Tissue-based miRNA mapping in alcoholic liver cirrhosis: different profiles in cirrhosis with or without hepatocellular carcinoma.

Context: Alcoholic liver cirrhosis is a significant risk factor for the development of hepatocellular carcinoma (HCC). The importance of tumour-associated cirrhosis in the development or progression of HCC is not understood. MiRNAs are important regulators for HCC development, but their role in HCC due to alcoholic liver cirrhosis is unclear.Objective: The aim of this study is the detection of miRNA expression in alcoholic liver cirrhosis, tumour-associated cirrhosis, and HCC.Materials and methods: We analysed the differences in the miRNA profiles of HCC, tumour-associated cirrhosis, and cirrhosis without HCC samples from 30 patients who underwent liver transplantation because of alcoholic liver disease.Results: Microarray analyses revealed 40 significantly differentially expressed miRNAs between HCC tissue and tumour-associated cirrhosis tissue. Furthermore, the microarray analysis discovered 56 differentially expressed miRNAs in tumour-associated cirrhosis and cirrhosis without HCC.Discussion: The differences of miRNA profile in alcoholic liver cirrhosis with and without HCC could improve understanding of HCC development, as well as lead to a new diagnostic tool in HCC screening.Conclusion: We were able to show for the first time, the differences of miRNA profile as promising biomarker in HCC, tumour-associated cirrhosis, and cirrhosis without HCC in context of alcoholic liver disease.

Milan criteria in the MELD era-is it justifiable to extend the limits for orthotopic liver transplantation?

BACKGROUND: The Milan criteria (MC) are widely used for the indication of liver transplantation (LTx) in hepatocellular carcinoma (HCC). Good long-term results have also been reported following LTx for patients exceeding the MC. In this article, we compare the overall and recurrence-free survival of our patients fulfilling and exceeding the MC according to the post-transplant histopathological results. PATIENTS AND METHODS: Data from 120 patients with HCC (22 females and 98 males) were analyzed. The median patient age was 61 years (Q1, Q3 54.7, 65.4), and the median MELD score was 11 (Q1, Q3 8, 15). The median follow-up period was 53 months (Q1, Q3 16.6, 78). Patients were categorized into established criteria (MC, up-to-seven (UTS), Asan criteria, AFP score), and the outcome of the individual groups was compared. RESULTS: Seventy-four of 120 patients fulfilled the MC, 86 patients met the UTS criteria, 85 patients fulfilled the Asan criteria, and 79 patients had an AFP score less than or equal to 2. The 1- and 5-year survival rates of all patients were 76.7% and 55.6%, respectively. In total, 14.2% of all patients (5.4% of patients who met the MC, 7% of patients who met the UTS criteria, 5.9% of patients who met the Asan criteria, and 6.3% of patients who had an AFP score less than 2) experienced recurrence. CONCLUSIONS: The outcomes of the patients were comparable to those reported in the current literature. In our population, similar recurrence and survival rates of the patients were noted for patients fulfilling the UTS criteria irrespective of fulfilling or exceeding the MC. Consequently, we consider using UTS criteria as the extended criterion for LTx indication.

The value of microparticles in detecting acute rejection episodes after liver transplantation.

CONTEXT: Non-invasive markers for diagnosis of acute rejection (AR) following liver transplantation have not been developed, yet. OBJECTIVE: We analyzed the correlation of plasma microparticle levels (MP) with AR. MATERIALS AND METHODS: MP (CD4, CD8, CD25, CD31, MHC) of 11 AR patients and 11 controls were analyzed within the first week after transplantation. RESULTS: CD4, CD8 and CD31 positive MP were higher in the AR, whereas overall MP count, CD25 and MHCI positive MP proportions did not differ between both groups. DISCUSSION AND CONCLUSION: MP dynamics within the first period of transplantation could help to clarify on-going mechanisms of immunomodulation.

Diagnosis of HCC for patients with cirrhosis using miRNA profiles of the tumor-surrounding tissue - A statistical model based on stepwise penalized logistic regression.

