Obesity and its influence on liver dysfunction, morbidity and mortality after liver resection.

Background: Obesity and associated steatosis is an increasing health problem worldwide. Its influence on post-hepatectomy liver failure (PHLF) and after liver resection (LR) is still unclear. Methods: Patients who underwent LR were investigated and divided into three groups [normal weight: body mass index (BMI) 18.5-24.9 kg/m2, overweight: BMI 25.0-29.9 kg/m2, obese: BMI ≥30 kg/m2] in this retrospective study. Primary aim of this study was to assess the influence of BMI and nonalcoholic steatohepatitis (NASH) on PHLF and morbidity. Results: Of 888 included patients, 361 (40.7%) had normal weight, 360 (40.5%) were overweight, 167 (18.8%) were obese. Median age was 62.5 years (IQR, 54-69 years). The primary indication for LR was colorectal liver metastases (CLM) (n=366, 41.2%). NASH was present in 58 (16.1%) of normal weight, 84 (23.3%) of overweight and 69 (41.3%) of obese patients (P<0.001). PHLF occurred in 16.3% in normal weight, 15.3% in overweight and 11.4% in obese patients (P=0.32). NASH was not associated with PHLF. There was no association between patients' weight and the occurrence of postoperative complications (P=0.45). At multivariable analysis, solely major LR [odds ratio (OR): 2.7, 95% confidence interval (CI): 1.83-4.04; P<0.001] remained a significant predictor for PHLF. Conclusions: Postoperative complications and PHLF are comparable in normal weight, overweight and obese patients and LRs using modern techniques can be safely performed in these patients.

Incidence and risk factors for anastomotic bile leakage in hepatic resection with bilioenteric reconstruction - A international multicenter study.

BACKGROUND: Anastomotic leak (AL) after bilioenteric reconstruction (BR) is a feared complication after bile duct resection, especially in combination with liver resection. Literature on surgical outcome is sparse. This study aimed to determine the incidence and risk factors for AL after combined liver and bile duct resection with a focus on operative or endoscopic reinterventions. METHODS: Data from consecutive patients who underwent liver resection and BR between 2004 and 2018 in 11 academic institutions in Europe were collected from prospectively maintained databases. RESULTS: Within 921 patients, AL rate was 5.4% with a 30d mortality of 9.6%. Pringle maneuver (p<0.001),postoperative external biliary (p=0.007) and abdominal drainage (p<0.001) were risk factors for clinically relevant AL. Preoperative biliary drainage (p<0.001) was not associated with a higher rate of AL. AL was more frequent in stented patients (76.5%) compared to PTCD (17.6%) or PTCD+stent (5.9%,p=0.017). AL correlated with increased incidence of postoperative liver failure (p=0.036), cholangitis, hemorrhage and sepsis (all p<0.001). CONCLUSION: This multicenter data provides the largest series to date of LR with BR and could help in the management of these patients which are often challenging and hampering the patients' postoperative course negatively.

von Willebrand Factor Antigen Predicts Outcomes in Patients after Liver Resection of Hepatocellular Carcinoma.

Background/Aims: von Willebrand factor antigen (vWF-Ag) is a noninvasive predictor of portal hypertension that serves as a negative prognostic marker in various malignancies. Increased portal hypertension is associated with higher postoperative morbidity and decreased survival after hepatectomy. The purpose of this study was to determine the correlation between vWF-Ag, postoperative morbidity and oncological outcome. Methods: This analysis includes 55 patients who underwent liver resection for hepatocellular carcinoma (HCC) between 2008 and 2015 with available preoperative vWF-Ag levels. The primary endpoints were postoperative complications and long-term outcome, including overall and disease-free survival. Results: The median plasma level of vWF-Ag was 191% (range, 162.5% to 277%). There was a significant correlation between vWF-Ag levels and tumor size in the resected specimens (p=0.010, r=0.350). Patients who developed any grade of postoperative complication had significantly higher preoperative vWF-Ag levels (216% [range, 178% to 283.25%] vs 176% [range, 148% to 246%], p=0.041). Median overall survival was 39.8 months in patients with high vWF-Ag levels (≥191%) compared with 73.4 months in patients with low levels (<191%, p=0.007). Of note, there was a remarkable disparity in the number of patients who died of HCC with low versus high vWF-Ag levels (14.8% vs 28.6%, p=0.011). Conclusions: vWF-Ag may serve as a prognostic marker for the outcome of patients undergoing liver resection for HCC that is closely connected to tumor size, postoperative complication rate and long-term outcome.

