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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.

Aim: To analyse incidence, treatment and outcomes of paediatric liver malignancies in Finland during 1987-2017., Methods: Medical records and national cancer registry data of 47 children with liver malignancies were reviewed. Survival was calculated with the Kaplan-Meier method., Results: During follow-up, liver malignancy incidence remained stable at 1.1:10 6 . Altogether, 42 patients with hepatoblastoma (n = 24), hepatocellular carcinoma (n = 11) and undifferentiated embryonal sarcoma (n = 7) underwent surgery at median age 4.6 (interquartile range, 2.0-9.6) years and were followed up for 13 (7.0-19) years. Cumulative 5-year survival was 86% for hepatoblastoma, 41% for hepatocellular carcinoma and 67% for undifferentiated embryonal sarcoma. Five-year survival was decreased among hepatoblastoma patients aged ≥ 2.4 years (73% versus 100%, P = .040), with PRETreatment EXTent of disease IV (PRETEXT, 60% vs 100%, P = .004), and with recurrent disease (67% vs 88%, P = .029). Recurrent/residual disease associated with decreased 5-year survival in hepatocellular carcinoma (0% vs 83%, P = .028). Survival was similar among 19 transplanted and 23 resected patients. In total, 14 deaths occurred either for the underlying malignancy (n = 8), adverse effects of chemotherapy (n = 5) or unrelated reasons (n = 1)., Conclusion: Outcomes for PRETEXT I-III hepatoblastoma and un-metastasized hepatocellular carcinoma were encouraging. Adverse effects of chemotherapy significantly contributed to mortality., (©2019 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Objective: Spontaneous hepatic tumor hemorrhage is a rare but challenging emergency especially among cirrhotic patients with poor hepatic function. This study aimed at analyzing the safety, efficacy and feasibility of transcatheter arterial embolization (TAE) in the treatment of hepatic tumor hemorrhage. Methods: This retrospective study included all patients undergoing embolization attempt for hepatic tumor hemorrhage in the Helsinki University Hospital during 2004-2017. Electronic medical records provided the study data. Outcomes included the 30-day rebleeding, complication and mortality rates, need for blood transfusions, durations of intensive care unit and hospital admissions, estimates of overall survival, and analysis of factors associated with 30-day mortality. Results: During the study period, 49 patients underwent angiography for hepatic tumor hemorrhage. TAE was technically feasible in 45 patients (92%), and controlled the bleeding with the first attempt in 84%. The 30-day complication and mortality rates were 57 and 33%, respectively. Major complications occurred in 33% of patients. In-hospital mortality was higher among cirrhotic than non-cirrhotic patients (55 versus 7%, p  < .001). Patients with bleeding hepatic metastases, but no cirrhosis, had an in-hospital mortality of 0% with no major complications. Patients with benign etiology had a good prognosis and no bleeding- or tumor-related mortality. Discussion: TAE is an effective method in controlling the bleeding in spontaneous hepatic hemorrhage. Underlying pathology determines the prognosis that is poor especially in cirrhotic patients with bleeding hepatocellular carcinoma.

A focal lesion in a healthy liver of a person not having cancer is almost always benign. Diagnosis is often achieved on the basis of anamnesis and imaging findings. A histologic specimen is required in the case of suspected malignant tumor or hepatocellular adenoma. Magnetic resonance imaging is the primary investigation for an unresolved focal lesion of a cancer patient, and the histologic specimen will, when necessary, be taken only after this. Early detection of metastases of colorectal cancer in particular is important, since metastases that have spread to the liver or lungs may be operable. A focal lesion in a cirrhotic liver is either a regenerative nodule or hepatocellular carcinoma.

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.

Aim: Prediction of prognosis in hepatocellular carcinoma (HCC) is difficult. The aim of this study was to evaluate the prognostic value of serum MMP-8, -9, -13, and TIMP-1 in patients with HCC., Methods: Pre-treatment serum samples from 134 patients with HCC were retrospectively analyzed. The serum concentration of MMP-8 was analyzed with immunofluorometric assay (IFMA), and those of MMP-9, MMP-13, and TIMP-1 were determined by enzyme-linked immunosorbent assays (ELISA). Clinical data were retrieved from patient records and survival data obtained from Statistics Finland., Results: The overall cumulative disease-specific survival was 69% at 1 year, 50% at 2 years, and 33% at 5 years. Kaplan-Meier overall survival analysis showed that patients with low concentrations of serum MMP-8 or TIMP-1 had a statistically significantly better overall survival than patients with high concentrations of serum MMP-8 or TIMP-1 (P=0.013 and P=0.003). Interestingly, the overall survival in patients with high MMP-9/TIMP-1 ratio was statistically significantly better than in those patients with low MMP-9/TIMP-1 ratio (P=0.004)., Conclusion: Our results suggest that serum MMP-8, TIMP-1, and the ratio of MMP-9/TIMP-1 might be useful adjuncts as predictors of prognosis in patients with HCC.