The presence of hepatocellular carcinoma (HCC) is a significant complication of cirrhosis because it changes the prognosis and the treatment of the patients. By now, contrast-enhanced CT and MR scans are the most reliable tools for the diagnosis of HCC; however, in some cases, a biopsy of the tumor is necessary for the final diagnosis. The aim of the study was to develop a diagnostic tool using the microRNA (miRNA) profiles of the tissue surrounding the HCC tumor combined with clinical parameters in statistical models. At a transplantation setting, 32 patients with HCC and cirrhosis (B) were compared to 22 patients suffering from cirrhosis only (A). The diagnosis and exclusion of HCC was confirmed following the histopathological examination of the explanted liver. The HCC patients were significantly older than the patients with cirrhosis only (B: 60.6 and A: 49.9, p<0.001) and showed higher levels of ALT (A: 0.76µkat/l, B: 1.02µkat/, p=0.006) and AFP (A: 5.8ng/ml, B: 70.3ng/ml, p<0.001), whereas the bilirubin levels were higher in the cirrhosis only group (p=0.002). Using age (cut-off 50.23years) and AFP (cut-off 4.2ng/ml) thresholds, the levels of expression of miR-1285-3p and miR-943 differentiated between the patients with HCC and cirrhosis from those with cirrhosis only with an accuracy of 96.3%. This is the first report about the use of stepwise penalized logistic regression and decision tree analyses of miRNA expressions in the tumor-surrounding tissue combined with clinical parameters for the diagnosis of HCC.

The value of hepatic resection in metastasic renal cancer in the Era of Tyrosinkinase Inhibitor Therapy.

BACKGROUND: The value of liver-directed therapy (LDT) in patients with metastasic renal cell carcinoma (MRCC) is still an active field of research, particularly in the era of tyrosinkinase inhibitor (TKI) therapy. METHODS: The records of 35 patients with MRCC undergoing LDT of metastasic liver lesions between 1992 and 2015 were retrospectively analyzed. Immediate postoperative TKI was given in a subgroup of patients after LDT for metastasic lesions. Uni- and multivariate models were applied to assess overall survival (OS), progression-free survival (PFS) and disease-free survival (DFS). RESULTS: Following primary tumor (renal cell cancer) resection and LDT, respectively, median OS was better for a total of 16 patients (41 %) receiving immediate postoperative TKI with 151 and 98 months, when compared to patients without TKI therapy with 61 (p = 0.003) and 40 months (p = 0.032). Immediate postoperative TKI was associated with better median PFS (47 months versus 19 months; p = 0.023), whereas in DFS only a trend was observed (51 months versus 19 months; p = 0.110). CONCLUSIONS: LDT should be considered as a suitable additive tool in the era of TKI therapy of MRCC to the liver. In this context, postoperative TKI therapy seems to be associated with better OS and PFS, but not DFS.

CD44 and CXCL9 serum protein levels predict the risk of clinically significant allograft rejection after liver transplantation.

The diagnosis of acute cellular rejection (ACR) after liver transplantation is based on histological analysis of biopsies because noninvasive biomarkers for allograft rejection are not yet established for clinical routines. CD31, CD44, and chemokine (C-X-C motif) ligand (CXCL) 9 have previously been described as biomarkers for cross-organ allograft rejection. Here, we assessed the predictive and diagnostic value of these proteins as serum biomarkers for clinically significant ACR in the first 6 months after liver transplantation in a prospective study. The protein levels were measured in 94 patients immediately before transplantation, at postoperative days (PODs) 1, 3, 7, and 14 and when biopsies were performed during episodes of biochemical graft dysfunction. The CD44 serum protein levels were significantly lower at POD 1 in patients who experienced histologically proven ACR in the follow-up compared with patients without ACR (P < 0.001). CXCL9 was significantly higher before transplantation (P = 0.049) and at POD 1 (P < 0.001) in these patients. Low CD44 values (cutoff, <200.5 ng/mL) or high CXCL9 values (cutoff, >2.7 ng/mL) at POD 1 differentiated between rejection and no rejection with a sensitivity of 88% or 60% and a specificity of 61% or 79%, respectively. The combination of both biomarker cutoffs at POD 1 had a positive predictive value of 91% and a negative predictive value of 67% for clinically significant ACR. Moreover, CD44 was significantly lower at the time of ACR (P < 0.001) and differentiated the rejection group from patients with graft dysfunction due to other reasons. Our results suggest that CD44 and CXCL9 may serve as predictive biomarkers to identify liver allograft recipients at risk for clinically significant ACR.

