Ex situ arterial reconstruction prior normothermic machine perfusion of liver grafts.

PURPOSE: Atypical variants of the hepatic artery are common and pose a technical challenge for normothermic machine perfusion (NMP). The transplant surgeon has three options when confronted with hepatic arterial variation in a liver graft to be subjected to NMP: to perform arterial reconstruction (i) prior, (ii) during, or (iii) following NMP. METHODS: Herein, we report our experience and technical considerations with pre-NMP reconstruction. Out of 52 livers, 9 had an atypical hepatic artery (HA): 3 replaced right HA, 3 replaced left HA, 1 accessory left HA, 1 accessory left and right HA, and 1 replaced left and right HA. RESULTS: Reconstruction was conducted during back-table preparation. A single vascular conduit was created in all grafts to allow single arterial cannulation for NMP, necessitating only one arterial anastomosis within the recipient. All grafts were subjected to NMP and subsequently successfully transplanted. CONCLUSION: Our approach is being advocated for as it preserves the ability to alter the reconstruction in case of problems resulting from the reconstruction itself, thereby allowing functional evaluation of the reconstruction prior transplantation, permitting simultaneous reperfusion in the recipient, and providing the shortest possible duration for vascular reconstruction once the graft is rewarming non-perfused within the recipient. In addition, in light of the frequency of technically demanding reconstructions with very small vessels, we consider our technique beneficial as the procedure can be performed under ideal conditions at the back-table.

[Chronic intestinal failure]. / Chronisches Darmversagen.

The term intestinal failure (IF) is understood as the transient or irreversible loss of the resorptive capacity of the bowels. This includes a multitude of diseases, some of which have anatomical causes and others functional causes. The functional capacity (absorption and motility) of the remaining digestive tract and the bacterial overgrowth and false colonization of the small bowel are of prognostic importance. After exclusion of pathological intestinal findings, such as stenosis and dilatation, initially conservative treatment is employed with the aim of intestinal adaptation. Before failure or complications, initially conservative surgery and then organ replacement by transplantation should be considered. The IF is a temporary or permanent condition. For adults a length of 100cm small bowel without the colon, 60cm still with continuity to the colon and 35cm small bowel with complete preservation of the colon including the ileocecal valve are potentially sufficient for intestinal autonomy.

Tumor Recurrence and Graft Survival in Renal Transplant Recipients with a History of Pretransplant Malignancy: A Matched Pair Analysis.

Organ scarcity demands critical decision-making regarding eligible transplant candidates and graft allocation to ensure best benefit from renal transplantation (RTx). Among the controversial relative contraindications is a history of pretransplant malignancy (PTM). While oncological outcomes of PTM-RTx recipients are well described, data on graft-specific outcome are scarce. A retrospective double case control matched pair analysis (60 months follow-up) was carried out and RTx-recipients were stratified for history of PTM. First, PTM-RTx recipients were matched according to age, sex and duration of immunosuppressive therapy. Next, PTM-RTx recipients were matched 1:1 for age, sex and cause of end-stage renal disease. Five-year patient and graft survival as well as oncological outcomes were analyzed. A total of 65 PTM-RTx recipients were identified. Post-RTx recurrence rate was 5%, while 20% developed second de novo malignancy, comparable to 14% in the control group. PTM-RTx recipients had a noticeable lower five-year death-censored as well as overall graft survival and Cox proportional hazard modeling showed a correlation between PTM and inferior graft survival. Although underlying reasons remain not fully understood, this study is the first to show inferior graft survival in PTM-RTx recipients and advocates necessity to focus on more meticulous graft monitoring in PTM recipients in addition to heightened surveillance for cancer recurrence.

Short- and Long-Term Outcomes of Different Reperfusion Sequences in Liver Transplantation.

