Cell-free DNA and chemoembolization in patients with liver metastases from colorectal cancer.

Transarterial chemoembolization with irinotecan loaded beads (DEBIRI-TACE) represents an investigative treatment option for patients with metastatic colorectal cancer (mCRC). The present study examined DEBIRI-TACE with concomitant mFOLOFX6-bevacizumab as a first-line treatment for mCRC and explored the clinical value of circulating cell-free DNA (cfDNA). Patients with limited mCRC of the liver who had not been treated with chemotherapy received up to 4 biweekly DEBIRI-TACE treatments. The endpoints examined included the response rate, survival, toxicity and translational analysis. Due to toxicity and lack of feasibility, the study closed prematurely. Total cfDNA was measured with a direct fluorescent assay. Between December 2012 and February 2014, 14 patients underwent a total of 49 DEBIRI-TACE treatments. With a median follow-up of 1.7 years, the median progression free survival and overall survival (OS) were 240 days [95% confidence interval (CI): 161-357] and 522 days (95% CI: 174-1,054), respectively. The response rate was 50%. Twelve patients experienced grade 3 toxicity or above. Dynamics of cfDNA showed biological variations in relation to therapy. To conclude, the present results indicated a response rate of 50% and median OS of 522 days for 14 patients with mCRC undergoing DEBIRI-TACE, but unacceptable toxicity and lack of feasibility with the applied schedule. The findings suggest that the level of cfDNA may be associated with the disease course, response to treatment and outcome. TRIAL REGISTRATION: The European Clinical Trials database (EudraCT no. 2012-000987-11) at 05-14-2012.

[Nuclear medicine techniques for selective internal radiotherapy of liver cancer].

Selective internal radiation therapy (SIRT) of hepatocellular carcinoma has been introduced at Aarhus University Hospital. 90Y-microspheres are implanted in the tumour by catheterization of the tumour feeding liver artery. Pretreatment angiography and test treatment using 99mTc-labelled particles followed by scintigraphy ensure a feasible and effective treatment. Post-treatment imaging of radiation from 90Y visualize the localization of microspheres. Currently, SIRT is also applied for liver metastases of neuroendocrine tumours. Future indications may include other liver tumours and metastases.

Combination of radiofrequency ablation with transarterial chemoembolization for treatment of hepatocellular carcinoma: experience from a Danish tertiary liver center.

BACKGROUND: Recent studies have shown that the combination of radiofrequency ablation (RFA) and transarterial chemoembolization (TACE) for unresectable hepatocellular carcinoma (HCC) may offer a survival advantage compared to monotherapy. PURPOSE: To study the effectiveness of combination therapy with RFA and TACE compared to that of TACE alone in a Scandinavian tertiary liver cancer center. MATERIAL AND METHODS: A retrospective study of the patients treated with combination therapy vis-à-vis TACE alone from June 2007 to November 2012 was performed. Eighteen patients were treated with a combination of RFA and TACE with an interval of 1-4 days between the treatments. For comparison, a group of 18 patients treated with TACE as monotherapy in the same time period was matched with the combination group by demographic data, tumor characteristics, biochemical and clinical parameters, and performance status (PS). RESULTS: Each group consisted of 14 patients with cirrhosis and four without. There were no significant differences between the groups regarding age, gender, tumor characteristics, causes of cirrhosis, levels of bilirubin, creatinine, prothrombin time, Child Pugh score, or World Health Organization (WHO) performance status. The median survival of patients in the RFA + TACE combination group was 586 days compared to 296 days in the control group. The difference was not statistically significant (P = 0.26). However, when we stratified the data for cirrhosis and WHO performance status, patients in the combination group had significantly better survival (P = 0.024). CONCLUSION: Combination therapy with RFA and TACE for unresectable HCC, compared to TACE alone, may offer a survival benefit for a selected group of patients with HCC.

Chemoembolization of intermediate stage hepatocellular carcinomas: results from a Nordic tertiary liver cancer center.

