuppression after OLT. Here we report the interim analysis after the allocation of 9 patients. All patients transplanted within the same time frame but not allocated to this study because of not fulfilling the inclusion or exclusion criteria served as control group. Results: Nine patients were allocated to the study group and were compared to 61 patients in the control group; three patients were excluded because they received combined kidney-liver transplant or no measurements could be obtained. We did not observe any rejection in the study group. Furthermore the safety profile was comparable except for a higher incidence of wound healing disturbances in the study group. Liver function tests were not significantly different but patients in the study group had a significantly better recovery of kidney function. Conclusion: This interim analysis shows that the new therapeutic regimen has an acceptable safety profile. Furthermore there are indications for an improvement of kidney function in patients with hepatorenal syndrome. We will continue with the ongoing study until the allocation of 29 patients as planned.
Abstract: Patients with chronic liver failure are at high risk of acute decompensation and severe infection due to immune depression. But patients presenting with acute on chronic liver failure (ACLF) and severe infection are commonly not considered for orthotopic liver transplantation (OLT) because of the need immunosuppression after OLT although their chances to receive an organ in the model-for-end-stage-liver-transplantation (MELD) allocation system will never be higher than in this situation.
We defined appropriate selection criteria for patients with severe infection to possibly undergo liver transplantation. Within 9 months we prospectively identified four patients with ACLF and severe life threatening infection. They were listed for OLT because they fulfilled our selection criteria, they had high MELD score, and because of the associated risk of death without OLT. After aggressive multimodal anti-infection and supportive therapy, OLT was performed and all three patients recovered quickly from infection due to reconstitution of liver function. We therefore propose that in patients with ACLF and severe infection it is time for action.
Abstract: Introduction: Acute renal dysfunction has been observed in up to 50% of all patients after orthotopic liver transplantation (OLT). More than 90% of patients receive calcineurin inhibitors (CNI) for immunosuppression after OLT, and nephrotoxicity of CNI contributes to renal impairment. Early renal dysfunction significantly increases the risk of chronic renal failure and subsequently the risk of premature death. Multiple trials investigated the effect of delayed CNI and reduced-dose CNI regimens or early withdrawal of CNI. Generally, avoidance of CNIs improves kidney function and does not result in higher rate of rejection when an adequate level of immunosuppression is maintained, e. g. by use of alternative, non-nephrotoxic agents such as mTOR- inhibitors and mycophenolate, or concomitant interleukin-2 receptor blockade by induction with anti- CD25 antibodies.
Methods: Based on the aforementioned data we conducted a prospective, non-controlled, test-of-concept study to evaluate the efficacy and safety of CNI-free de-novo immunosuppression after OLT. Here we report the interim analysis after the allocation of nine patients. All patients transplanted within the same time frame but not allocated to this study because of not fulfilling the inclusion or exclusion criteria served as control group.
Results: Nine patients were allocated to the study group and were compared to 61 patients in the control group; three patients were excluded because they received combined kidney-liver transplant or no measurements could be obtained. We did observe one rejection in the study group. Furthermore the safety profile was comparable except for a higher incidence of wound healing disturbances in the study group. Liver function tests were not significantly different but patients in the study group had a better recovery of kidney function. Graft and patient survival were not different in this small group of patients.
Conclusion: This interim analysis shows that the new therapeutic regimen has an acceptable safety profile. Furthermore there are indications for an improvement of kidney function in patients with hepatorenal syndrome. We will continue with the ongoing study until the allocation of 29 patients as planned.
Abstract: Background: Combined hepatocellular-cholangiocarcinoma (HCC-CC) is a rare hepatobiliary neoplasm combining hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). Pre-operative diagnosis is important to determine the optimal therapy, but challenging. Only a few cases of liver transplantation in HCC-CC have been reported, yet.
Methods: In this retrospective observational study we report our single-center experience of 7 patients with HCC-CC initially diagnosed HCC, who under- went liver transplantation according to the Milan criteria. We compare these findings with a matched control group of 50 HCC regarding clinicopathological characteristics and outcome.
