Radioembolization for neuroendocrine liver metastases is safe and effective prior to major hepatic resection.

BACKGROUND: Radioembolization (RE) is well established in the treatment of neuroendocrine liver metastases. However surgery is rarely performed after RE, although liver resection is the gold standard in the treatment of localized neuroendocrine liver metastases. Therefore, aim of the present study was to evaluate the safety and feasibility of liver resection after RE in a homogenous cohort. METHODS: From a prospective surgical (n=494) and nuclear medical (n=138) database patients with NELM who underwent liver resection and/or RE were evaluated. Between September 2011 and December 2017 eight patients could be identified who underwent liver resection after RE (mean therapeutic activity of 1,746 Mbq). Overall and progression free survival were evaluated as well as epidemiological and perioperative factors. The surgical specimens were analyzed for necrosis, fibrosis, inflammation, and steatosis. RESULTS: The mean hepatic tumor load of patients, who had liver surgery after RE, was 31.4% with a mean Ki-67 proliferation index of 5.9%. The majority of these patients (7/8) received whole liver RE prior to liver resection, which did not increase morbidity and mortality compared to a surgical collective. Indications for RE were oncological (6/8) or carcinoid syndrome associated reasons (2/8). Mean overall survival was 25.1 months after RE and subsequent surgery. Tumor necrosis in radioembolized lesions was 29.4% without evidence of fibrosis and inflammation in hepatic tissue. CONCLUSIONS: This is the first study analyzing the multimodal therapeutic approach of liver resection following whole liver RE. This treatment algorithm is safe, does not lead to an increased morbidity and is associated with a favorable oncological outcome. Nonetheless, patient selection remains a key issue.

The Prognostic Value of Presepsin for Sepsis in Abdominal Surgery: A Prospective Study.

INTRODUCTION: Rapid diagnosis accompanied by appropriate treatment is essential in the therapy of sepsis. However, there is no blood marker available, which reliably predicts sepsis and associated mortality. Therefore, the aim of the present study was to evaluate presepsin and endotoxin in comparison with established blood markers in patients undergoing emergency visceral surgery for abdominal infection. PATIENTS AND METHODS: This prospective study included 31 patients with abdominal infection undergoing emergency surgery between March and August 2014. The Sepsis-2 and Sepsis-3 definitions of sepsis were used. Blood markers (presepsin, endotoxin, C-reactive protein, procalcitonin (PCT), interleukin 6 (IL-6), white blood count) were analyzed preoperatively and correlated with the clinical course and mortality. Additionally, a combination of the three markers, which performed best, was tested. RESULTS: Twenty patients (64.5%) in the analyzed cohort developed sepsis from an abdominal focus according to the latest sepsis definition. Out of the analyzed blood markers, presepsin exhibited the highest area under the curve, sensitivity, and specificity for the prediction of the development of sepsis. Moreover, presepsin had the highest predictive value for mortality as opposed to both endotoxin and previously established blood markers (i.e., PCT, IL-6). The multimarker approach, which included PCT, IL-6, and presepsin, showed no additional predictive value over presepsin alone. CONCLUSION: The present study suggests that presepsin is a novel predictor of sepsis and mortality from sepsis in patients undergoing surgery for intra-abdominal infections. The findings of the present study should be validated in a larger cohort.

Association between donor age and risk of graft failure after liver transplantation: an analysis of the Eurotransplant database.

Grafts from elderly donors are increasingly used for liver transplantation. As of yet there is no published systematic data to guide the use of specific age cutoffs the effect of elderly donors on patient outcomes must be clarified. This study analyzed the Eurotransplant database (01/01/2000-31/07/2014; N = 26 294) out of whom 8341 liver transplantations were filtered to identify for this analysis. 2162 of the grafts came from donors >60 including 203 from octogenarians ≥80 years. Primary outcome was the risk of graft failure according to donor age using a confounder adjusted Cox-Regression model with frailty terms (or random effects). The proportion of elderly grafts increased during the study period [i.e., octogenarians 0.1% (n = 1) in 2000 to 3.4% (n = 45) in 2013]. Kaplan-Meier and Cox-analyses revealed a reduced survival and a higher risk for graft failure with increasing donor age. Although the age effect was allowed to vary non-linearly, a linear association hazard ratio (HR = 1.1 for a 10 year increase in donor age) was evident. The linearity of the association suggests that there is no particular age at which the effect increases more rapidly, providing no evidence for a cutoff age. In clinical practice, the combination of high donor age with HU-transplantations, hepatitis C, high MELD-scores and long cold ischemic time should be avoided.