BACKGROUND: Transarterial chemoembolization (TACE) is used as palliative treatment of hepatocellular carcinoma (HCC). Most publications are from HCC patient populations where viral hepatitis is the primary cause of liver disease. In the Nordic countries, most patients have either alcohol-induced cirrhosis or are noncirrhotic. The aim of this single-center study was to evaluate patient characteristics, survival, and side effects of TACE in a Danish referral center for HCC treatment. METHODS: Fifty-nine consecutive patients with HCC, treated with TACE, either chemoembolization with drug-eluting beads or conventional-TACE with Lipiodol, were included in the study. Their medical records were retrospectively reviewed, computed tomography images analyzed, and biochemical markers recorded. The primary endpoint was overall survival. Analyses were by intention to treat. RESULTS: Thirty-five patients (59 %) had HCC on a background of liver cirrhosis most often caused by alcohol (60 % of cirrhotics or 35 % overall). Before the first chemoembolization, the patients had a median Child-Pugh score of 6 (5-7) and a median MELD score of 10 (6-21). Median survival after chemoembolization was 18.9 months (13.1-24.7). TACE patients were hospitalized for an average of 3 days (2-30). Prolonged stay was most often due to side effects-eg. pain (31 %), fever (14 %), nausea (10 %), and infection (10 %). Thirty-three patients (56 %) did not have any side effects. CONCLUSIONS: In this cohort, we observed an acceptable survival following TACE without significant side effects.

Treatment of Budd-Chiari syndrome with a focus on transjugular intrahepatic portosystemic shunt.

AIM: To evaluate long-term complications and survival in patients with Budd-Chiari syndrome (BCS) referred to a Danish transjugular intrahepatic portosystemic shunt (TIPS) centre. METHODS: Twenty-one consecutive patients from 1997-2008 were retrospectively included [15 women and 6 men, median age 40 years (range 17-66 years)]. Eighteen Danish patients came from the 1.8 million catchment population of Aarhus University Hospital and three patients were referred from Scandinavian hospitals. Management consisted of tests for underlying haematological, endocrinological, or hypercoagulative disorders parallel to initiation of specific treatment of BCS. RESULTS: BCS was mainly caused by thrombophilic (33%) or myeloproliferative (19%) disorders. Forty-three percents had symptoms for less than one week with ascites as the most prevalent finding. Fourteen (67%) were treated with TIPS and 7 (33%) were manageable with treatment of the underlying condition and diuretics. The median follow-up time for the TIPS-treated patients was 50 mo (range 15-117 mo), and none required subsequent liver transplantation. Ascites control was achieved in all TIPS patients with a marked reduction in the dose of diuretics. A total of 14 TIPS revisions were needed, mostly of uncovered stents. Two died during follow-up: One non-TIPS patient worsened after 6 mo and died in relation to transplantation, and one TIPS patient died 4 years after the TIPS-procedure, unrelated to BCS. CONCLUSION: In our BCS cohort TIPS-treated patients have near-complete survival, reduced need for diuretics and compared to historical data a reduced need for liver transplantation.

[Chronic Budd-Chiari syndrome can cause liver cirrhosis]. / Kronisk Budd-Chiaris syndrom kan være årsag til levercirrose.

Budd-Chiari syndrome (BCS) is a rare disease defined by congestive hepatopathy with obstruction of the hepatic venous outflow tract. Classical symptoms and signs include ascites, hepatomegaly, abdominal pain and various degrees of liver dysfunction. BCS is predominantly caused by thrombosis, malformations and venous compression. We present a case, in which BCS was the cause of liver cirrhosis complicated with refractory ascites and which can be misinterpreted as hepatocellular carcinoma nodules. The diagnosis was confirmed during the transjugular intrahepatic portosystemic shunt procedure with successful vascular stenting resolving the ascites formation.

Radiofrequency ablation of colorectal liver metastases downstaged by chemotherapy.

