Multimodality treatment of hepatocellular carcinoma: How field practice complies with international recommendations.

BACKGROUND: Management of hepatocellular carcinoma (HCC) is framed within standardized protocols released by Scientific Societies, whose applicability and efficacy in field practice need refining. AIM: We evaluated the applicability and effectiveness of guidelines for the treatment of HCC of the American Association for the Study of the Liver (AASLD). METHODS: 370 consecutive cirrhotic patients with de novo HCC in different stages, 253 BCLC A, 66 BCLC B, 51 BCLC C received treatment through a multidisciplinary team (MDT) decision and were followed until death or end of follow-up. RESULTS: Treatment was adherent to AASLD recommendations in 205 (81%) BCLC A patients, 36 (54%) BCLC B, and 27 (53%) BCLC C. Radiological complete response was achieved in 165 (45%) patients after the first-line treatment, in 22 (19%) after a second-line and in 9 (23%) after a third-line treatment. Adherence to AASLD recommendation allowed a lower yearly mean mortality rate in BCLC A patients compared with other treatment (5.0% vs 10.4% P = .004), whereas upward treatment stage migration compared with the standard of care was associated with reduced yearly mortality in BCLC B (8.6% vs 20.7%, P = .029) and BCLC C (42.6% vs 59.0%, P = .04) patients. CONCLUSIONS: HCC multimodality treatment including other than first-line therapy is common in clinical practice and impact on the achievement of complete response. Personalized treatment was able to provide survival benefits to patients whose profile is not accounted for by international recommendations, which need to be amended.

Transarterial chemoembolization with drug-eluting beads is effective for the maintenance of the Milan-in status in patients with a small hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is the standard of care for the treatment of patients with an intermediate (Barcelona Clinic Liver Cancer [BCLC] B) hepatocellular carcinoma and to bridge patients with an early cancer to liver transplantation (LT). We explored the efficacy of TACE with drug-eluting beads (DEB) in BCLC A patients. Included are all BCLC A patients unsuitable for resection or locoregional ablation who underwent a DEB TACE between 2006 and 2012. Treatment was carried out "a la demande" until complete tumor devascularization or progression beyond Milan criteria. In patients with a complete response (CR), a contrast computed tomography (CT) scan was repeated at 3-month intervals during the first 2 years and then every 6 months alternating with abdominal ultrasound in the subsequent 3 years. Fifty-five patients had 79 tumor nodules ranging 7 to 50 mm; 32 (58%) achieved a CR that was maintained up to 4 and 7 months in 21 (38%) and 17 (31%) patients, respectively. The 24- and 36-month tumor-free survivals were 21% and 9%, respectively. The overall cumulative progression beyond Milan criteria at 3, 6, 12, and 24 months was 2%, 5%, 30%, and 54%. LT eligibility was maintained for a median of 19 months (range, 2-63 months). CR to first TACE was the strongest independent predictor of Milan-in maintenance. In conclusion, DEB TACE may effectively bridge patients with an early cancer to LT, and a CR to the first procedure may guide patient prioritization during the waiting list.

Prophylactic intraoperative uterine artery embolization for the management of major placenta previa.

PURPOSE: Placenta previa is a major cause of maternal morbidity and mortality, associated to a high risk of peripartum hemorrhage and hysterectomy. We aimed to verify if prophylactic intraoperative uterine artery embolization in patients with placenta previa and at least one additional risk of bleeding (major placenta previa), can reduce hemorrhage, need for blood transfusions, peripartum hysterectomy and maternal morbidity. MATERIALS AND METHODS: We enrolled 76 patients with major placenta previa; a specific multidisciplinary protocol was designed for management, including ultrasound evaluation, hospitalization at 34 weeks, antenatal corticosteroids and scheduled cesarean section at 35-36 weeks. 44 patients (control group or CTR) were treated with elective cesarean section, 32 patients (embolized group or EMB) underwent selective catheterization of bilateral uterine arteries before cesarean section and subsequent uterine embolization. In both cases cesarean section was performed by a senior surgeon. RESULTS: Significant differences were found in term of intraoperative blood loss (CTR: 1431 ml; EMB: 693 ml); despite an high percentage of CTR patients had a bleeding greater than 1000 ml (56%), the need for blood transfusion was not significantly different between the two groups. Time of surgery was higher in the EMB group, considering that embolization procedure required approximatively 30 min. Three patients from the CTR group needed hysterectomy and ICU admission, compared to none in the EMB group. Duration of hospitalization and neonatal outcome were similar. Uterine embolization was not related to any short or long-term complications; return to normal menses and preservation of fertility were confirmed at follow up. CONCLUSIONS: Our results are promising, although we believe that a major contribution is referable to the multidisciplinary approach rather than the procedure itself. Nevertheless, we demonstrated the feasibility and safety of preventive uterine embolization in patients with placenta previa; in order to establish its prophylactic role in the prevention of peripartum hemorrhage, randomized trial should be carried out, on a larger population.