The value of indocyanine green clearance assessment to predict postoperative liver dysfunction in patients undergoing liver resection.

Postoperative liver dysfunction remains a major concern following hepatic resection. In order to identify patients who are at risk of developing liver dysfunction, indocyanine green (ICG) clearance has been proposed to predict postoperative liver function. All patients who underwent liver resection at the Medical University Vienna, Austria between 2006 and 2015 with preoperative ICG clearance testing (PDR, R15) were analyzed in this study. Postoperative liver dysfunction was analyzed as defined by the International Study Group of Liver Surgery. Overall, 698 patients (male: 394 (56.4%); female: 304 (43.6%)) with a mean age of 61.3 years (SD: 12.9) were included in this study, including 313 minor liver resections (44.8%) and 385 major liver resections (55.2%). One hundred and seven patients developed postoperative liver dysfunction after liver resection (15.3%). Factors associated with liver dysfunction were: male sex (p = 0.043), major liver resection (p < 0.0001), and preoperative ICG clearance (PDR (p = 0.002) and R15 (p < 0.0001)). Notably ICG clearance was significantly associated with liver dysfunction in minor and major liver resections respectively and remained a predictor upon multivariable analysis. An optimal cut-off for preoperative ICG clearance to accurately predict liver dysfunction was PDR < 19.5%/min and R15 > 5.6%. To the best of our knowledge, this is the largest study analyzing the predictive value of preoperative ICG clearance assessment in patients undergoing liver resection. ICG clearance is useful to identify patients at risk of postoperative liver dysfunction.

Quantifying changes in innate immune function following liver transplantation for chronic liver disease.

BACKGROUND: Liver transplantation (LT) offers patients with cirrhosis long-term survival, however many die from sepsis whilst awaiting LT. The liver's role in innate immunity may be key to improving outcomes, but the immune effects of LT have not been quantified. METHODS: Innate immune capacity was assessed by clearance of 99mTc-Albumin nanospheres in patients with chronic liver failure before and after LT. RESULTS: Twenty-eight patients with chronic liver disease on the LT waiting list entered the study during the twelve-month study period and nine patients underwent LT and completed the study protocol. One patient developed hepatic artery thrombosis in <7 days and was excluded from the study. Innate immune function was significantly impaired in patients with chronic liver disease on the LT waiting list and this was directly correlated with MELD score. LT normalised innate immune function by day 1 post LT with further improvement occurring by day 7 post LT. Donor liver weight was the only factor correlated with innate immune function at day 1 post LT but this effect was negated by day 7 post LT. CONCLUSION: Recognising the immune effects of LT may facilitate treatment of cirrhosis and inform development of extracorporeal liver support systems.

Liver resection for non-colorectal metastases.

Whereas liver resection for colorectal metastasis has become standard of care, hepatectomy in patients with non-colorectal metastases remains controversial, mainly due to a heterogeneous tumor biology and missing data from prospective trials. This review aims at giving an overview about the indications and limits of liver surgery in patients with an advanced disease of a non-colorectal malignancy. Even though prospective trials are largely missing, results from retrospective studies indicate a survival benefit for liver resection in selected patients. Thus, in metastasized patients, treatment strategies should be developed in a multidisciplinary tumor board including an experienced liver surgeon.

Microscopic biliary and perineural invasion and clinical outcome after neoadjuvant bevacizumab-based chemotherapy and liver resection in patients with colorectal liver metastases.