BACKGROUND: Radiofrequency ablation (RFA) continues to evolve, improving the potentials of this technique. It is now a widely used procedure in the treatment of patients with unresectable colorectal liver metastases, increasing the number of potentially curable patients. PURPOSE: To evaluate the long-term survival of patients treated by RFA for colorectal liver metastases after downstaging by systemic chemotherapy. MATERIAL AND METHODS: In a retrospective review of our prospective colorectal liver metastasis RFA database, 36 patients (20 males, 16 females; median age 67 years) were identified during an 8-year period (1999-2007). All patients were initially unsuitable for local treatment, and referred to systemic chemotherapy by our multidisciplinary team. Multinodularity and/or location of tumor was the main cause of patients being unsuitable for local treatment. Chemotherapy mainly consisted of 5-fluorouracil and leucovorin combined with oxaliplatin or irinotecan. After downstaging with chemotherapy, patients were treated by RFA. Patients with extrahepatic disease were excluded from RFA treatment. Pre- and posttreatment evaluation was performed with multidetector computed tomography (MDCT) scans. RESULTS: The median time from diagnosis of hepatic metastases to first RFA was 10 months. A total of 158 tumors were treated with RFA during the study period. Median follow-up period was 27 months. The estimated median survival time after diagnosis of hepatic metastasis was 39 months, with a 5-year survival rate of 34%. CONCLUSION: In selected patients with colorectal liver metastases downstaged by chemotherapy, RFA is an important modality that may contribute to improved survival. Furthermore, all patients responding to systemic chemotherapy should be re-evaluated by a multidisciplinary team.

The IGF system after insertion of a transjugular intrahepatic porto-systemic shunt in patients with liver cirrhosis.

OBJECTIVE: Insertion of a transjugular intrahepatic porto-systemic shunt (TIPS) into patients with liver cirrhosis usually induces a gain in body cell mass. Changes in the IGF system in favor of anabolism may be involved. We, therefore measured blood concentrations of the components of the IGF system in cirrhosis patients before and after elective TIPS. DESIGN AND METHODS: The study comprised 17 patients and 11 healthy controls. Patients were examined before and 1, 4, 12, and 52 weeks after TIPS. Biochemical analyses of the IGF system were compared with changes in body composition (bioimpedance analysis), glucose and insulin, and metabolic liver function (galactose elimination capacity). RESULTS: After TIPS, body cell mass rose by 3.2 kg (95% confidence interval (CI): 1.0-5.5) at 52 weeks, in correlation with baseline liver function (r(2)=0.22; P=0.03). Peripheral blood concentrations of total IGF1 and 2, bioactive IGF1, and the IGF-binding proteins (IGFBP-1, -2, and -3) remained unchanged throughout the study period. There was no change in fasting glucose, whereas fasting insulin rose by 40% (CI: 11-77%) and glucagon by 58% (CI: 11-132%) from baseline to 52 weeks after TIPS. CONCLUSION: Our data confirm that TIPS was associated with an increase in body cell mass in patients with liver cirrhosis, but without any change in the circulating IGF system. Thus, the results do not support the notion that effects on the circulating IGF system are involved in the anabolic effects of TIPS insertion.

[Radiofrequency ablation in the treatment of colorectal liver metastases--a secondary publication]. / Kolorektale levermetastaser behandlet med radiofrekvensablation. Sekundaerpublikation.

Radiofrequency ablation (RFA) was evaluated with regard to long-term survival and the rate of complications in the treatment of colorectal liver metastases. 102 patients (332 tumours) were treated. Treatment monitoring was conducted with CT. Survival was estimated with the Kaplan-Meier method. Median survival was 52 months. Five-year survival was 44%. Major complications were seen following 12 RFA treatments (6.9%). RFA offers efficient treatment of colorectal liver metastases. Survival is similar to surgical resection. Complication rates are low.