Transarterial chemoembolization with epirubicin-eluting beads versus transarterial embolization before liver transplantation for hepatocellular carcinoma.

PURPOSE: To retrospectively compare radiologic tumor response and degree of necrosis in explanted livers after chemoembolization with epirubicin-loaded DC Bead versus bland embolization in patients on a transplant waiting list. MATERIALS AND METHODS: From 2003 to 2007, 49 patients with hepatocellular carcinoma (HCC) underwent transplantation at a single center. Sixteen patients were treated with bland embolization (n = 8) with 100-300-microm Embosphere particles or chemoembolization with epirubicin-loaded 100-300-microm DC Bead particles (n = 8) every other month until complete tumor devascularization. Computed tomography was performed every 3 months until recurrence. Explanted livers were analyzed to evaluate the degree of necrosis in the nodules. After orthotopic liver transplantation (OLT), patients were followed up for survival and disease status. RESULTS: The groups were comparable for baseline characteristics. Most patients had Child-Pugh class A disease. Solitary HCC was found in 75% of patients. Mean target lesion size was 32 mm +/- 15.4. Chemoembolization with drug-eluting beads achieved complete necrosis in 77% of lesions whereas bland embolization achieved complete necrosis in 27.2% of lesions. There was a significant difference between bland embolization and chemoembolization with DC Bead with regard to histologic necrosis (P = .043). No significant treatment-related complications were observed for either group. Fifteen patients are alive with no tumor recurrence. CONCLUSIONS: Chemoembolization with drug-eluting beads before OLT achieved higher rates of complete histologic response than bland embolization, with no serious adverse events observed. Because of the retrospective data analyses and small sample size, further studies are warranted to confirm these promising results.

The Role of Spleen and Liver Elastography and Color-Doppler Ultrasound in the Assessment of Transjugular Intrahepatic Portosystemic Shunt Function.

The reference standard for assessing transjugular intrahepatic portosystemic shunt (TIPS) function is venography with portosystemic pressure gradient (PPG) measurement. This procedure is invasive and expensive; thus, we assessed the feasibility, reproducibility and diagnostic accuracy of color-Doppler ultrasound (CDUS) and spleen and liver stiffness (LS) measurements for identifying TIPS dysfunction. Twenty-four patients (15 undergoing TIPS placement and nine undergoing TIPS revision) consecutively underwent CDUS examination and LS and spleen stiffness (SS) determination by transient elastography (TE) and point shear-wave elastography (pSWE). All parameters were taken before TIPS placement/revision (1-15 d before) and 24 h after, just before revision by venography. pSWE inter-observer agreement was assessed by intra-class correlation coefficient (ICC). CDUS and elastographic data were correlated (Pearson coefficient) with pressure gradients (hepatic venous pressure gradient [HVPG], PPG). Main determinants of TIPS dysfunction were investigated by linear regression. Forty-nine paired examinations were performed in total: 49 (100%) SS reliable measurements by pSWE and 38 (88%) by TE. The ICC for pSWE values was 0.90 (95% confidence interval [CI] 0.81‒0.94). SS values significantly correlated with HVPG and PPG (R = 0.51, p = 0.01). The area under the Receiver-Operating Characteristic (AUROC) curve of SS for diagnosing TIPS dysfunction was 0.86 (95% CI 0.70‒0.96) using a 25 kPa cutoff. At multivariate analysis, the flow direction of the intrahepatic portal vein branches and SS values were independently associated to TIPS dysfunction. The intrahepatic portal vein branches flow direction and SS value are two simple, highly sensitive parameters accurately excluding TIPS dysfunction. SS measurement by pSWE is feasible, reproducible and both positively and significantly correlates with HVPG and PPG values.

TIPS for Budd-Chiari syndrome: long-term results and prognostics factors in 124 patients.