Results: HCC-CC patients were male in 86%, with a median age of 60 years and cirrhosis in 86%. Recurrence was observed in 57%, with a 3-year recurrence-free survival of 44.4% (confidence interval (CI) 0.167?1) and a 3- year overall survival of 34.3% (CI 0.112?1). Vascular invasion was observed in 43%, and lymph node metastasis in 14%. HCC patients were male in 82%, with a median age of 63 years and cirrhosis in 96%. Recurrence was observed in 20%, with a 3-year recurrence-free survival of 75.2% (CI 0.629-0.9) (P = 0.0335) and a 3-year overall survival of 58.4% (CI 0.458?0.744). Vascular invasion was observed in 32%, but no lymph node metastasis. Conclusions: Although HCC-CC shared many features with HCC, the recurrence-free survival was significantly shorter than compared with HCC. From similar overall survival rates we conclude that liver transplantation in HCC-CC should be considered as therapeutic option. In advanced cases, an aggressive multimodal approach should be evaluated in further studies.
Abstract: Background and objective: Interleukin 2 receptor antagonists (IL2Ra) are used as induction therapy for prophylaxis against acute rejection in liver transplant recipients. This study aims to systematically identify and summarize the effects of using an IL2Ra, as an addition to standard therapy.
Methods: MEDLINE (1966?November 2009), EMBASE (1980?November 2009) and the Transplant Library (1970?November 2009) were searched for trials in liver transplant recipients were IL2Ra was compared to placebo or no treatment. Titles and abstracts were independently screened by two reviewers and selected according to pre-specified quality criteria. For the final analysis only prospective, randomized, controlled trials were included with or without blinding.
Results: Fourteen trials including 2559 participants were included in the meta- analysis. Depending on co-medication three subgroups were identified: same co-medication in both groups, reduced or delayed calcineurin inhibitors (CNI) in experimental group, reduced corticosteroids in experimental group. Pooling estimates in fixed and random effects models, independently of subgroups, the incidence of acute rejection at 12 months or later (see figure) was significantly reduced in patients receiving IL2Ra (RR 0.81, 95%-CI 0.71 to 0.92) whereas the incidence of graft loss (RR 0.98, 95%-CI 0.72 to 1.33) and death (RR 0.86, 95%-CI 0.66 to 1.12) where not significantly different. Subgroup analyses show better renal function in patients with IL2Ra and reduced or delayed CNI compared to patients without IL2Ra and standard dose CNI.
Conclusion: The use of IL2Ra reduces the incidence of acute rejection independently of immunosuppressive co-medication but does not reduce graft loss or mortality. Additionally reducing calcineurin inhibitors may improve renal function without increase of adverse events.
Abstract: Einleitung: Ein erhöhter portalvenöser Druck in der frühen Phase nach Leberlebendspende ist mit einer schlechten Prognose vergesellschaftet. Dabei sind das Transplantat/Gewichtsverhältnis und der venöse Abfluss Faktoren, die den portalen Druck beeinflussen. Weiterhin kann eine Rotation des Organs bei der anterioren Implantation der Lebervene des Spenders in die V. cava eine Abflussbehinderung bedingen. Folglich könnte eine rechtslaterale Implantation der Spendervene den Abfluss entsprechend verbessern.
Material und Methoden: Bei 22 Patienten wurde eine Leberlebendspende-Transplantation des rechten Leberlappens durchgeführt. Bei 7 Patienten wurde herkömmliche anteriore Implantation der Spendervene durchgeführt und bei 15 Patienten eine rechtslaterale Implantation. Neben
den demographischen Daten wurden beide Gruppen bezüglich des Transplantat/Gewichtsverhältnisses verglichen. Intraoperativ wurde der portalvenöse Druck und der zentrale Venendruck erfasst. Postoperativ wurden neben Bilirubin und Quick, die Transaminasen für 14 Tage
täglich zweimal gemessen.
Ergebnisse: Beide Gruppen waren bezüglich der demographischen Daten und des Transplantat/Gewichtsverhältnisses vergleichbar. Der intraoperative zentrale Venendruck war statistisch nicht unterschiedlich (7,7+/-2,6 vs. 9,1+/-4,1). Im Gegensatz zu den anterior Implantierten konnte bei
den rechtslaterale Implantierten ein signifikant niedrigerer portalvenöser Druck (18,6+/-2,0 vs. 13,1+/-1,9) gemessen werden. Postoperative zeigten die rechtslaterale implantierten
Patienten signifikant niedrigere Bilirubin- (max. Unterschied Tag 12) und Transaminasen-Werte (max. Unterschied Tag 3). Der statistische Unterschied war ab dem 15. Tag für Bilirubin und am dem 7. Tag für die Transaminasen nicht mehr zu erfassen.