Long-term health-related quality of life of living kidney donors: a single-center experience.

PURPOSE: Over the last few years, the evaluation of the health-related quality of life (HRQoL) of living kidney donors (LKD) has become of particular interest. The present study sought to evaluate the physical and mental HRQoL after kidney removal. The clinical and paraclinical course of these patients was examined, and the impact of preoperative donor evaluation, donor nephrectomy, and surgical recovery was evaluated. These data were compared with reference data of the general population. METHODS: Between 1998 and 2010, 72 living kidney donations were performed at our institution. To assess the HRQoL, two questionnaires-the Short Form 36 (SF-36) and a special LKD questionnaire-were sent to all 72 living donors. The records of the follow-up examinations of all 72 donors were retrospectively analyzed in order to assess the clinical and paraclinical data after kidney donation. RESULTS: Out of 72 donors, 55 (76.4 %) responded to the questionnaires. There was no change in systolic and diastolic blood pressure during the 7-year follow-up (p > 0.05). Mild proteinuria (>150 mg/l) was observed in six cases. Kidney donors had a higher HRQoL compared to the general population with mean values of the physical and mental summation scale (PCS and MCS, respectively) being 51.3 (SD = 7.6) and 50.6 (SD = 8.1). Peri- or postoperative complications were associated with lower values for physical function and physical component summary (PCS) (p < 0.05). DISCUSSION: Living donor kidney transplantation appears to be safe for donors. The HRQoL is excellent. To ensure a positive outcome for donors, a good clinical evaluation of potential donors is essential.

Dynamic Parameters of Hypothermic Machine Perfusion-An Image of Initial Graft Function in Adult Kidney Transplantation?

Kidney allografts are subjected to ischemia reperfusion injury during the process of transplantation. Hypothermic machine perfusion (HMP) of deceased donor kidneys from organ procurement until transplantation is associated with a superior outcome when compared to static cold storage (SCS). Nevertheless, cold ischemia time (CIT) remains an independent risk factor for delayed graft function (DGF) in HMP-preserved kidney allografts as well. We performed a retrospective single-center study including all adult recipients who underwent deceased donor kidney-only transplantation at our center between January 2019 and December 2020. Beside the clinicopathological donor and recipient data, flow and resistance data during HMP were assessed. Short- and long-term kidney allograft outcome after end-ischemic HMP and SCS were analyzed and compared. Organ preservation consisted of either SCS (n = 88) or HMP (n = 45). There were no differences in recipient demographics and donor details between groups. CIT was significantly longer in the HMP group (16.5 [8.5−28.5] vs. 11.3 [5.4−24.1], p < 0.0001). The incidence of DGF as well as serum creatinine at discharge and at 1 year post transplant were comparable between groups. Duration of SCS prior to HMP was comparable among grafts with and without DGF. Flow rate and organ resistance at the start of HMP were significantly worse in DGF-kidney grafts (arterial flow 22.50 [18.00−48.00] vs. 51.83 [25.50−92.67] ml/min, p = 0.0256; organ resistance 123.33 [57.67−165.50] vs. 51.33 [28.17−111.50] mmHg/mL/min, p = 0.0050). Recipients with DGF had significantly worse creatinine levels at discharge (2.54 [1.08−7.64] vs. 1.67 [0.90−6.56], p < 0.0001) and at 1 year post transplant (1.80 [1.09−7.95] vs. 1.59 [0.87−7.40], p = 0.0105). In conclusion, baseline HMP parameters could be applied as a predictive tool for initial graft function, which in turn determines long-term outcome.

How Old Is Old? An Age-Stratified Analysis of Elderly Liver Donors above 65.

In liver transplantation, older donor age is a well-known risk factor for dismal outcomes, especially due to the high susceptibility of older grafts to ischemia-reperfusion injury. However, whether the factors correlating with impaired graft and patient survival following the transplantation of older grafts follow a linear trend among elderly donors remains elusive. In this study, liver transplantations between January 2006 and May 2018 were analyzed retrospectively. Ninety-two recipients of grafts from donors ≥65 years were identified and divided into two groups: (1) ≥65-69 and (2) ≥ 70 years. One-year patient survival was comparable between recipients of grafts from donors ≥65-69 and ≥70 years (78.9% and 70.0%). One-year graft survival was 73.1% (donor ≥65-69) and 62.5% (donor ≥ 70), while multivariate analysis revealed superior one-year graft survival to be associated with a donor age of ≥65-69. No statistically significant differences were found for rates of primary non-function. The influence of donor age on graft and patient survival appears not to have a distinct impact on dismal outcomes in the range of 65-70 years. The impact of old donor age needs to be balanced with other risk factors, as these donors provide grafts that offer a lifesaving graft function.