[Treatment of portal hypertension with transjugular intrahepatic portosystemic shunt: guidelines for referring suitable patients]. / Behandling af portal hypertension med transjugulaer intrahepatisk portosystemisk shunt: vejledning i henvisning af egnede patienter.

The transjugular intrahepatic portosystemic shunt (TIPS) is a percutaneous, minimally invasive method of creating a portosystemic shunt for the treatment of portal hypertension. These guidelines define indications and contraindications for referral of candidate patients to Danish TIPS-centres and are in accordance with international recommendations and local experience. TIPS will prevent re-bleeding from varices and decrease the need for repeated large volume paracentesis in patients with refractory ascites.

Description of patients with midgut carcinoid tumours: clinical database from a Danish centre.

BACKGROUND: We have initiated a clinical database of patients with neuroendocrine tumours (n = 132). Data on patients with well-differentiated endocrine carcinoma (WHO classification) previous classified as midgut carcinoid patients, are presented. PATIENTS AND METHODS: Retrospectively, 56 patients with midgut carcinoid tumours were evaluated with respect to symptoms, primary tumour size, metastases, tumour markers, treatment and survival. RESULTS: Flushing was described in 29%, diarrhoea in 52%, abdominal pain in 34%, bronchial constriction in 2% and carcinoid heart disease in 4% of the patients. Fifty-two percent had liver metastases at referral. Twenty-seven percent were considered to have had radical surgery. Patients not considered for radical surgery and patients with liver metastases had significantly higher tumour marker levels (serum chromogranin A (CgA), serum serotonin and urinary 5-hydroxyindolic acid (5-HIAA)) compared to radically-operated patients and to patients without liver metastases (p<0.05, respectively). For all the midgut carcinoid tumour patients the overall 5-year survival rate was 72%. The radically-operated patients had a 5-year survival rate of 100% (other death causes excluded). The patients with normal CgA or <5 liver metastases at referral had a 100% 5-year survival rate. The patients with <5 liver metastases had a significantly better 5-year survival rate compared to patients with multiple liver metastases (100% vs. 50%, p<0.05). CONCLUSION: This group of patients exhibited the same characteristic clinical features with similar survival as reported from other specialised centres. Radical surgery, normal CgA level and <5 liver metastases indicated a good prognosis and patients with <5 liver metastases had a significantly better survival compared to patients with multiple liver metastases.

Hepatic microcirculation assessed by positron emission tomography of first-pass ammonia metabolism in porcine liver.

AIMS/BACKGROUND: Intrahepatic branching of the hepatic artery (HA) to liver microcirculatory units, the acini, is more heterogeneous than that of the portal vein (PV). Furthermore, part of HA blood enters the sinusoid partially downstream between the in- and outlets. We examined the effects of these vascular variations on porcine hepatic first-pass ammonia metabolism, which is characterised by high uptake and separate periportal urea and perivenous glutamine formations. METHODS: (13)NH(3) was given via the PV, HA or caval vein, followed by 22 min dynamic liver positron emission tomography (PET) recordings in six pigs. Heterogeneity of liver (13)N-metabolism was quantified by the coefficient of variation of tissue (13)N-radioactivity measured 10 min after tracer infusion. Sinusoidal zonal clearances of (13)NH(3) into (13)N-urea and (13)N-glutamine were calculated by kinetic PET modelling. RESULTS: Liver metabolic heterogeneity was 0.65+/-0.20 (mean+/-SD, n=6) following (13)NH(3)-infusion into HA, 0.34+/-0.17 into PV and 0.10+/-0.02 into the caval vein. Clearance of (13)NH(3) to (13)N-urea was of similar magnitude following (13)NH(3) administration into HA and PV: 0.27+/-0.11 ml/min/g (mean+/-SD) and 0.29+/-0.09 ml/min/g, respectively. Clearances of (13)NH(3) to (13)N-glutamine when (13)NH(3) was given into HA and PV were also similar: 0.47+/-0.18 and 0.50+/-0.13 ml/min/g, respectively. CONCLUSIONS: The present measurements of the hepatic metabolism of (13)NH(3) showed metabolic heterogeneity compatible with variation of the HA supply of the acini. Second, results of PET modelling of the sinusoidal zonation metabolism of (13)NH(3) to (13)N-urea and to (13)N-glutamine did not indicate metabolically important partial downstream arterial entry into the sinusoids.