Schlussfolgerung: Durch die Anwendung der hier erstmals vorgestellten Anastomosentechnik
für die Implantation der Spendervene in die V. cava bei der Leberlebendspende können intraoperativ niedrigere portalvenöse Druckverhältnisse erreicht werden. Dies ist mit einer besseren
Organfunktion in der frühen postoperativen Phase vergesellschaftet.
Abstract: Einführung: Lebermetastasen neuroendkriner Tumoren (NET) repräsentieren circa 10% aller sekundären Lebertumoren und treten in 25-90% aller Patienten mit NET auf. Häufig treten sie multifokal und bilateral auf, so daà eine kurative Resektion schwierig ist. Tumor bulk-Syndrom und Hormonsyndrom sind häufige Symptome. Lebertransplantation (Ltx) wird als Mittel der letzten Wahl in Patienten durchgeführt welche konventioneller Therapie nicht mehr zugänglich sind.
Jedoch ist die Ltx als Therapieoption weiterhin umstritten, da in einigen retrospektive Kohortenanalysen ein vergleichsweise schlechtes gesamt- und rezidivfreies Ãberleben gezeigt werden konnte. Daher
werden werder von UNOS noch ET Patienten mit Lebermetastasen eines NET bei der Allokation bevorzugt behandelt und sind somit auf eine Allokation nach dem MELD-System angewiesen.
Methoden: Ziel dieser retrospektiven Auswertung unseres Kollektivs von Patienten
mit Lebermetastasen eines NET welche einer Ltx zugeführt worden sind ist es einerseits die Aussicht einer Allokation nach MELD zu analysieren und andererseits die Ãberlebenszeit diese Kollektivs zu
vergleichen mit einem repräsentativen Vergleichskollektivs.
Ergebnnisse: Sieben Patienten mit Lebermetastasen eines NET sind in unserem Zentrum
transplantiert worden. Nach MELD-Allokation hätte keiner der Patienten zeitnah ein Organ erhalten. Das 5-Jahres-Ãberleben ist 71% und damit vergleichbar mit der Referenzkohorte.
Diskussion: Patienten mit Lebermetastasen eines NET können von einer Ltx profitieren. Eine prospektive Prognosestudie ist notwendig, um ggf. eine eine Ãnderung der Allokation zu erreichen.
Abstract: Background: Elevated portal pressure (EPP) might be a result of impaired outflow and is a central problem after adult living donor liver transplantation (ALDLT). EPP results in graft dysfunction indicated by hyperbilirubinemia, coagulopathy, and poor graft outcome. Therefore we modified the caval anastomosis to improve hepatic outflow.
Methods: The modified technique is based on the latero-dorsal enlargement of the caval orifice. We have assessed the modified technique in a study cohort of 22 patients between March 2000 and May 2007: 7 received a common end-to-end anastomosis of the right hepatic vein (group I) and 15 patients the modified surgical technique (group II). Portal vein pressure was measured intraoperative, before and after ALDLT. Hyperbilirubinemia, coagulopathy, and graft function were monitored in the first 20 days. Graft outcome was evaluated for 5 years.
Results: Overall portal vein pressure (PVP) was reduced by 4 mmHg (P value < 0.001) in patients of group II (median PVP 14 mmHg) compared to patients in group I (median PVP 18 mmHg). Patients of group II had less bilirubinemia in the first 20 days after ALDLT (P value < 0.001). In particular, patients with small grafts profit from this surgical procedure (P value = 0.04). Other liver function tests were not significantly altered and long term outcome was comparable.
Conclusion: The modified surgical procedure facilitates hepatic outflow, prevents elevated PVP after ALDLT, which is associated with improved liver function. Patients with a small graft may benefit from latero-dorsal enlargement of the caval orifice.
Abstract: Purpose: After liver transplantation more than 90% of the patients receive an immunosuppressive regimen based on calcineurin inhibitors. Aim of this study was to establish estimators of the safety and efficacy of calcineurin inhibitors for de-novo immunosuppression after liver transplantation. These may then be used as reference in therapeutic exploratory studies of calcineurin inhibitor free de-novo immunosuppression.