BACKGROUND & AIMS: Budd-Chiari syndrome (BCS) is a rare and life-threatening disorder secondary to hepatic venous outflow obstruction. Small series of BCS patients indicate that transjugular intrahepatic portosystemic shunt (TIPS) may be useful. However, the influence of TIPS on patient survival and factors that predict the outcome of TIPS in BCS patients remain unknown. METHODS: One hundred twenty-four consecutive BCS patients treated with TIPS in 6 European centers between July 1993 and March 2006 were followed until death, orthotopic liver transplantation (OLT), or last clinical evaluation. RESULTS: Prior to treatment with TIPS, BCS patients had a high Model of End Stage Liver Disease and high Rotterdam BCS prognostic index (98% of patients at intermediate or high risk) indicating severity of liver dysfunction. However, 1- and 5-year OLT-free survival were 88% and 78%, respectively. In the high-risk patients, 5-year OLT-free survival was much better than that estimated by the Rotterdam BCS index (71% vs 42%, respectively). In the whole population, bilirubin, age, and international normalized ratio for prothrombin time independently predicted 1-year OLT-free survival. A prognostic score with a good discriminative capacity (area under the curve, 0.86) was developed from these variables. Seven out of 8 patients with a score >7 died or underwent transplantation vs 5 out of 114 patients with a score <7. CONCLUSIONS: Long-term outcome for patients with severe BCS treated with TIPS is excellent even in high-risk patients, suggesting that TIPS may improve survival. Furthermore, we identified a small subgroup of BCS patients with poor prognosis despite TIPS who might benefit from early OLT.

Is there still a role for the hepatic locoregional treatment of metastatic neuroendocrine tumors in the era of systemic targeted therapies?

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) frequently present with distant metastases at the time of diagnosis and the liver is the most frequent site of spreading. The early identification of metastatic disease represents a major prognostic factor for GEP-NENs patients. Radical surgical resection, which is feasible for a minority of patients, is considered the only curative option, while the best management for patients with unresectable liver metastases is still being debated. In the last few years, a number of locoregional and systemic treatments has become available for GEP-NEN patients metastatic to the liver. However, to date only a few prospective studies have compared those therapies and the optimal management option is based on clinical judgement. Additionally, locoregional treatments appear feasible and safe for disease control for patients with limited liver involvement and effective in symptoms control for patients with diffuse liver metastases. Considering the lack of randomized controlled trials comparing the locoregional treatments of liver metastatic NEN patients, clinical judgment remains key to set the most appropriate therapeutic pathway. Prospective data may ultimately lead to more personalized and optimized treatments. The present review analyzes all the locoregional therapy modalities (i.e., surgery, ablative treatments and transarterial approach) and aims to provide clinicians with a useful algorithm to best treat GEP-NEN patients metastatic to the liver.

Cirrhosis and portal hypertension: The importance of risk stratification, the role of hepatic venous pressure gradient measurement.

Portal hypertension is the main prognostic factor in cirrhosis. The recent emergence of potent antiviral drugs and new algorithm of treatment for the management of complications due to portal hypertension have sensibly changed our perception of cirrhosis that can be now considered as a multistage liver disease whose mortality risk can be reduced by a tailored approach for any stage of risk. Experts recommend to move toward a pathophysiological classification of cirrhosis that considers both structural and functional changes. The hepatic venous pressure gradient HVPG, is the reference gold standard to estimate the severity of portal hypertension in cirrhosis. It correlates with both structural and functional changes that occur in cirrhosis and carries valuable prognostic information to stratify the mortality risk. This article provides a general overview of the pathophysiology and natural course of cirrhosis and portal hypertension. We propose a simplified classification of cirrhosis based on low, intermediate and high mortality stage. The prognostic information provided by HVPG is presented according to each stage. A comparison with prognostic models based on clinical and endoscopic variables is discussed in order to evidence the additional contribute given by HVPG on top of other clinical and instrumental variables widely used in clinical practice.

Four-year survival after trans-jugular intrahepatic porto-systemic shunt for veno-occlusive disease following autologous bone marrow transplantation.

Severe hepatic veno-occlusive disease is still a potentially lethal complication after bone marrow transplantation. We here report the case of a patient who developed liver veno-occlusive disease with severe hemodynamic dysfunction and was successfully treated by means of a trans-jugular intrahepatic portosystemic shunt. After three years, he is still disease-free with a functioning shunt and a normal laboratory liver profile. A trans-jugular intrahepatic portosystemic shunt is a treatment option that has been used in very few patients affected by hepatic veno-occlusive disease; its indications and timing remain to be established.

Drug delivery embolization systems: a physician's perspective.