Surgical treatment of pNET - Experience of a "high-volume" center.

BACKGROUND: Neuroendocrine tumors of the pancreas (pNETs) are a rare disease. Grading according to the Ki67-index is the most validated risk factor. Nevertheless, controversies exist concerning other prognostic factors. The aim of this study was to evaluate published risk factors. METHODS: Patients with pancreatic NETs who underwent surgery at our department from 2000 to 2014 were analyzed. The patient and tumor characteristics were evaluated. Kaplan-Meier analyses, univariate calculations as well as multivariate analyses were performed. RESULTS: In total, 98 patients underwent surgery due to a pNET. The final study population consisted of 88 patients. Univariate analysis demonstrated that overall survival is influenced by tumor grading, local resection margin and presence of distant metastases. However, in the multivariate analysis, only grading and the resection margin had prognostic significance. The size of the primary tumor directly correlated with the probability of metastases. Multivisceral operations had no influence on morbidity or mortality. CONCLUSIONS: Resection of pNETs is the only curative treatment and is safe. Since the incidence of pNETs is low, treatment should be performed at a high-volume center.

Neuroendocrine tumors of the small intestine causing a desmoplastic reaction of the mesentery are a more aggressive cohort.

BACKGROUND: Desmoplastic reaction of the mesentery is commonly seen in patients with neuroendocrine tumors of the small intestine. However, it is not clear whether desmoplastic reaction is associated with tumor-specific characteristics and diminished prognosis. Therefore, the aim of this study was to investigate whether the presence of a desmoplastic reaction correlates with prognostic and molecular markers of neuroendocrine tumors of the small intestine. METHODS: Patients with neuroendocrine tumors of the small intestine operated at our department from 2000 to 2016 were analyzed. Patient and tumor characteristics were evaluated. Kaplan-Meier and multivariate analyses were performed. RESULTS: In total, 148 patients underwent surgery, and preoperative imaging was available in 113 patients. A total of 45 patients showed desmoplastic reaction of the mesentery and progression-free survival was significantly impaired (26 months versus 65.4 months) compared with patients without desmoplastic reaction. These patients had significantly more often distant metastases (84.4% vs 39.7%), lymphatic vessel (68.9% vs 44.1%), and perineural tissue infiltration (57.8% vs 17.6%) compared with patients without desmoplastic reaction. However, proliferation index (positive desmoplastic reaction 4.1% versus negative desmoplastic reaction 3.3%) and tumor size (positive desmoplastic reaction 2 cm versus negative desmoplastic reaction 1.9 cm) were not diverging significantly. CONCLUSION: This study revealed that tumors leading to desmoplastic reaction are more aggressive, despite similar Ki67 indices.

Effect of Intraoperative Single-Shot Application of Vancomycin in Liver Transplant Recipients on Postoperative Infections With Enterococcus faecium and Enterococcus faecalis.