Methods: A systematic review of studies comparing the safety and efficacy of tacrolimus and cyclosporine has been published. But the overall common effects of calcineurin inhibitors have not been reported. The data of 16 controlled clinical trials was used as source data for the meta-analysis. Several methods to estimate the overall common effects and their appropriate confidence interval were evaluated: weighted average with exact confidence interval, a fixed and random effects model with logit transformed rates, estimation of the marginal mean proportion as described by Fleiss, and weighted average with a confidence interval obtained by bootstrap. In a simulation with 10 studies, with variable true common rate, variable sample size, and variable between study variance weighted average with a confidence interval obtained by bootstrap was the most robust method to infer the common true rate and its confidence interval.
Results: The following estimates were obtained by weighted average with 95% bootstrap confidence interval: mortality 14.58% [11.52; 17.12], graft loss 18.25% [14.3; 21.57], acute rejection 42.38% [29.56; 52.1], steroid resistant rejection 12.61% [6.36; 18.65], post transplant de-novo dialysis 2.06% [0.25; 6.95], post transplant de-novo diabetes 18% [5.72; 37.2], and post transplant lymphoproliferative disease 1.08% [0.35; 2.56].
Conclusion: A robust estimation of the overall common effects of calcineurin inhibitors in liver transplant patients has been obtained by weighted average with a bootstrap confidence interval.
Abstract: Einführung: Nach Lebertransplantation erhalten derzeit mehr als 90% der Patienten ein immunsuppressives Regime, welches auf Calcineurininhibitoren basiert. Ziel dieser Meta-Analyse ist es Schätzer für die Wirksamkeit und Sicherheit von Calcineurininhibitoren in der de-novo Immunsuppression nach Lebertransplantation zu etablieren. Diese können dann als Referenzwert für therapeutisch explorative Studien zur Calcuneurininhibitor-freien de-novo Immunsuppression herangezogen werden
Methoden: Meta-Analysen von Studien in welchen die Wirksamkeit und Sicherheit
von Tacrolimus und Cyclosporin verglichen wurden sind bereits veröffentlicht worden. Aber über den Gesamteffekt beider Substanzen ist bisher nicht berichtet worden. Für die vorliegende Meta-Analyse
wurden die Schätzer von 16 kontrollierten klinischen Studien als Quelldaten herangezogen. Mehrere Methoden zur Schätzung des Gesamteffektes wurden evaluiert: fixed effects models und random effects models mit studien-spezifischen und populations-spezifischen Varianzen, estimation of the marginal mean proportion und gewichtetes Mittel mit bootstrap-Konfidenzintervall. In einer Simulationsstudie
wurden bootstrap-Konfidenzintervall, estimation of the marginal mean und random effects model mit populations-spezifischer Varianz als beste Methoden identifiziert, um eine reliable Schätzung zu erhalten.
Ergebnisse: Gesamtschätzer für die Wirksamkeit und Sicherheit der de-novo
Immunsuppression mit Calcineurininhibitoren ein Jahr nach Lebertransplantation wurden anhand des gewichteten Mittels mit 95% bootstrap-Konfidenzintervall ermittelt: Mortalität 14,5% [11,29;
17,26], Organverlust 17,32% [12,76; 21,88], akute AbstoÃung 41,47% [29,17; 53,77], steroid-resistente AbstoÃung 12,79% [6,45; 18,8], de-novo Dialysepflichtigkeit 2,18% [0,24; 7,44], de-novo Diabetes
17,12% [5,32; 36,44], lymphoproliferative Erkrankungen 1,06% [0,22; 2,9].
Konklusion: Eine robuste Schätzung der Gesamteffekte von Calcineurininhibitoren
als de-novo Immunsuppression bei Patienten nach Lebertransplantation konnte mittels boostrap-Methode erreicht werden.
Abstract: Einleitung: Die ABO-inkompatible Leberlebendtransplantation (ABOi-LDLT) ist mittlerweile ein in Japan und den USA, etabliertes Verfahren, um den Donorpool zu erweitern. ABO-inkompatible Lebertransplantationen sind auch in Europa durchgeführt worden, Publikationen aus Deutschland gibt es jedoch bisher nicht. Die besonderen Risiken der ABOi-LTX sind a) die humorale AbstoÃung durch blutgruppenspezifische Isohämagglutinine, b) vaskuläre und c) biliäre Komplikationen. Ein allgemein etabliertes Protokoll zur Verringerung dieser Risiken existiert nicht. Dies ist ein erster Bericht über Erfahrungen mit der ABOi-LDLT in Deutschland.