BACKGROUND Although most centers perform primary portal vein reperfusion (PV) in orthotopic liver transplantation (OLT) for historical reasons, there is so far no sound evidence as to whether this technique is superior. The present study evaluated the long-term outcome of 3 different reperfusion sequences: PV vs primary arterial (A) vs simultaneous reperfusion (SIM). MATERIAL AND METHODS All patients at our center who underwent OLT (who received a primary, whole-organ liver graft) from 2006 to 2007 were evaluated for analysis. RESULTS A total of 61 patients were found eligible (PV: 25, A: 22, SIM: 14). Twenty-one patients (35%) were still alive after the follow-up period of 12 years. Despite poorer starting conditions such as higher recipient age (59 y (SIM) vs 55 y (A) vs 50 y (PV), P=0.01) and donor age (56 y (SIM) vs 51 y (PV) vs 50 y (A), n.s.), higher MELD scores (22 vs 19 (PV) vs 17 (A), n.s.), as well as a higher number of marginal donor organs (79% (SIM) vs 36% (A/PV), P=0.02), SIM-recipients demonstrated superior outcomes. Overall survival was 8.1 y (SIM), 4.8 y (PV), and 5.9 y (A, n.s.)). None of the SIM-recipients underwent re-transplantation, while the rate was 32% in the PV-group. The 8.1 y graft survival in SIM-recipients was significantly longer than in the other 2 groups, which were 3.3 y (PV) and 5.5 y (A, P=0.013). CONCLUSIONS Although SIM-reperfused recipients were the oldest and received grafts of inferior quality, these recipients showed superior results in terms of overall patient and graft survival. Multicentric randomized controlled trials with larger study populations are required to confirm this finding.

mTOR Inhibition Is Most Beneficial After Liver Transplantation for Hepatocellular Carcinoma in Patients With Active Tumors.

OBJECTIVE: The aim of this study was to evaluate the survival benefit of sirolimus in patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC) (exploratory analysis of the SiLVER-trial). SUMMARY AND BACKGROUND DATA: Patients receiving LT) for HCC are at a high risk for tumor recurrence. Calcineurin inhibitors have shown evidence to promote cancer growth, whereas mammalian target of rapamycin (mTOR) inhibitors like sirolimus have anticancer effects. In the SiLVER-trial (Clinicaltrials.gov: NCT00355862), the effect of sirolimus on the recurrence of HCC after LT was investigated in a prospective randomized trial. Although the primary endpoint of improved disease-free survival (DFS) with sirolimus was not met, outcomes were improved for patients in the sirolimus-treatment arm in the first 3 to 5 years. To learn more about the key variables, a multivariate analysis was performed on the SiLVER-trial data. PATIENTS AND METHODS: Data from 508 patients of the intention-to-treat analysis were included in exploratory univariate and multivariate models for overall survival (OS), DFS and a competing risk analysis for HCC recurrence. RESULTS: Sirolimus use for ≥3 months after LT for HCC independently reduced the hazard for death in the multivariate analysis [hazard ratio (HR): 0.7 (95% confidence interval, CI: 0.52-0.96, P = 0.02). Most strikingly, patients with an alpha-fetoprotein (AFP) ≥10 ng/mL and having used sirolimus for ≥3 months, benefited most with regard to OS, DFS, and HCC-recurrence (HR: 0.49-0.59, P = 0.0079-0.0245). CONCLUSIONS: mTOR-inhibitor treatment with sirolimus for ≥3 months improves outcomes in LT for HCC, especially in patients with AFP-evidence of higher tumor activity, advocating particularly for mTOR inhibitor use in this subgroup of patients. CLINICAL TRIAL REGISTRATION: EudraCT: 2005-005362-36 CLINICALTRIALS.GOV:: NCT00355862.

Impact of nighttime procedures on outcomes after liver transplantation.