INTRODUCTION: The number of patients suffering from primary and secondary liver tumoral diseases is on the increase worldwide. The development of new technologies and drugs requires an increasingly multidisciplinary approach in the management of these diseases. Therapies should be based on scientifically supported guidelines and at the same time should be designed to suit the individual patient. In this decision-making process, an understanding of the advantages and disadvantages of every treatment is very important. The efficacy of transarterial chemoembolization (TACE) in improving survival and its role in the management of hepatocellular carcinoma (HCC) have been demonstrated in several clinical trials. The introduction of drug-eluting beads seems to have overcome some of the limitations of conventional TACE. AREAS COVERED: This review provides an overview of the spread of primary and secondary liver cancers, then it explains the basis for the use of conventional TACE and its potential benefits and, finally, outlines its clinical application and possible future uses. EXPERT OPINION: The management of the treatment of focal liver lesions is a difficult process, which must involve various specialists such as the interventional radiologist. The use of drug-eluting microspheres seems to improve the results of TACE both in HCC and in colorectal liver metastases.

Transarterial chemoembolization for hepatocellular carcinoma with drug-eluting microspheres: preliminary results from an Italian multicentre study.

The purpose of this article is to present the early results of a multicentre trial using HepaSphere microspheres loaded with chemotherapeutic agents for transarterial chemoembolization (TACE) in patients with unresectable hepatocellular carcinoma. From December 2005 to March 2007, 50 patients (36 male and 14 female, mean age 68.4 years) were treated by selective TACE using HepaSphere microspheres loaded with doxorubicin or epirubicin. The diameter of the treated lesions ranged from 20 to 100 mm (mean 42.5; maximum of 4 tumor nodules). Tumor response was evaluated by computed axial tomography according to the World Health Organization criteria as modified by the European Association for the Study of Liver Diseases. All of the procedures were technically successful, and there were no major complications. At 1-month follow-up, complete tumor response was observed in 24 of 50 (48%), partial response in 18 of 50 (36%), and stable disease in 8 of 50 (16%) patients, and there were no cases of disease progression. At 6-month follow-up (31 of 50 patients), complete tumor response was obtained in 16 of 31 (51.6%), partial response in 8 of 31 (25.8%), and progressive disease in 7 of 31 (22.6%) patients. Within the initial 9-month follow-up, TACE with HepaSphere was successfully repeated twice in 3 patients, whereas 3 patients underwent the procedure 3 times. Our initial multicentre experience demonstrates that TACE using HepaSphere is feasible, is well tolerated, has a low complication rate, and is associated with promising tumor response. When complete tumor response in not achieved, additional treatments can be performed without difficulties. Longer follow-up on larger series is mandatory to confirm these preliminary results.

Diastolic dysfunction is associated with poor survival in patients with cirrhosis with transjugular intrahepatic portosystemic shunt.

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) is a treatment for portal hypertension-related complications. Accurate prediction of the outcome of patients treated with TIPS is important, because some patients have very short survival. Diastolic dysfunction is frequently observed in patients with cirrhosis. AIM: To investigate whether or not diastolic dysfunction can predict the outcome after TIPS. METHODS: Echocardiography with Doppler exploration was performed before and 28 days after TIPS insertion in 32 patients with cirrhosis. Several echocardiographic measures, including the early maximal ventricular filling velocity/late filling velocity (E/A) ratio as indicative of diastolic function, as well as laboratory, clinical and demographic variables were evaluated as predictors of survival. RESULTS: Univariate analysis revealed that the presence of diastolic dysfunction observed 28 days after TIPS (E/A ratio 1 survived. CONCLUSIONS: Diastolic dysfunction estimated using E/A ratio is a promising predictor of death in patients with cirrhosis who are treated with TIPS.

Humoral and cardiac effects of TIPS in cirrhotic patients with different "effective" blood volume.

The aim of this study was to evaluate the cardiac effects of transjugular intrahepatic portosystemic shunts (TIPS) in cirrhotic patients with different effective blood volume. Two-dimensional echocardiography was performed before and 7 and 28 days after TIPS insertion in 7 cirrhotic patients with PRA <4 ng/mL/h (group A, normal effective blood volume) and 15 with PRA >4 ng/mL/h (group B, reduced effective blood volume). Before TIPS, most cirrhotic patients showed diastolic dysfunction as indicated by reduced early maximal ventricular filling velocity (E)/late filling velocity (A) ratio. Patients of group B differed from patients of group A because of smaller left ventricular volumes and stroke volume, indicating central underfilling. After TIPS insertion, portal decompression was associated with a significant increase of cardiac output (CO) and a decrease of peripheral resistances. The most important changes were recorded in patients of group B, who showed a significant increase of both the end-diastolic left ventricular volumes and the E/A ratio and a significant decrease of PRA. In conclusion, these results show that the hemodynamic effects of TIPS differ according to the pre-TIPS effective blood volume. Furthermore, TIPS improves the diastolic cardiac function of cirrhotic patients with effective hypovolemia. This result is likely due to a TIPS-related improvement of the fullness of central blood volume.