Current Treatment of Colorectal Liver Metastasis as a Chronic Disease.

BACKGROUND/AIM: The treatment of colorectal liver metastases is challenging and requires multidisciplinary strategies. Unfortunately, only 25% of patients with colorectal liver metastases are eligible for liver resection. Due to the variety of therapeutic approaches, this percentage has increased; however, at the same time, the definition of resectability has become complex. The aim of this review was to provide an overview of current surgical therapies for colorectal liver metastases. MATERIALS AND METHODS: Relevant studies published before June 2019 were identified using PubMed. A comprehensive review of the current literature regarding the impact of and innovations in the therapy of colorectal liver metastases was carried out. RESULTS: The major advances in the resectability of colorectal liver metastases were effective chemotherapy regimens and preoperative liver volume modulation techniques. In addition, health professionals face rapid technical developments in interventional local therapies, minimally invasive surgery, robot-assisted surgery and even liver transplantation. CONCLUSION: Currently, liver metastases from colorectal cancer are considered a chronic disease. In cases of advanced colorectal liver metastases, the definition of resectability and the indications for surgical treatment should be exclusively determined by experienced hepatobiliary surgeons.

Isolation of primary human hepatocytes after partial hepatectomy: criteria for identification of the most promising liver specimen.

Demands for primary human hepatocytes are continuously increasing, while supply is insufficient due to limited cell sources. To improve cell availability, the present study investigates the influence of donor liver characteristics on the outcome of hepatocyte isolation from surgically removed liver tissue (n = 50). Hepatocytes were isolated from liver specimens using a standardized two-step collagenase perfusion technique. The patient's sex, previous chemotherapy, or histopathology have shown no influence. Donor age significantly affected the isolation outcome, but was not found suitable for predicting cell yields. Preoperative blood parameters did not correlate with cell yield, although cell function was affected: total protein, albumin synthesis, and cell viability were significantly decreased for serum gamma-glutamyl-transferase (GGT) levels >60 U/L. Specimens from patients with benign diseases gave significantly higher cell yields than tissue removed due to secondary and primary tumors, respectively. The indication for surgery is a valuable basis for identifying the most yielding specimens. Hepatocytes from donors with high GGT levels appear to show reduced functional properties.

Tumor necrosis and infiltrating macrophages predict survival after curative resection for cholangiocarcinoma.

Background. Tumor necrosis as well as tumor-associated macrophages (TAMs) in the tumor invasive front (TIF) have been suggested to have a prognostic value in selected solid tumors, inclusive hilar cholangiocarcinoma. However, little is known regarding their influence on tumor progression and prognosis in intrahepatic cholangiocarcinoma (iCC). Methods. We analyzed surgically resected tumor specimens of human iCC (n = 88) for distribution and localization of TAMs, as defined by expression of CD68, formation of necrosis and extent of peritumoral fibrosis. Abundance of TAMs, tumor necrosis and grade of fibrosis were assessed immunohistochemically and histologically and correlated with clinicopathological characteristics, tumor recurrence and patients' survival. Statistical analysis was performed using SPSS software. Results. Patients with tumors characterized by low levels of TAMs in TIF or necrosis showed a significantly decreased 1-, 3- and 5-y recurrence-free survival and a significantly decreased overall survival, when compared with patients with tumors showing high levels of TAMs in TIF or no necrosis. Patients with high density of TAMs in TIF showed significantly lower incidence of tumor recurrence, as well (p < 0.05). Absence of tumor necrosis and TAMs in TIF were confirmed as independent prognostic variables in the multivariate survival analysis (all p < 0.05). Conclusions. High levels of TAMs in TIF or absence of histologic tumor necrosis are associated with a significantly improved recurrence-free and overall survival of patients with iCC. These results suggest TAMs and necrosis as valuable prognostic markers in routine histopathologic evaluation, and might indicate more individualized therapeutic strategies.