[Transjugular intrahepatic portosystemic shunt (TIPS) for the treatment of complications of portal hypertension in patients with liver cirrhosis]. / Transjugulaer intrahepatisk portosystemisk shunt (TIPS) til behandling af komplikationer ved portal hypertension hos patienter med levercirrose.

Portal hypertension is a main cause for the development of esophago-gastric varices, ascites and hepatic nephropathy in liver cirrhosis. Reduction of portal pressure by a transjugular intrahepatic portosystemic shunt (TIPS) procedure has been possible for the last decade. The treatment reduces the risk for variceal bleeding, reduces ascites formation and may improve renal function in hepatic nephropathy. Improved survival, however, has not yet been documented. Complications comprise procedure related events (puncture of liver capsule, bleeding, infection, hemolysis with mortality 1-5%), shunt stenosis (30-80% during the first year but reversible), and encephalopathy (30% intermittent, 10% chronic). Indications for the procedure are primarily variceal bleeding resistant to conventional pharmacologic and endoscopic treatment. Absolute and relative contraindications are severe hepatic failure, a history of hepatic encephalopathy, infections, respiratory failure, and non-hepatic renal insufficiency.

[TIPS--transjugular intrahepatic portosystemic shunt. Experiences from a recently started center]. / TIPS--transjugulaer intrahepatisk portosystemisk shunt. Erfaring fra en nystartet centerfunktion.

The transjugular intrahepatic portosystemic shunt (TIPS) is a percutaneous, minimally invasive, method of creating a portosystemic shunt for the treatment of portal hypertension. The results of the first 54 TIPS procedures are reported. There were no severe procedure-related complications. TIPS implantation was successful in 52 patients. Rebleeding was seen in 13% of the patients. Hepatic encephalopathy developed in 19%, but only in 11% as a chronic complication. Seven out of 9 patients with refractory ascites no longer required paracentesis after six months. The cumulative survival for the whole group was 81% after one year and 62% after three years.

[Radiofrequency ablation of malignant liver tumors]. / Radiofrekvensablation af maligne levertumorer.

INTRODUCTION: Radio-frequency ablation (RFA) is a minimally invasive therapy for malignant liver tumours. In a pilot study, we evaluated the technique and its ability to achieve local tumour control. The treatments were performed either as a percutaneous procedure in inoperable patients or intraoperatively during partial hepatectomy to destroy unresectable metastases. MATERIAL AND METHODS: Fourteen patients with liver metastases from colorectal (11) or endocrine (3) tumours were treated with cooled-needle electrode RFA. The electrodes were placed in the treated tumours under ultrasound guidance. Two patients were excluded from the study and in the remaining 12 patients, 52 metastases (7-50 mm in diameter) were treated in 26 sessions. Procedure efficacy was evaluated with contrast enhanced CT and ultrasound guided biopsy performed 1, 3, and 6 months after treatment. RESULTS: Complete response was achieved in 89% of treated metastases, evaluated after a follow-up of 4-35 months (mean 15 months). Complications were seen in five of 26 treatment sessions, among these the most serious was a gall bladder fistula. DISCUSSION: RFA appears to be a promising therapeutic modality in the treatment of hepatic malignancies. The clinical use of RFA has shown an ability to achieve local tumour control in about 90% of treated metastases. The patients treated were inoperable, but the nevertheless survival data are encouraging. The role of RFA as the treatment of choice has still to be tested against surgery in a large, prospective, randomised series with a long observational period. RFA is a commendable treatment, because of its minimal invasiveness, the low rate of complications, and the low cost.