Methoden: Wegen fortgeschrittener Lebercirrhose (N=2) oder nicht-resektablen cholangiocellulären Carcinoms (CCC; N=1) erhielten drei Patienten in unserer Klinik eine ABOi-LDLT. Zur Reduktion der Isohämagglutinine führten wir bei allen Patienten präoperativ Plasmapheresen durch. Um die Menge der residenten B-Zellen zu verringern, wurde bei zwei Patienten die Transplantation mit einer Splenektomie kombiniert. Die Induktionsimmunsuppression wurde mit Methylprednisolon durchgeführt, beim letzten Patienten zusätzlich mit Antithymozytenglobulin (ATG). Die Basisimmunsuppression beinhaltete Tacrolimus und Prednisolon in Kombination mit Sirolimus oder Mycophenolsäure.
Ergebnisse: Bei allen drei Patienten bestand eine gute Primärfunktion des Transplantats und eine akute AbstoÃung konnte histologisch bei allen Patienten ausgeschlossen werden. Zwei Patienten wurden am 49. bzw. 55. postoperativen Tag nach Hause entlassen; ein Patient verstarb an einem Multiorganversagen infolge einer Sepsis.
Schlussfolgerung: Die drei Falldarstellungen demonstrieren die Durchführbarkeit der blutgruppen-inkompatiblen Lebertransplantation. Eine humorale AbstoÃung oder andere für die ABOi-LDLT typische Komplikationen trat bei keinem Patienten auf. Da die Splenektomie in publizierten gröÃeren Fallzahlen zu einer erhöhten Morbidität und Mortalität durch postoperative Infektionen führt, wurde, analog zu aktuellen Protokollen, beim letzten Patienten darauf verzichtet. Statt dessen wird zur Depletion der B-Zellen häufig der anti-CD20-Antikörper Rituximab eingesetzt. Wir entschieden uns beim letzten Patienten die Induktionsimmunsuppression mit ATG durchzuführen, denn zusätzlich zur Depletion von T-Zellen induziert ATG eine Apoptose in B- und Plasmazellen, welche umfassender sein könnte als durch Rituximab alleine. Es zeigt sich, daà auch dieses alternative Vorgehen die humorale AbstoÃung verhindern kann. Die Möglichkeit der ABOi-LDLT sollte auch in Europa weiter exploriert werden und die Ergebnisse in einem Register der multizentrischen Auswertung zugänglich gemacht werden.
Abstract: Einführung: Akute Nierenfunktionsstörungen werden in bis zu 50% der Patienten nach
Lebertransplantation (Ltx) beobachtet. Mehr als 90% der Patienten erhalten eine Immunsuppression basierend auf Calcineurininhibitoren (CNI) und deren Neprotoxizität trägt wesentlich zur Nierenschädigung bei. Nierenfunktionsstörungen in der Frühphase nach Ltx erhöhen das
Risiko einer chronischen Niereninsuffizienz und subsequent das Risiko frühzeitig zu versterben.
In mehreren klinischen Studien wurde der Effekt einer verspäteten oder reduzierten Gabe von Calcineurininhibitoren nach Lebertransplantation untersucht. Generell führt die Vermeidung von CNI zu einer verbesserten Nierenfunktion ohne Kompromittierung der Sicherheit, wenn ein adäquates Niveau der Immunsuppression erhalten wird mittels nicht-nephrotoxischer Immunuppressiva, z. B. mTOR-Inhibitoren oder Antimetabolite. Basierend auf diesen Erkenntnissen wurde ein
Studienprotokoll entwickelt, um die Wirksamkeit und Sicherheit einerCNI-freien de-novo Immunsuppression nach Lebertransplantation zu untersuchen.
Methoden und Design: Eine prospektive, therapeutisch-explorative, nicht-Plazebokontrollierte, zweistufige, monozentrische Studie in 29 Patienten nach Lebertransplantation wurde entwickelt, um die
Sicherheit und Wirksamkeit einer de-novo CNI-freien Immunsuppression mit Basiliximab, Mycophenolat-Natrium, Everolimus und Prednisolon zu untersuchen. Der primäre Endpunkt ist die Rate steroid-resistente AbstoÃungen ein Jahr nach Ltx. Sekundäre Endpunkte sind die Inzidenz
akuter Rejektionen, Nierenfunktion (gemessen an der glomerulären Filtrationsrate und der Rate und Länge der Nierenersatztherapie), Leberfunktion, die Rate von Nebenwirkungen und Mortalität bis ein Jahr nach Ltx.