OBJECTIVES: Infections are major causes of morbidity and mortality in the early postoperative period after liver transplant. We observed a high rate of enterococcal infections at our center. Therefore, we added an intraoperative single shot of vancomycin to the standard regimen of meropenem given over 5 days. The aim of this study was to determine the prevalence of both Enterococcus faecium and Enterococcus faecalis infections during the first 28 days after surgery depending on the type of antibiotic prophylaxis and their implications on mortality and morbidity. MATERIALS AND METHODS: Our retrospective cohort analysis included 179 patients: 93 patients received meropenem only and 86 patients were treated with meropenem plus vancomycin. RESULTS: During the first 28 days after transplant, microbiological tests showed that 51 patients (28.5%) were positive for Enterococcus faecium and 25 patients (14.0%) were positive for Enterococcus faecalis. Enterococcus faecium infections appeared significantly more often in patients without vancomycin (P = .013). In the second week after transplant, there was a significant reduction in Enterococcus faecium infections in the meropenem plus vancomycin group (P = .015). Enterococcus faecalis infections occurred more often in the patients receiving meropenem alone, but results were not statistically significant (P = .194). There was a trend toward more frequent renal replacement therapy in the meropenem plus vancomycin group. We found no differences between the groups regarding survival after 1 and 2 years, length of hospital stay, or duration in the intensive care unit. Overall 1-year survival was 78.8% (141/179 patients). CONCLUSIONS: Although postoperative Enterococcus species infections can be reduced after liver transplant by adding vancomycin to the intraoperative antibiotic regimen, it does not improve the long-term outcomes.

External Beam Radiation Therapy for Resectable Soft Tissue Sarcoma: A Systematic Review and Meta-Analysis.

PURPOSE: The aim of this study was to evaluate the role of preoperative and postoperative external beam radiation therapy (EBRT) in the treatment of resectable soft tissue sarcomas (STSs) of different tumor locations. METHODS: A systematic literature search was performed to identify studies investigating the effects of EBRT (versus no EBRT) on local recurrence (LR) and overall survival (OS) or comparing different EBRT sequences. Random effects meta-analyses were calculated and presented as cumulative odds ratios (ORs). RESULTS: Sixteen studies (n = 3958 patients) comparing EBRT versus no EBRT, including one randomized controlled trial (RCT) in extremity sarcoma, were analyzed. EBRT appeared to reduce LR in both retroperitoneal tumors (OR 0.47, p < 0.0001) and other locations (OR 0.49, p = 0.001). OS was improved by EBRT in retroperitoneal STSs (OR 0.37, p < 0.0001) but not in other tumor locations. Eleven studies (n = 2140), including one RCT, compared preoperative and postoperative radiotherapy. LR was less frequent following preoperative EBRT in retroperitoneal STSs (OR 0.03, p = 0.02), as well as in other tumor locations (OR 0.67, p = 0.01), while wound complications in extremity sarcoma were more frequent following preoperative EBRT (OR 2.92, p < 0.0001). Several studies included in this meta-analysis bear a high risk of bias and no RCT has been published for retroperitoneal STS. CONCLUSIONS: This meta-analysis supports the use of EBRT for local tumor control in patients with resectable STSs. Based on a small number of non-randomized studies, a positive effect on OS may exist in the subgroup of retroperitoneal STSs.

Temporary Intra-Operative Portocaval Shunts, Post-Operative Infections, and Mid-Term Survival after Cava-Sparing Liver Transplantation.

BACKGROUND: Temporary intra-operative portocaval shunts (TPCS) are believed to improve outcomes after cava-sparing liver transplantation. We hypothesize that decompression of the portal venous system via a TPCS reduces gut congestion, thereby decreasing bacterial translocation. Thus, we sought to clarify whether transplantation with a TPCS alters rates of post-operative infections and survival. PATIENTS AND METHODS: Patients undergoing liver transplantation (n = 189) were stratified by usage of a TPCS and the type of intra-operative antibiotic prophylaxis. Rates of post-operative infections were analyzed using the χ2 test. The log-rank test was used to compare 120-d survival. RESULTS: The analysis of patients transplanted with a TPCS and meropenem revealed increased infection rates with gut-specific pathogens (Escherichia coli, Escherichia faecalis, Escherichia faecium; p = 0.04) and equal 120-d survival in comparison with patients transplanted without a TPCS. When vancomycin was added to meropenem infection rates did not differ and patients transplanted with a TPCS had better survival in comparison with patients transplanted without a TPCS (p = 0.02). Within the TPCS group, the administration of meropenem and vancomycin was associated with improved survival in comparison with meropenem only (p = 0.03). CONCLUSION: Survival of patients may be improved by usage of a TPCS when gut-specific pathogens are covered by intra-operative antibiotic prophylaxis.