BACKGROUND: Sleep deprivation is a well-known risk factor for the performance of medical professionals. Solid organ transplantation (especially orthotopic liver transplantation (oLT)) appears to be vulnerable since it combines technically challenging operative procedures with an often unpredictable start time, frequently during the night. Aim of this study was to analyze whether night time oLT has an impact on one-year graft and patient survival. MATERIAL AND METHODS: Deceased donor oLTs between 2006 and 2017 were retrospectively analyzed and stratified for recipients with a start time at day (8 a.m. and 6 p.m.) or at night (6 p.m. to 8 a.m.). We examined donor as well as recipient demographics and primary outcome measure was one-year patient and graft survival. RESULTS: 350 oLTs were conducted in the study period, 154 (44%) during daytime and 196 (56%) during nighttime. Donor and recipient variables were comparable. One-year patient survival (daytime 75.3% vs nighttime 76.5%, p = 0.85) as well as graft survival (daytime 69.5% vs nighttime 73.5%, p = 0.46) were similar between the two groups. Frequencies of reoperation (daytime 53.2% vs nighttime 55.1%, p = 0.74) were also not significantly different. CONCLUSION: Our retrospective single center data derived from a German transplant center within the Eurotransplant region provides evidence that oLT is a safe procedure irrespective of the starting time. Our data demonstrate that compared to daytime surgery nighttime liver transplantation is not associated with a greater risk of surgical complications. In addition, one-year graft and patient survival do not display inferior results in patients undergoing nighttime transplantation.

Protocol Duodenal Graft Biopsies Aid Pancreas Graft Surveillance.

BACKGROUND: Histological evaluation of the pancreas graft is usually done on demand resulting in significant delays. This analysis reports on endoscopic protocol duodenal graft biopsies at regular intervals to determine feasibility, safety, and monitoring benefits. METHODS: Protocol duodenal graft biopsies in 27 consecutive pancreas transplants (10 simultaneous pancreas kidney [SPK], 17 pancreas after kidney [PAK]) with a follow-up of a minimum of 12 months were performed at days 14, 30, 90, 180, 360, 430. University of Pittsburgh Medical Center classification for intestinal rejection was used. C4d staining was performed when antibody-mediated rejection was suspected. RESULTS: Overall patient and pancreas graft survival was 100% and 93% at a mean follow-up of 2.8 years. One hundred sixty-seven endoscopic biopsy procedures were performed in 27 grafts without any complication. Biopsies revealed rejection in 3 (30%) SPK recipients and in 15 (82%) of PAK recipients as early as 14 days posttransplant. Two patients underwent PAK retransplantation diagnosed with acute rejection at day 180. All except 1 recipient being treated for rejection, showed histological improvement following antirejection treatment. Following transient treatment success, a total of 3 pancreas grafts were lost for immunological reason. One loss was immediate despite antirejection treatment, 1 secondary to nonresolving rejection at 7 months and the third due to recurrent rejection 15 months posttransplantation. Additionally, biopsies detected vascular (venous thrombosis) and overimmunosuppression (cytomegalovirus infection) complications. CONCLUSIONS: Protocol graft duodenal biopsies detect complications after whole-organ pancreas transplantation, are useful in guiding therapy, and carry potential for improving outcome.

Solid organ transplantation following allogeneic haematopoietic cell transplantation: experience from a referral organ transplantation center and systematic review of literature.

Solid organ transplantation (SOT) following haematopoietic cell transplantation (HCT) is a rare event. Uncertainty exists whether such recipients are at higher risk of relapse of underlying haematological disease or at increased risk of developing infectious or immunological complications and malignancies following SOT. The experience at our referral organ transplantation center and the present literature of SOT (n = 198) in recipients following previous HCT was systematically reviewed. Outcome analysis of 206 SOT recipients following HCT challenges the validity of the frequently stated comparable outcome with recipients without prior HCT. SOT recipients after HCT are younger and have a higher mortality and morbidity in comparison with "standard" recipients. Rejection rates for SOT recipients following HCT appear to be lower for all organs, except for liver transplantation. In the setting of liver transplantation following HCT, mortality for recipients of deceased donor grafts appears to be exceptionally high, although experience with grafts of living donors are favourable. Morbidity was mostly associated with infectious and malignant complications. Of note some SOT recipients who received solid organ donation from the same HCT donor were able to achieve successful withdrawal of immune suppression. Despite limited follow-up, recipients with prior HCT show a different course after SOT, necessitating attention and closer follow-up.