Diskussion: Die vorliegende therapeutisch-explorative Studie repräsentiert ein intermediäres Element auf dem Weg zu einer CNI-freien Immunsuppression nach Lebertransplantation. Wenn die Sicherheit des hier beschriebenen Immunsuppressiven Regimes gezeigt werden kann, sollte die Wirksamkeit in einer prospektiven, kontrollierten klinischen Studie bestätigt werden.
Abstract: Purpose: Acute renal dysfunction has been observed in up to 50% of all patients after orthotopic liver transplantation (OLT). More than 90% of patients receive calcineurin inhibitors (CNIs) for immunosuppression after OLT, and nephrotoxicity of CNIs contributes to renal impairement. Early renal dysfunction significantly increases the risk of chronic renal failure und subsequently the risk of premature death. Multiple trials investigated the effect of delayed CNI and reduced-dose CNI regimens or early withdrawal of CNI in patients with renal dysfunction after OLT. Generally, avoidance of CNIs improves kidney function and does not result in higher rate of rejection when an adequate level of immunosuppression is maintained. Based on the aforementioned data this study protocol was designed to evaluate the efficacy and safety of CNI-free de-novo immunosuppression after liver transplantation.
Methods and Design: A prospective therapeutic exploratory, non-placebo controlled, two stage monocenter trial in a total of 29 liver transplant patients was designed to assess the safety and efficacy of de-novo CNI-free immunosuppression with basiliximab, mycophenolate sodium, everolimus, and prednisolone. The primary endpoint is the rate of steroid resistant reject. Secondary endpoints are the incidence of acute rejection, kidney function, liver allograft function (assessed by measurement of AST, ALT, total bilirubine, AP, GGT), treatment failure (reintroduction of CNI), incidence of adverse events, and mortality up to one year after OLT.
Discussion: The ongoing clinical trial represents an intermediate element of the research chain, along which a scientific hypothesis has to go by, in order to reach the highest level of evidence; a prospective therapeutic exploratory study. If the data of this ongoing research project confirms feasibility of de-novo CNI-free immunosuppression, this should be confirmed in a randomized, prospective, controlled double-blinded clinical.
Abstract: Introduction:
ABO blood group incompatible (ABO-I) living donor liver transplantation (LDLT) is rapidly emerging as an effective treatment for selected patients with end-stage liver disease in Japan and the USA, but not in germany. Different protocols for patient management and immunosuppression have been developed and improved over the last 15 years and generally accepted protocols do not exist. Here we present the first experiences with ABO-I LDLT in germany applying different protocols.
Patients:
We have transplanted three patients with ABO-I grafts from living donors. Two patients suffered from severe cirrhosis and one patient had a cholangiocellulary carcinoma. All three donors underwent right hemihepatectomy without major complications and are alive today. Preoperative plasmapheresis was performed in all three recipients to reduce anti-A/B antibody titers. Splenectomy was carried out in the first two patients to suppress antibody production. Immunosuppression was induced with methylprednisolone and daclizumab in the first two two patients and with methylprednisolone and antithymocyte globulin (ATG) in the last patient. Basal immunosuppression included tacrolimus and prednisolone in combination with either sirolimus or mycophenolic acid. One of the first two patients had a complicated course and died 110 days after transplantation due to multiorgan failure. The other patient died one year later due to recurrence of her underlying malign disease. The last patient had an uncomplicated postoperative course and is alive half a year after transplantation.
Discussion:
Here we present three patients with ABO-I LDLT. In all three patients no acute rejection was observed (verified histologically). Reinforced immunosuppression in combination with splenectomy and plasmapheresis may increase the risk for infection and sepsis. Subsequently we reduced immunosuppression and did nor perform splenectomy in the last patient. Current publications endorse preoperative induction of immunosuppression with retuximab, but we have seen recurrent anti-A/B antigen titers after repeated plasmapheresis in a patient we did not transplant due to extrahepatic malign disease. Since ATG has been shown to trigger apoptosis in B-cells and plasma cells we successfully applied induction with ATG in out last patient.