Results of the TOP Study: Prospectively Randomized Multicenter Trial of an Ex Vivo Tacrolimus Rinse Before Transplantation in EDC Livers.

BACKGROUND: Organ shortage results in the transplantation of extended donor criteria (EDC) livers which is associated with increased ischemia-reperfusion injury (IRI). Experimental studies indicate that an organ rinse with the calcineurin inhibitor tacrolimus before implantation protects against IRI. The tacrolimus organ perfusion study was initiated to examine the effects of ex vivo tacrolimus perfusion on IRI in transplantation of EDC livers. METHODS: A prospective randomized multicenter trial comparing ex vivo perfusion of marginal liver grafts (≥2 EDC according to Eurotransplant manual) with tacrolimus (20 ng/mL) or histidine-tryptophane-ketoglutarate solution (control) was carried out at 5 German liver transplant centers (Munich Ludwig-Maximilians University, Berlin, Heidelberg, Mainz, Regensburg) between October 2011 and July 2013. Primary endpoint was the maximum alanine transaminase (ALT) level within 48 hours after transplantation. Secondary endpoints were aspartate transaminase (AST), prothrombine ratio, and graft-patient survival within an observation period of 1 week. After an interim analysis, the study was terminated by the scientific committee after the treatment of 24 patients (tacrolimus n = 11, Control n = 13). RESULTS: Tacrolimus rinse did not reduce postoperative ALT peaks compared with control (P = 0.207; tacrolimus: median, 812; range, 362-3403 vs control: median, 652; range, 147-2034). Moreover, ALT (P = 0.100), prothrombine ratio (P = 0.553), and bilirubin (P = 0.815) did not differ between the groups. AST was higher in patients treated with tacrolimus (P = 0.011). Survival was comparable in both groups (P > 0.05). CONCLUSIONS: Contrary to experimental findings, tacrolimus rinse failed to improve the primary endpoint of the study (ALT). Because 1 secondary endpoint (AST) was even higher in the intervention group, the study was terminated prematurely. Thus, tacrolimus rinse cannot be recommended in transplantation of EDC livers.

Temporary Intraoperative Porto-Caval Shunts in Piggy-Back Liver Transplantation Reduce Intraoperative Blood Loss and Improve Postoperative Transaminases and Renal Function: A Meta-Analysis.

BACKGROUND: The value of temporary intraoperative porto-caval shunts (TPCS) in cava-sparing liver transplantation is discussed controversially. Aim of this meta-analysis was to analyze the impact of temporary intraoperative porto-caval shunts on liver injury, primary non-function, time of surgery, transfusion of blood products and length of hospital stay in cava-sparing liver transplantation. METHODS: A systematic search of MEDLINE/PubMed, EMBASE and PsycINFO retrieved a total of 909 articles, of which six articles were included. The combined effect size and 95 % confidence interval were calculated for each outcome by applying the inverse variance weighting method. Tests for heterogeneity (I 2) were also utilized. RESULTS: Usage of a TPCS was associated with significantly decreased AST values, significantly fewer transfusions of packed red blood cells and improved postoperative renal function. There were no statistically significant differences in primary graft non-function, length of hospital stay or duration of surgery. CONCLUSION: This meta-analysis found that temporary intraoperative porto-caval shunts in cava-sparing liver transplantation reduce blood loss as well as hepatic injury and enhance postoperative renal function without prolonging operative time. Randomized controlled trials investigating the use of temporary intraoperative porto-caval shunts are needed to confirm these findings.

Rescue management of early complications after liver transplantation-key for the long-term success.