Hand-assisted living-donor nephrectomy: a retrospective comparison of two techniques.

BACKGROUND: Living-donor nephrectomy (LDN) is challenging, as surgery is performed on healthy individuals. Minimally invasive techniques for LDN have become standard in most centers. Nevertheless, numerous techniques have been described with no consensus on which is the superior approach. Both hand-assisted retroperitoneoscopic (HARS) and hand-assisted laparoscopic (HALS) LDNs are performed at Zurich University Hospital. The aim of this study was to compare these two surgical techniques in terms of donor outcome and graft function. METHOD: Retrospective single-center analysis of 60 consecutive LDNs (HARS n = 30; HALS n = 30) from June 2010 to May 2012, including a one-year follow-up of the recipients. RESULTS: There was no mortality in either group and little difference in the overall complication rates. Median warm ischemia time (WIT) was significantly shorter in the HARS group. The use of laxatives and the incidence of postoperative vomiting were significantly greater in the HALS group. There was no difference between right- and left-sided nephrectomies in terms of donor outcome and graft function. CONCLUSIONS: Both techniques appear safe for both donors and donated organs. The HARS technique is associated with a shorter WIT and a reduced incidence of postoperative paralytic ileus. Therefore, we consider HARS LDN a valuable alternative to HALS LDN.

Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial.

BACKGROUND: We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC). METHODS: In a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor-free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor-free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint. RESULTS: Recurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age ≤60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874). CONCLUSIONS: Sirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC.

Aorto-hepatic bypass in liver transplantation in the MELD-era: outcomes after supraceliac and infrarenal bypasses.

PURPOSE: Poor arterial inflow during orthotopic liver transplantation (OLT) may necessitate arterial revascularisation using aorto-hepatic bypasses with supraceliac (SC) or infrarenal (IR) allografts. This study compared both techniques focusing on the patients' preoperative conditions, postoperative graft/organ function, complications and survival. METHODS: Fifteen out of 114 OLT patients underwent revascularisation (7 IR/8 SC) between 2005 and 2008 and were included in the study. The patients' records were reviewed retrospectively. RESULTS: IR patients presented with a higher BMI, received more male donor organs and their reperfusion sequence was predominately portal venous (SC: primary arterial). SC patients presented a significantly worse preoperative creatinine clearance and a trend towards a higher MELD score. The postoperative graft/organ function, morbidity and mortality did not differ between the groups despite a trend towards a worse survival in the SC group. A deteriorated preoperative creatinine clearance and higher MELD score negatively impacted the survival. Postoperative bleeding episodes and major re-interventions also affected the outcome. CONCLUSIONS: We found no evidence for superiority of either bypass technique in our OLT patients. The trend toward a worse survival in SC patients was most likely caused by the worse preoperative conditions of these patients and highlights the importance of the impact of the MELD score on the outcome after OLT.

Liver transplantation versus supraselective transarterial chemoembolization in palliative patients with hepatocellular carcinoma exceeding the Milan Criteria - is it time for a more individual approach?