BACKGROUND: The value of microscopic biliary and perineural invasion as prognostic biomarkers in patients with resectable colorectal liver metastases (CLM) who undergo neoadjuvant chemotherapy and liver resection is still unclear. This retrospective study was performed to elucidate this issue. METHODS: Histologic slides of resected CLM of patients who underwent neoadjuvant bevacizumab-based chemotherapy and liver resection were investigated with respect to biliary and perineural invasion. Presence of invasion was correlated with radiologic and histologic response, recurrence-free survival (RFS) and overall survival (OS). RESULTS: One hundred forty-one patients were enrolled. There was a significant association between biliary and perineural invasion, respectively (P = 0.001). Moreover, both biliary and perineural invasion were associated with bilobar metastatic spread and higher number of metastases, while perineural invasion was also associated with a higher Fong score. No significant association was found with response. In univariable analysis, biliary and perineural invasion were associated with shorter RFS (median 10.1 vs. 13.5 months, HR 2.09, P = 0.010 and 7.6 vs. 14.0, HR 2.23, P = 0.001, respectively). Biliary invasion was also associated with shorter OS (median 32.8 months vs. not reached, HR 2.78, P = 0.010), however these results did not remain significant in multivariable analysis. CONCLUSIONS: In patients with resectable colorectal liver metastases undergoing neoadjuvant bevacizumab-based chemotherapy and liver resection, biliary and perineural invasion are associated with higher tumor load but may not be prognostic biomarkers.

Inflammatory response and oxidative stress during liver resection.

BACKGROUND: Postoperative complications are still a major concern after liver resection (LR). Systemic inflammation and deregulated reactive oxygen species during major abdominal surgery may impair outcome after hepatectomy. METHODS: Patients undergoing LR were included in this study (n = 40). Oxidative stress (OS) was measured peri- and post-operatively as static oxidation-reduction potential markers (sORP) and antioxidant capacity ORP (cORP) by using the RedoxSYS Diagnostic system. Furthermore, Th1- and Th2-specific cytokines were assessed. RESULTS: Whereas there was no significant change in systemic sORP during LR and in the early postoperative course, there was a substantial decrease of cORP immediately post-surgery, and on postoperative days 1 and 3 (p<0.001). OS response was tightly regulated, as there was a significant correlation between sORP and cORP (p<0.0001; R2:0.457). An increase of OS (sORP) after LR of more than 3 mV was predictive for severe postoperative complications (53.8% vs. 12.5; p = 0.017). There was a significantly higher IL-2 (p = 0.006) and IL-5 (p = 0.001) increase during hepatectomy in patients who developed a severe morbidity. CONCLUSION: Antioxidant capacity remained stable during LR but dropped during the post-surgical period, suggesting a consumption of antioxidants to maintain OS within healthy range. Severe postoperative complications were associated with a pronounced inflammatory response during surgery.

Impact of Neoadjuvant Chemotherapy on Clinical Risk Scores and Survival in Patients with Colorectal Liver Metastases.

BACKGROUND: Several clinical risk scores for patients with colorectal liver metastases (CLM) were established in cohorts of patients undergoing liver resection (LR) without neoadjuvant chemotherapy (NAC). The purpose of the study was to evaluate the predictive values of four common risk scores in the setting of NAC and the impact of score changes during NAC. METHODS: Risk scores (Fong, Nordlinger, Nagashima, and Konopke) were retrospectively calculated for 336 patients undergoing LR for CLM, including 109 patients without and 227 patients with NAC. In patients with NAC, the scores were calculated before and after NAC. RESULTS: In patients without NAC (n = 109), all risk scores except the Konopke score showed a significant correlation with disease-free survival (DFS). Only the Nagashima score also was predictive for overall survival (OS). In patients with NAC (n = 227), all scores except the Konopke score were predictive for DFS and OS before and after NAC. Score changes in the Fong and the Nagashima score showed a significant correlation with DFS and OS. CONCLUSIONS: Nagashima score was the most universally applicable score and predicted prognosis in all tested scenarios.