The value of liver resection for focal nodular hyperplasia: resection yes or no?

BACKGROUND: Focal nodular hyperplasia (FNH) are benign lesions in the liver. Although liver resection is generally not indicated in these patients, rare indications for surgical approaches indeed exist. We here report on our single-center experience with patients undergoing liver resection for FNH, focussing on preoperative diagnostic algorithms and quality of life (QoL) after surgery. METHODS: Medical records of 100 consecutive patients undergoing liver resection for FNH between 1992 and 2012 were retrospectively analyzed with regard to diagnostic pathways and indications for surgery. Quality of life (QoL) before and after surgery was evaluated using validated assessment tools. Student's t test, one-way ANOVA, χ (2), and binary logistic regression analyses such as Wilcoxon-Mann-Whitney test were used, as indicated. RESULTS: A combination of at least two preoperative diagnostic imaging approaches was applied in 99 cases, of which 70 patients were subjected to further imaging or tumor biopsy. In most patients, there was more than one indication for liver resection, including tumor-associated symptoms with abdominal discomfort (n = 46, 40.7 %), balance of risk for malignancy/history of cancer (n = 54, 47.8 %/n = 18; 33.3 %), tumor enlargement/jaundice of vascular and biliary structures (n = 13, 11.5 %), such as incidental findings during elective operation (n = 1, 0.9 %). Postoperative morbidity was 19 %, with serious complications (>grade 2, Clavien-Dindo classification) being evident in 8 %. Perioperative mortality was 0 %. Liver resection was associated with a significant overall improvement in general health (very good-excellent: preoperatively 47.4 % vs. postoperatively 68.1 %; p = 0.015). CONCLUSIONS: Liver resection remains a valuable therapeutic option in the treatment of either symptomatic FNH or if malignancy cannot finally be ruled out. If clinically indicated, liver resection for FNH represents a safe approach and may lead to significant improvements of QoL especially in symptomatic patients.

Single-center experience using organs after rescue allocation for pancreas transplant in the eurotransplant region.

OBJECTIVES: Because of the shortage of available organs for transplants, graft allocation polices have been modified recently. This report deals with the effect of using organs after rescue allocation for pancreas transplant in a single center in the Eurotransplant Region to possibly expand the donor pool. MATERIALS AND METHODS: A retrospective analysis was performed. Between 2007 and 2010, thirty-one pancreas transplants were performed at the University Hospital of Leipzig, in Leipzig, Germany. Among these, 7 cases used rescue organs. These organs had been officially offered to, but rejected by, at least 3 consecutive transplant centers. Donor/recipient and clinical/laboratory transplant/posttransplant outcomes from patients receiving rescue organs were collected and were compared with organs from conventional donors. RESULTS: Mean donor age was greater in the rescue organ group than in the conventional donor group (28.3 ± 10.7 y vs 23.0 ± 12.5 y). During follow-up (2.3 ± 0.6 y rescue organ group vs 3.9 ± 1.2 y conventional donor group), patient, kidney, and pancreas graft survival rates were 85% in all 3 categories in the rescue organ group, whereas outcomes for conventional donors were 88%, 85%, and 83%. Incidences of pancreatic graft thrombosis, delayed graft function, acute and late rejection episodes (eg, perioperative complications) were comparable between groups. No differences existed between mean serum urea levels and mean HbA1c levels between groups 2 years after transplant. Whereas 2 years after surgery, mean serum creatinine levels (rescue organ group, 78.8 ± 21.0 µmol/L vs 114.3 ± 28.4 µmol/L in the conventional donor group) showed significant differences between groups. CONCLUSIONS: Results are promising. Further pro-spective studies are warranted to evaluate routine transplant of organs after rescue allocation.

The collateral caval shunt as an alternative to classical shunt procedures in patients with recurrent duodenal varices and extrahepatic portal vein thrombosis.