PURPOSE: Postoperative complications may have not only immediate but also long-term effects on the outcomes. Here, we analyzed the effect of postoperative complications requiring a reoperation (grade 3b) within the first 30 days on patients' and graft survival following liver transplantation. METHODS: Graft and patient survival in relation to donor and recipient variables and the need of reoperation for complications of 277 consecutive liver transplants performed from January 2007 to December 2012 were analyzed. RESULTS: Two hundred seventy-seven liver transplants were performed in 252 patients. Overall patient and graft survival at 1, 2, and 3 years were significantly reduced in patients requiring a reoperation. The labMELD score was significantly elevated (p = 0.04) and cold ischemia time was prolonged (p = 0.03) in recipients undergoing reoperations. Kaplan-Meier curves indicate that complications impact the outcome primarily within the first 3 months after transplantation. In multivariate analyses, the actual need of reoperation (p < 0.001), the labMELD score (p = 0.05), cold ischemia time (p = 0.02), and the need for hemodialysis pre-transplant (p = 0.05) were the only variables which correlated with the overall survival. CONCLUSION: Postoperative complications resulting in reoperations have a significant impact on the outcome primarily in the early phase after liver transplantation. Successful management of postoperative complications is key to every successful liver transplant program.

Liver Resection for Non-colorectal Non-neuroendocrine Metastases: Where Do We Stand Today Compared to Colorectal Cancer?

The continuing controversy about surgery for non-colorectal non-neuroendocrine liver metastases (NCRNNE) necessitates identifying risk factors of worsened outcomes to improve patient selection and survival. Prospectively collected data of 167 patients undergoing hepatectomy for NCRNNE were analyzed, and a comparison to a matched population of colorectal liver metastases (CLM) was performed. Overall survival (OS) (35 vs. 54 months; P = 0.008) and recurrence-free survival (RFS) (15 vs. 29 months; P = 0.004) of NCRNNE patients were significantly shorter compared to those with CLM. The best survival was found in the genitourinary (GU; OS, 45 months; RFS, 21 months) NCRNNE subgroup, whereas survival for gastrointestinal (GI) metastases was low (OS, 8 months; RFS, 7 months). Patients with renal cell carcinoma (RCC) showed excellent outcomes when compared to CLM (OS, 50 vs. 51 months; P = 0.901). Extrahepatic disease (EHD) was identified as independent prognostic factor for reducing both RFS (P = 0.040) and OS (P = 0.046). The number of liver lesions (P = 0.024), residual tumor (P = 0.025), and major complications (P = 0.048) independently diminished OS. The degree of survival advantage by surgery is determined by the primary tumor site, EHD, the number of metastases, and residual tumor. Thus-even more than in CLM-these oncological selection criteria must prevail. GU metastases, especially RCC, represent a favorable subgroup.

SDF-1/CXCR4/CXCR7 is pivotal for vascular smooth muscle cell proliferation and chronic allograft vasculopathy.

Chronic rejection remains a major obstacle in transplant medicine. Recent studies suggest a crucial role of the chemokine SDF-1 on neointima formation after injury. Here, we investigate the potential therapeutic effect of inhibiting the SDF-1/CXCR4/CXCR7 axis with an anti-SDF-1 Spiegelmer (NOX-A12) on the development of chronic allograft vasculopathy. Heterotopic heart transplants from H-2bm12 to B6 mice and aortic transplants from Balb/c to B6 were performed. Mice were treated with NOX-A12. Control animals received a nonfunctional Spiegelmer (revNOX-A12). Samples were retrieved at different time points and analysed by histology, RT-PCR and proliferation assay. Blockade of SDF-1 caused a significant decrease in neointima formation as measured by intima/media ratio (1.0 ± 0.1 vs. 1.8 ± 0.1, P < 0.001 AoTx; 0.35 ± 0.05 vs. 1.13 ± 0.27, P < 0.05 HTx). In vitro treatment of primary vascular smooth muscle cells with NOX-A12 showed a significant reduction in proliferation (0.42 ± 0.04 vs. 0.24 ± 0.03, P < 0.05). TGF-ß, TNF-α and IL-6 levels were significantly reduced under SDF-1 inhibition (3.42 ± 0.37 vs. 1.67 ± 0.33, P < 0.05; 2.18 ± 0.37 vs. 1.0 ± 0.39, P < 0.05; 2.18 ± 0.26 vs. 1.6 ± 0.1, P < 0.05). SDF-1/CXCR4/CXCR7 plays a critical role in the development of chronic allograft vasculopathy (CAV). Therefore, pharmacological inhibition of SDF-1 with NOX-A12 may represent a therapeutic option to ameliorate chronic rejection changes.