Transection Speed and Impact on Perioperative Inflammatory Response - A Randomized Controlled Trial Comparing Stapler Hepatectomy and CUSA Resection.

BACKGROUND: Parenchymal transection represents a crucial step during liver surgery and many different techniques have been described so far. Stapler resection is supposed to be faster than CUSA resection. However, whether speed impacts on the inflammatory response in patients undergoing liver resection (LR) remains unclear. MATERIALS AND METHODS: This is a randomized controlled trial including 40 patients undergoing anatomical LR. Primary endpoint was transection speed (cm2/min). Secondary endpoints included the perioperative change of pro- and anti-inflammatory cytokines, overall surgery duration, length of hospital stay, morbidity and mortality. RESULTS: Mean transection speed was significantly higher in patients undergoing stapler hepatectomy compared to CUSA resection (CUSA: 1 (0.4) cm2/min vs. Stapler: 10.8 (6.1) cm2/min; p<0.0001). Analyzing the impact of surgery duration on inflammatory response revealed a significant correlation between IL-6 levels measured at the end of surgery and the overall length of surgery (p<0.0001, r = 0.6188). Patients undergoing CUSA LR had significantly higher increase of interleukin-6 (IL-6) after parenchymal transection compared to patients with stapler hepatectomy in the portal and hepatic veins, respectively (p = 0.028; p = 0.044). C-reactive protein levels on the first post-operative day were significantly lower in the stapler cohort (p = 0.010). There was a trend towards a reduced overall surgery time in patients with stapler LR, especially in the subgroup of patients undergoing minor hepatectomies (p = 0.020). CONCLUSIONS: Liver resection using staplers is fast, safe and suggests a diminished inflammatory response probably due to a decreased parenchymal transection time. TRIAL REGISTRATION: ClinicalTrials.gov NCT01785212.

The cutting (w)edge--comparative evaluation of renal baseline biopsies obtained by two different methods.

BACKGROUND: The assessment of donor-derived damage of transplanted kidneys might be instrumental for estimating donor organ quality and for predicting short- and long-term organ outcome. In the present study, we report a new standardized method for obtaining pre-transplant kidney biopsy specimens. Instead of taking wedge biopsies (WBs), a skin punch biopsy (PB) tool was utilized to obtain standardized biopsy samples that also represented deeper cortical zones. METHODS: We compared 147 PB specimens and 114 WBs with respect to the number of glomeruli and arterial vessels they contained. The performance of the two biopsy methods in detecting glomerular damage, interstitial fibrosis/tubular atrophy (IF/TA) and arteriosclerosis was determined by evaluation of subsequent transplant core biopsies of the patients. Statistical comparison employed Kruskal-Wallis and kappa (κ) tests. RESULTS: Significantly more PB samples (89%) than WBs (66%) were diagnostically adequate according to the Banff criteria. Despite a higher number of glomeruli in WBs (34.6 versus 21.7 in punch biopsies), arteries were present in only 68% of WBs but could be found in 93% of punch biopsies. The comparison of findings in pre-transplant biopsies with lesions in corresponding post-transplant core biopsies revealed a superior diagnostic concordance for IF/TA and arteriosclerosis for punch biopsies than for WBs, reaching kappa values of 0.823 versus 0.729 and 0.661 versus 0.516, respectively. CONCLUSION: The use of skin PB tools for obtaining baseline biopsies from transplanted kidneys is a safe and effective method for assessment of donor-derived damage of the organ.

The effect of steroid pretreatment of deceased organ donors on liver allograft function: a blinded randomized placebo-controlled trial.