BACKGROUND: This study evaluated the effect of liver transplantation (LTX) and STACE on overall survival in palliative patients with HCC exceeding Milan criteria. MATERIAL AND METHODS: At a single center 63 HCC patients exceeding Milan criteria were retrospectively analyzed. Forty patients underwent STACE as palliative therapy modality and 23 palliative patients were scheduled for LTX. The primary endpoint was overall patient survival. Statistical analysis included Kaplan-Meier method, log rank, chi squared tests and Cox regression model for the identification of prognostic factors. RESULTS: There was no significant difference when comparing the 2 groups (LTX vs. no LTX) in terms of Child classification, co-morbidities, underlying disease, and sex. Overall survival was significantly prolonged after LTX was performed (p=0.012). In the Cox regression model, LTX (p=0.021), LTX <3Mo (p=0.047), CHILD stage (p=0.007), AFP (p=0.020), and tumor size of largest HCC nodule <40 mm (p=0.028) were independent prognostic factors for survival. CONCLUSIONS: Palliative patients beyond Milan have a significant survival benefit after they received early liver transplantation in comparison with STACE. The current approach to waiting list candidacy based on Milan criteria should be modified with a more individualized approach that considers age, AFP level, and tumor size.

Early conversion to a sirolimus-based, calcineurin-inhibitor-free immunosuppression in the SMART trial: observational results at 24 and 36months after transplantation.

Early conversion to a calcineurin-inhibitor (CNI)-free maintenance immunosuppression with sirolimus (SRL), mycophenolate mofetil (MMF) and steroids was associated with an improved 1-year renal function as compared with a cyclosporine (CsA)-based regimen (SMART core-study). This observational follow-up describes 132 patients followed up within the SMART study framework for 36months. At 36months, renal function continued to be superior in SRL-treated patients [ITT-eGFR(@36m) : 60.88 vs. 53.72 (CsA) ml/min/1.73m(2) , P=0.031]. However, significantly more patients discontinued therapy in the SRL group 59.4% vs.42.3% (CsA). Patient [99% (SRL) vs.97% (CsA) and graft 96% (SRL) vs.94% (CsA)] survival at 36months was excellent in both arms. There was no difference in late rejection episodes. Late infections and adverse events were similar in both arms except of a higher rate of hyperlipidemia in SRL and a higher incidence of malignancy in CsA-treated patients. In a multivariate analysis, donor age >60years, S-creatinine at conversion >2mg/dl, CMV naïve(-) recipients and immunosuppression with CsA were predictive of an impaired renal function at 36months. Early conversion to a CNI-free SRL-based immunosuppression is associated with a sustained improvement of renal function up to 36months after transplantation. Patient selection will be key to derive long-term benefit and avoid treatment failure using this mTOR-inhibitor-based immunosuppressive regimen.

Renal function, efficacy, and safety of sirolimus and mycophenolate mofetil after short-term calcineurin inhibitor-based quadruple therapy in de novo renal transplant patients: one-year analysis of a randomized multicenter trial.

BACKGROUND: De novo sirolimus in calcineurin inhibitor-free regimens, although potentially useful to improve early renal function, are complicated by various drug-related side effects. METHODS: We report a prospective open-label, multicenter, randomized trial to evaluate early conversion from a CsA-based to a sirolimus (SRL)-based regimen 10 to 24 days after renal transplantation. Of the 196 patients, 141 patients with a low-to-moderate immunological risk were eligible to be converted to SRL or to continue CsA. All patients received antithymocyte globulin-F single-bolus induction, mycophenolate mofetil, and steroids. RESULTS: The primary endpoint, renal function determined by S-creatinine and estimated glomerular filtration rate calculated by Nankivell formula at 12 months was significantly better in the SRL group (1.51+/-0.59 vs. 1.87+/-0.98 mg/dL or 64.5+/-25.2 vs. 53.4+/-18.0 mL/min/1.73 m). Patient survival, graft survival, and incidence of biopsy-proven acute rejection after conversion were not statistically different. Drug discontinuations were significantly higher in the SRL group (36.2% vs. 19.7%). Significantly, more patients in the SRL group reported acne, aphtous, and temporary hyperlipidemia, whereas cytomegalovirus viremia was significantly decreased (7.3% vs. 28.2%). CONCLUSIONS: Early conversion to a calcineurin inhibitor-free regimen with SRL in combination with mycophenolate mofetil may be a useful strategy to improve renal function. The identification of appropriate candidates and safe management of SRL-related adverse events will be a key to avoid the high rate of dropouts, which currently limit the broad applicability of this protocol.