En-bloc resection of a giant retroperitoneal lipoma: a case report and review of the literature.

BACKGROUND: Retroperitoneal lipomas are an extremely rare condition with only 17 cases described in the literature since 1980. They can reach enormous size and cause significant abdominal symptoms. The most important differential diagnosis is the well-differentiated liposarcoma, which preoperatively often may not definitely be ruled out. CASE PRESENTATION: We present the case of a 73 year-old Caucasian patient with a giant retroperitoneal lipoma of 9 kg measuring 55 cm in diameter. The patient presented with abdominal pain and swelling that had been slowly progressive for the last 15 years. On computerized tomography an immense retroperitoneal tumor was revealed. Intraoperatively, the tumor did not show any signs of infiltrative growth, therefore sole tumor extirpation was performed. CONCLUSION: Retroperitoneal lipomas are not clearly distinguishable from well-differentiated liposarcomas on imaging and even biopsies may be misleading. Moreover, abdominal symptoms, i.e. pain, obstipation and dysphagia may occur due to mechanical displacement. Therefore, surgical exploration with complete oncological resection is the therapy of choice if malignity cannot be ruled out.

Intraoperative simulation of remnant liver function during anatomic liver resection with indocyanine green clearance (LiMON) measurements.

OBJECTIVE: Post-hepatectomy liver failure (PHLF) is the major cause of death following liver resection. The aim of this study was to evaluate the feasibility of an intraoperative simulation of post-resection liver function. METHODS: Intraoperative liver function was measured by indocyanine green (ICG) clearance using the LiMON technology. In 20 patients undergoing anatomic liver resection, ICG plasma disappearance rate (PDR (%/min) and ICG retention at 15 min (R15 ) (%) were measured immediately after the induction of anaesthesia (t0 ), after selective arterial and portovenous inflow trial clamping (TC) of the resected liver segments (t1 ), after the completion of resection (t2 ) and before the closure of the abdominal cavity (t3 ). RESULTS: The median baseline (t0 ) PDR was 16.5%/min. Trial clamping of the inflow (t1 ) resulted in a significant reduction in PDR to 10.5%/min. Results under TC were similar to those obtained after resection (t2 ) (median PDR: 10.5%/min). Linear regression modelling showed that post-resection liver volume could be accurately predicted by TC of liver inflow (P < 0.0001), but not by determining the resected liver volume. Simulated post-resection liver function under TC correlated well with PHLF and length of hospital stay. CONCLUSIONS: Intraoperative ICG clearance measurements allow real-time monitoring of intraoperative liver function during surgery. Trial clamping of arterial and portovenous inflow accurately predicts immediate post-resection liver function. The intraoperative measurement of liver function and simulation of post-resection liver function may help to avoid PHLF.

Loss of liver transplant surgeons into alternate career paths.

In Germany, long-term commitment of surgeons to transplantation is rare. Most surgeons leave transplant surgery after a short stint and follow careers in other surgical fields. This rapid turnover of liver transplant surgeons may result in poor resource utilization and potentially compromise patient safety. In this report, we have analyzed the caseload and the careers of 25 surgeons in liver transplantation over a period of 22 years. The median time in liver transplantation was short. Of all surgeons who engaged in liver transplantation, the median time was 3.5 years. Surgeons who completed their training remained in the field for 7 years. Surgeons who prematurely stopped their training remained for 2 years. Individual total caseloads of transplant surgeons were relatively low. The median number of procedures was 40 for all surgeons, 153 for currently active surgeons, 51 for surgeons who completed training, 27 for surgeons currently in training, and a median of four liver transplantations for surgeons who prematurely stopped liver transplantation. The vast majority (75%) of surgeons prematurely quit liver transplantation to follow alternate surgical careers. Structural changes in academic transplant surgery have to be made to facilitate long-term commitments of interested surgeons and to avoid "futile" transplant careers.