BACKGROUND & AIMS: Brain death-associated inflammatory response contributes to increased risk of impaired early liver allograft function, which might be counterbalanced by steroid pretreatment of the organ donor. The aim of this randomized controlled trial was to elucidate whether steroid pretreatment of liver donors improves early liver allograft function, prevents rejection and prolongs survival. METHODS: A placebo-controlled blinded randomized clinical trial was performed in three different centers in Austria and Hungary between 2006 and 2008. Ninety deceased organ donors received either 1000 mg of methylprednisolone or placebo 6h before recovery of organs. The primary end point was the concentration slope of transaminases within the first week. The secondary end point included survival and biopsy-confirmed acute rejection (BCAR) within 3 years after transplantation. RESULTS: Of the 90 randomized donors, 83 recipients were eligible for study. The trajectories of ALT and AST were not different between treatments (p=0.40 and p=0.13, respectively). Eight subjects died in the steroid and 13 in the placebo group within 3 years after engraftment (RR=0.63 95% CI [0.29,1.36], p=0.31). Eleven recipients experienced biopsy-confirmed rejection (BCAR) in the steroid and 11 in the placebo group (RR=1.02 95% CI [0.50,2.10], p=1.00). No effect modification could be identified in the predefined strata of donor age, sex, cold ischemic time, and cause of donor death. CONCLUSIONS: Steroid pretreatment of organ donors did not improve outcomes after liver transplantation.

Colorectal liver metastasis in the setting of lymph node metastasis: defining the benefit of surgical resection.

BACKGROUND: For patients with colorectal liver metastasis (CLM), the presence of concomitant perihepatic/para-aortic lymph node metastasis (LNM) is considered a contraindication to liver resection. We sought to determine the benefits of liver resection among patients with CLM + LNM by examining long-term outcomes among a large cohort of patients. METHODS: Between October 1996 and December 2007, 61 patients with CLM and pathologically proven LNM were identified from an international multi-institutional database of 1629 patients. The effect of LNM, as well as other prognostic factors, on recurrence-free and overall survival was analyzed. RESULTS: Median overall survival was 32 months, and 1-, 3-, and 5-year overall survival were 86, 35, and 18%, respectively. Five patients were alive and disease-free at last follow-up. Survival was associated with location of LNM. Specifically, 5-year overall survival was 30% among patients with LNM along the hepatoduodenal ligament/retropancreatic area (area 1), 14% among patients with LNM along the common hepatic artery/celiac axis (area 2), and there was only one long-term survivor who experienced recurrent disease among patients who had CLM + para-aortic LNM (area 3) (P = 0.004). On multivariate analyses, overall margin status (hazard ratio [HR] = 2.0), treated number of metastases >6 (HR = 2.3) and para-aortic lymph node involvement (HR = 2.6) each remained significantly associated with increased risk of death (all P < 0.05). CONCLUSIONS: Although overall survival in the setting of LNM is only 18%, certain subsets of patients with LNM can benefit from surgical resection. Specifically, patients with CLM + LNM isolated to area 1 had a 5-year survival of approximately 30%, while long-term survival among patients with para-aortic LNM was rare.

Effect of intraportal infusion of tacrolimus on ischaemic reperfusion injury in orthotopic liver transplantation: a randomized controlled trial.

The increased use of older and/or marginal donor organs in liver transplantation over the last decade calls for strategies to minimize ischaemic reperfusion (I/R) injury to prevent early graft failure. Tacrolimus, a very potent and effective calcineurin inhibitor, was selected because of its ability to ameliorate I/R injury. A randomized, blinded, controlled single-centre trial of 26 liver transplant recipients was performed between February 2008 and December 2009. Donor organs were randomized to be perfused intraportally during liver transplantation with 1.5 l 5% albumin infusion containing either 20 ng/ml tacrolimus or placebo. The primary end point was liver function as assessed by aspartate transaminase (AST) or alanine transaminase (ALT) levels 6 days after transplantation. Treatment effectiveness was tested by transcriptome-wide analysis of biopsies. There was no difference in the primary end point, i.e. AST (IU/l) and ALT (IU/l) at day 6 after transplantation between groups. Furthermore, choleastatic parameters as well as parameters of liver synthesis were not different between groups. However, tacrolimus treatment suppressed inflammation and immune response in the transplanted liver on a genome-wide basis. Intrahepatic administration of tacrolimus did not result in a reduction of AST and ALT within the first week after transplantation.