Aim: Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most frequent cause of cancer death worldwide. The aim of this study was to evaluate the prognostic value of serum tumor-associated trypsin inhibitor (TATI) and the free β subunit of human chorionic gonadotropin (hCGβ) in patients with HCC., Methods: The serum concentrations of TATI and hCGβ were determined by time-resolved immunofluorometric assays (IFMA) in pretreatment serum samples from 144 patients with HCC. Clinical data were retrieved from patient records and survival data obtained from Statistics Finland., Results: The overall cumulative disease-specific survival was 69% at 1 year, 50% at 2 years and 33% at 5 years. Disease-specific median survival time was 26 months. The overall survival in patients with low serum concentrations of TATI or hCGβ was statistically significantly better than in patients with elevated concentrations (p = 0.003 and 0.003, respectively). In multivariate analysis, both serum TATI and serum hCGβ were independent prognostic markers., Conclusion: The results imply that elevated serum concentrations of TATI and hCGβ are predictors of adverse prognosis in patients with HCC and appear to be useful adjuncts in predicting prognosis in patients with HCC.

Background: The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC., Methods/design: The study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 21/2 -year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating., Discussion: If our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC., Trial Register: Trial registered at http://www.clinicaltrials.gov: NCT00355862(EudraCT Number: 2005-005362-36).

The role of adjuvant systemic chemotherapy in liver transplantation (LT) for hepatocellular carcinoma (HCC) is controversial. Here, we report the results of a Nordic prospective, randomized, multi-centre trial of systemic low-dose doxorubicin in patients with HCC. Between February 1996 and April 2004, 46 patients were randomized to receive either neoadjuvant doxorubicin in combination with LT (chemo group; n = 19) or LT alone (control group; n = 27). In the chemo group, doxorubicin was administered intravenously, 10 mg/m(2) weekly, starting from acceptance onto the waiting list for LT. One intraoperative dose of 15 mg/m(2) was given, and postoperatively doxorubicin was given weekly at a dose of 10 mg/m(2), depending on the clinical course, up to a cumulative dose of 400 mg/m(2). Actuarial, 3-year overall survival (OS) and disease-free survival (DFS) in the control group were 70% and 50%, respectively. In the chemo group, both OS and DFS were 63%. Freedom from recurrence at 3 years was 55% in the control group and 74% in the chemo group. None of the differences was statistically significant. Neoadjuvant treatment with systemic low-dose doxorubicin seems not to improve either survival or freedom from recurrence in patients with HCC undergoing LT.

Hepatobiliary cystadenomas and cystadenocarcinomas are rare tumors. Differentiating between these tumors and benign hepatic cysts may be difficult. Because of their rarity, diagnosis is often delayed and may result in inaccurate treatment, resulting in unnecessary morbidity and mortality. The purpose of this report is to draw attention to these entities and their complications. We report on two cases with spontaneous rupture of hepatobiliary cystadenoma and cystadenocarcinoma cysts, initially treated as simple hepatic cysts by aspiration, or by aspiration combined with sclerotherapy. The spontaneous rupture of the cysts appeared years after the initial treatment of the cysts, leading in one case to a prolonged stay in an intensive care unit. In both cases, a formal liver resection was carried out and microscopic investigations revealed a mucinous cystadenocarcinoma and cystadenoma. In conclusion, although hepatobiliary cystadenomas and cystadenocarcinomas are rare findings, they should not be forgotten in the diagnostic workshop when examining patients with hepatic cysts. If hepatobiliary cystadenomas and cystadenocarcinomas cannot be excluded following radiological imaging, surgery is recommended.

Background/aims: Hepatobiliary malignancies are frequently seen in primary sclerosing cholangitis (PSC) and they complicate the evaluation of patients and timing of liver transplantation., Methods: Data from all Nordic PSC patients listed for liver transplantation during 1990-2001 were recorded prospectively. Predictors of hepatobiliary malignancy and patient survival rates have been analysed., Results: Hepatobiliary malignancy was found in 52/255 (20%) patients accepted to the waiting list. Recent diagnosis of PSC, no ursodeoxycholic acid (UDCA) treatment, clinical suspicion and previous colorectal-cancer were predictors of malignancy. Among 89 patients with a strong suspicion of malignancy prior to acceptance, 35 (39%) had confirmed malignancy. A clinical suspicion had been raised in 35/52 (67%) patients with malignancy. Malignancy was found in 31/223 patients who received a liver allograft. The 1-, 3- and 5-year patient survival rates following transplantation for patients with PSC and cholangiocarcinoma were 65, 35 and 35%, respectively., Conclusions: Hepatobiliary malignancy is suspected in 1/3 of the PSC patients and found in 1/5. Although cholangiocarcinoma is regarded as a contraindication to liver transplantation (LTX), PSC patients with cholangiocarcinoma had a 35% 5-year survival following transplantation.