Kidney-autotransplantation before radiotherapy: a case report.

BACKGROUND: A 28-year-old man suffering from a Ewing tumour arising from the 9th-11th ribs with infiltration of neuroforamina without distant metastases was planned to receive radiotherapy following primary intralesional surgery and induction chemotherapy. Due to pleural infiltration and effusion, a hemithorax irradiation with a sequential boost to the primary tumour site had to be administered. Different treatment planning variants failed to provide sufficient radiotherapy planning in view of target volume coverage and avoidance of organs at risk, especially due to high calculated radiation doses potentially compromising the left kidney. MATERIALS AND METHODS: To prevent left kidney organ exposure, an autotransplantation of the left kidney into the right fossa iliaca was performed. An infiltration of the kidney was initially excluded. RESULTS: Postoperatively, a renal scintigraphy showed a normal function of both kidneys allowing sufficient radiotherapy treatment planning. Target volume coverage was easily obtained using a combination of hemithorax irradiation and a sequential boost by an intensity-modulated-radiotherapy technique. CONCLUSION: In difficult individual treatment situations, surgical transpositions as well as organ autotransplantation might be useful in reducing radiotherapy organ dose levels.

Normothermic perfusion: a new paradigm for organ preservation.

OBJECTIVE: Transplantation of organs retrieved after cardiac arrest could increase the donor organ supply. However, the combination of warm ischemia and cold preservation is highly detrimental to the reperfused organ. Our objective was to maintain physiological temperature and organ function during preservation and thereby alleviate this injury and allow successful transplantation. BACKGROUND DATA: We have developed a liver perfusion device that maintains physiological temperature with provision of oxygen and nutrition. Reperfusion experiments suggested that this allows recovery of ischemic damage. METHODS: In a pig liver transplant model, we compared the outcome following either conventional cold preservation or warm preservation. Preservation periods of 5 and 20 hours and durations of warm ischemia of 40 and 60 minutes were tested. RESULTS: After 20 hours preservation without warm ischemia, post-transplant survival was improved (27%-86%, P = 0.026), with corresponding differences in transaminase levels and histological analysis. With the addition of 40 minutes warm ischemia, the differences were even more marked (cold vs. warm groups 0% vs. 83%, P = 0.001). However, with 60 minutes warm ischemia and 20 hours preservation, there were no survivors. Analysis of hemodynamic and liver function data during perfusion showed several factors to be predictive of posttransplant survival, including bile production, base excess, portal vein flow, and hepatocellular enzymes. CONCLUSIONS: Organ preservation by warm perfusion, maintaining physiological pressure and flow parameters, has enabled prolonged preservation and successful transplantation of both normal livers and those with substantial ischemic damage. This technique has the potential to address the shortage of organs for transplantation.

Intrathoracic psammomatous melanotic schwannoma associated with the Carney complex.

The Carney complex is a multiple neoplasia syndrome characterized by myxomas, schwannomas, mucocutaneous spotty pigmentations, and endocrine overactivity with or without endocrine tumors. Herein, we report the rare case of a 49-year-old man with a paravertebral intrathoracic tumor, a history of bilateral adrenalectomy, and resection of an atrial myxoma. A thoracoscopic en-bloc tumor extirpation with minimal safety margins was performed. Histopathologic examination revealed the diagnosis of a malignant psammomatous melanotic schwannoma that is associated with the Carney complex in 50% of these patients. Prognosis of all melanotic schwannomas is usually poor due to local recurrences or metastases. Although treatment guidelines for this rare tumor do not exist, radiotherapy was performed in our patient to prevent possible recurrence or regrowth of this malignant tumor. Twenty-four months after operation the patient showed no signs of tumor recurrence or metastases.