Liver resection for colorectal metastases in presence of extrahepatic disease: results from an international multi-institutional analysis.

BACKGROUND: Hepatic resection for colorectal liver metastasis (CLM) with concomitant extrahepatic disease (EHD) is a controversial topic. We sought to evaluate the long-term outcome of patients undergoing liver resection for CLM in presence of EHD and identify factors associated with prognosis. METHODS: From 1996 to 2007, a total of 1629 patients who underwent resection of CLM were identified from an international multi-institutional database. One hundred seventy-one patients (10.4%) underwent resection of EHD. Clinicopathologic and outcome data were collected and analyzed by univariate and multivariate analyses. RESULTS: Median number of treated CLM was 2 (range, 1-18); most patients had solitary EHD (n = 114; 66.6%) a single anatomic site of EHD (n = 153; 89.4%). The 5-year survival for patients with EHD was 26% compared with 58% for those without EHD (P < 0.001). Recurrence was common (84%). Among patients with EHD, R1 margin status, multiple EHD sites, and location of EHD were associated with worse survival (all P < 0.05). Patients with multiple EHD sites or aortocaval lymph node metastasis had a 5-year survival of 14% and 7%, respectively. When survival was stratified by the total number of metastases treated, the presence of EHD still had a prognostic impact, but the relative impact of EHD diminished as the total number of metastases treated increased. CONCLUSION: Concurrent resection of hepatic and EHD in well-selected patients may provide the possibility of long-term survival. The risk of recurrence, however, remains high, and a worse outcome is associated with both number of metastases and location of EHD.

Osteopontin expression predicts overall survival after liver transplantation for hepatocellular carcinoma in patients beyond the Milan criteria.

BACKGROUND & AIMS: Microarray data showed that osteopontin overexpression predicts early HCC-recurrence after liver resection. Osteopontin (OPN) expression could serve as a predictor of HCC-recurrence after OLT. METHODS: Osteopontin expression was investigated immunohistochemically in a unique population of 125 HCC-patients undergoing OLT between 1982 and 2002, including 81 patients (65%) outside the Milan criteria. Multivariate analysis of factors associated with median overall survival (OS) and time to recurrence (TTR) was performed. RESULTS: Osteopontin was expressed in 40/125 (32%) of the HCCs. Overall survival post-OLT at 1, 2, 3, 5 years was 77%, 62%, 52%, and 43% (median survival 37 months). Overall survival was significantly longer without expression of OPN (p < 0.05; (median OS: 56 vs. 23 months). The same was true for median TTR (p = 0.008). Outside Milan criteria, patients without OPN-expression had better prognosis (median OS: 37.8 vs. 19.2 months, p = 0.003). Tumor recurrence in patients transplanted outside Milan criteria occurred in 43% (23 of 54) of patients without and 70% (19 of 27, p = 0.018) of patients with OPN-expression after a median TTR of 83.5 vs. 13.9 months. On multivariate analysis, vascular invasion and OPN-expression were independently associated with OS and TTR in HCC-patients after OLT. CONCLUSIONS: Immunohistochemically detectable Osteopontin in HCC is an independent predictor of tumor recurrence and survival in patients beyond Milan criteria undergoing OLT.

What defines 'cure' after liver resection for colorectal metastases? Results after 10 years of follow-up.