Upper gastrointestinal bleeding episodes from variceal structures are severe complications in patients with portal hypertension. Endoscopic sclerotherapy and variceal ligation are the treatment options preferred for upper variceal bleeding owing to extrahepatic portal hypertension due to portal vein thrombosis (PVT). Recurrent duodenal variceal bleeding in non-cirrhotic patients with diffuse porto-splenic vein thrombosis and subsequent portal cavernous transformation represent a clinical challenge if classic shunt surgery is not possible or suitable.In this study, we represent a case of recurrent bleeding of duodenal varices in a non-cirrhotic patient with cavernous transformation of the portal vein that was successfully treated with a collateral caval shunt operation.

Liver resection in multimodal concepts improves survival of metastatic melanoma: a single-centre case-matched control study.

BACKGROUND/AIM: The aim of the present study was to define prognostic factors and to evaluate liver resection as an additive tool in metastatic melanoma. PATIENTS AND METHODS: In a case-control study, 32 patients with hepatic melanoma metastasis were analyzed between 1998-2012. Sixteen patients who underwent liver resection (6 patients with multimodal therapy) were matched to 16 patients scheduled for non-surgical approaches. Univariate and multivariate analyses were performed. RESULTS: Following primary resection and liver resection, respectively, survival was better for patients who underwent surgery in addition to multimodal therapy with 219 and 28 months, when compared to patients scheduled for non-surgical approaches with 64 (p=0.04) and 8 months (p=0.6). Following primary resection, primary tumor site, metastatic time <70 months, combination of multimodal therapy and surgery were of prognostic value (p<0.05). CONCLUSION: Liver resection should be considered a suitable additive tool in multimodal therapy of resectable metastatic melanoma.

Independent effects of sham laparotomy and anesthesia on hepatic microRNA expression in rats.

BACKGROUND: Studies on liver regeneration following partial hepatectomy (PH) have identified several microRNAs (miRNAs) that show a regulated expression pattern. These studies involve major surgery to access the liver, which is known to have intrinsic effects on hepatic gene expression and may also affect miRNA screening results. We performed two-third PH or sham laparotomy (SL) in Wistar rats to investigate the effect of both procedures on miRNA expression in liver tissue and corresponding plasma samples by microarray and qRT-PCR analyses. As control groups, non-treated rats and rats undergoing anesthesia only were used. RESULTS: We found that 49 out of 323 miRNAs (15%) were significantly deregulated after PH in liver tissue 12 to 48 hours postoperatively (>20% change), while 45 miRNAs (14%) were deregulated following SL. Out of these miRNAs, 10 miRNAs were similarly deregulated after PH and SL, while one miRNA showed opposite regulation. In plasma, miRNA upregulation was observed for miR-133a and miR-133b following PH and SL, whereas miR-100 and miR-466c were similarly downregulated following anesthesia and surgery. CONCLUSIONS: We show that miRNAs are indeed regulated by sham laparotomy and anesthesia in rats. These findings illustrate the critical need for finding appropriate control groups in experimental surgery.

Renal autotransplantation--a possibility in the treatment of complex renal vascular diseases and ureteric injuries.

BACKGROUND: We report our contemporary experiences with renal autotransplantation in patients with complicated renal vascular diseases and/or complex ureteral injuries. Since its first performance, renal autotransplantation has been steadily improved and become a safe and effective procedure. MATERIAL/METHODS: Between 1998 and 2006, 6 renal autotransplantations in 6 patients were performed at the University Medical Center of Leipzig. After nephrectomy and renal perfusion ex vivo, the kidney was implanted standardized in the fossa iliaca. The vessels were anastomized to the iliac vessels, the ureter was reimplanted in an extravesical tunneled ureteroneocystostomy technique according to Lich-Gregoir. Demographic, clinical, and laboratory data of the patients were collected and analyzed for pre-, intra-, and postoperative period. RESULTS: Indications for renal autotransplantation were complex renovascular diseases in 2 patients (1 with fibromuscular dysplasia and 1 with Takayasu's arteritis) and in 4 patients with complex ureteral injuries. The median duration of follow-up was 9.7 years (range: 5.6-13.3). The laboratory values of our 6 patients showed improvements of creatinine, urea and blood pressure levels in comparison to the preoperative status at the end of follow-up period. CONCLUSIONS: The present study reports excellent results of renal autotransplantation in patients with renovascular disease or complex ureteric injuries. After a median follow-up of 9.7 years all 6 patients present with stable renal function as well as normal blood pressure values. Postoperative complications were observed with a rate comparable to other studies.