BACKGROUND: During the last two decades, resection of colorectal liver metastases (CLM) in selected patients has become the standard of care, with 5-year survival rates of 25-58%. Although a substantial number of actual 5-year survivors are reported after resection, 5-year survival rates may be inadequate to evaluate surgical outcomes because a significant number of patients experience a recurrence at some point. OBJECTIVES: This study aimed to analyse longterm results and prognostic factors in liver resection for CLM in patients with complete 10-year follow-up data. METHODS: A total of 369 patients who underwent liver resection for CLM between 1985 and 1998 were identified from a bi-institutional database. Postoperative deaths and patients with extrahepatic disease were excluded. Clinicopathological prognostic factors were analysed using univariate and multivariate analyses. RESULTS: The sample included 309 consecutive patients with complete 10-year follow-up data. Five- and 10-year overall survival rates were 32% and 23%, respectively. Overall, 93% of recurrences occurred within the first 5 years of follow-up, but 11% of patients who were disease-free at 5 years developed later recurrence. Multivariate analysis demonstrated four independent negative prognostic factors for survival: more than three metastases; a positive surgical margin; tumour size >5 cm, and a clinical risk score >2. CONCLUSIONS: Five-year survival rates are not adequate to evaluate surgical outcomes of patients with CLM. Approximately one-third of actual 5-year survivors suffer cancer-related death, whereas patients who survive 10 years appear to be cured of disease.

KiSS-1 overexpression as an independent prognostic marker in hepatocellular carcinoma: an immunohistochemical study.

The KiSS-1 gene has been reported to play an important role as a metastasis suppressor gene in various human malignancies. However, there is little information about its possible role in hepatocellular carcinoma (HCC). In this study, we evaluated the prognostic significance of the expression of KiSS-1 and its receptor AXOR12 in 142 HCC tissue specimens by immunohistochemistry. By using a cutoff level of 50%, immunoreactivity of KiSS-1 and AXOR12 was found in 6 (4%) and 11 (8%) HCCs. The expression of KiSS-1 and AXOR12 in HCC correlated with each other (r = 0.42, p < 0.0001) and with the expression in corresponding, surrounding liver tissue (both r = 0.35, p < 0.0001). Positive AXOR12 immunoreactivity in HCC correlated with advanced pT-stage of tumors and low tumor grading (r = 0.18, p = 0.032; r = -0.18, p = 0.029). High KiSS-1 expression in HCC had a statistically significant influence on diminished disease-free and overall survival in uni- (p = 0.006 and p = 0.002) and multivariate analysis (r = 2.874, p = 0.027 and r = 2.913, p = 0.026). In this study, we report for the first time that elevated KiSS-1 expression level in HCC correlates with worsened clinical outcome, as an independent prognostic marker for the aggressiveness of HCC.

Mcl-1 overexpression in hepatocellular carcinoma: a potential target for antisense therapy.

BACKGROUND/AIMS: Recently, the anti-apoptotic Mcl-1 protein has been reported as a resistance factor in various types of cancer. Here we investigated the presence of Mcl-1 protein in hepatocellular carcinoma (HCC) tissues and its potential role as a molecular drug target for HCC therapy. METHODS: HCC specimens of 149 patients were examined by immunohistochemistry for Mcl-1 expression. Antisense oligonucleotides (ASO) targeting Mcl-1 were evaluated as monotherapy and in combination with cisplatin in the HCC cell lines HepG2 and Snu398. Protein regulation, cell viability, and apoptosis were assessed by western blotting, cell counting, and FACS analysis. RESULTS: Mcl-1 protein is overexpressed in 51% of all cases irrespective of underlying disease. Targeting Mcl-1 by ASO specifically downregulated Mcl-1 protein expression and led to significant dose and time dependent single agent activity in HCC cells characterized by increased apoptosis and decreased cell viability. No significant target regulation or cell death was observed for control oligonucleotide treatment. Upon combination with cisplatin, Mcl-1 ASO revealed a significant chemosensitizing effect. CONCLUSIONS: Mcl-1 is overexpressed in half of HCC-tissues. ASO targeting Mcl-1 revealed a prominent single agent and chemosensitizing activity against HCC in vitro. Targeting Mcl-1 might qualify as a promising novel approach in HCC therapy.