Randomized controlled study of TIPS versus paracentesis plus albumin in cirrhosis with severe ascites.

The transjugular intrahepatic portosystemic shunt (TIPS) has been shown to be effective in the control of refractory or recidivant ascites. However, the effect of TIPS on survival as compared with that of large-volume paracentesis plus albumin is uncertain. A multicenter, prospective, clinical trial was performed in 66 patients with cirrhosis and refractory or recidivant ascites (16 Child-Turcotte-Pugh class B and 50 Child-Turcotte-Pugh class C) randomly assigned to treatment with TIPS (n = 33) or with large-volume paracentesis plus human albumin (n = 33). The primary endpoint was survival without liver transplantation. Secondary endpoints were treatment failure, rehospitalization, and occurrence of complications. Thirteen patients treated with TIPS and 20 patients treated with paracentesis died during the study period, 4 patients in each group underwent liver transplantation. The probability of survival without transplantation was 77% at 1 year and 59% at 2 years in the TIPS group as compared with 52% and 29% in the paracentesis group (P = .021). In a multivariate analysis, treatment with paracentesis and higher MELD score showed to independently predict death. Treatment failure was more frequent in patients assigned to paracentesis, whereas severe episodes of hepatic encephalopathy occurred more frequently in patients assigned to TIPS. The number and duration of rehospitalizations were similar in the two groups. In conclusion, compared to large-volume paracentesis plus albumin, TIPS improves survival without liver transplantation in patients with refractory or recidivant ascites.

Segmental transcatheter arterial chemoembolization treatment in patients with cirrhosis and inoperable hepatocellular carcinomas.

PURPOSE: To establish whether segmental transcatheter arterial chemoembolization (TACE) treatment may improve the rates of survival in patients with compensated cirrhosis and inoperable hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Fifty-six patients with compensated cirrhosis and inoperable HCC were treated with segmental TACE. One hundred forty treatments (mean, 2.5 per patient; 30-60 mg Epirubicin, 4-10 mL Lipiodol, and Gelfoam particles) were administered. RESULTS: During the 69-month study, 25 patients (45%) died of tumor progression, 12 (21%) of liver failure, nine (16%) of gastrointestinal hemorrhage, and three (5%) of other causes; seven patients (13%) are still alive. The 3-year rate of survival was 32%. Intention-to-treat analysis determined that patients with Child-Pugh class A disease (n = 44; 79%) or a single <5-cm HCC (n = 21; 37%) had a higher rate of survival than those with Child-Pugh class B disease (n = 12; 21%; P <.002) or a larger HCC (n = 35; 63%; P <.02) and patients (n = 41) who were treated with more than one course of TACE had a higher rate of survival than those who were treated with a single TACE procedure (n = 15; P <.0003). Multivariate analysis was used to predict rates of survival by number of treatments (hazard ratio, 0.6; CI, 0.48-0.86; P <.004), Child-Pugh class (hazard ratio, 2.8; CI, 1.41-5.74; P <.003), and tumor size (hazard ratio, 3.8; CI, 1.81-8.01; P <.001). The 3-year rate of survival in patients with Child-Pugh class A disease and a < or =5-cm-HCC (n = 16) was 56%. This result was similar to the 50% 3-year rate of survival in untreated historic controls with similar characteristics. CONCLUSION: The rate of survival in patients with compensated cirrhosis and inoperable HCC did not appear to improve with use of TACE therapy.

MELD score is better than Child-Pugh score in predicting 3-month survival of patients undergoing transjugular intrahepatic portosystemic shunt.

BACKGROUND/AIMS: Patients undergoing transjugular intrahepatic portosystemic shunt (TIPS) are at risk of early death due to end-stage liver failure. The aim of this study was to compare model of end-stage liver disease (MELD) and Child-Pugh scores as predictors of survival after TIPS. METHODS: We studied 140 cirrhotic patients treated with elective TIPS. Concordance (c)-statistic was used to assess the ability of MELD or Child-Pugh scores to predict 3-month survival. The prediction of overall survivals was estimated by comparing actuarial curves of subgroups of patients stratified according to either Child-Pugh scores or MELD risk scores. RESULTS: During a median follow-up of 23.7 months, 55 patients died, 14 underwent liver transplantation and seven were lost to follow-up. For 3-month survival, the discrimination power of MELD score was superior to Child-Pugh score (0.84 vs. 0.70, z=2.07; P=0.038). Unlike Pugh score, MELD score identified two subgroups of Child C patients with different overall survivals (P=0.027). The comparison between observed and predicted survivals showed that MELD score overrates death risk. CONCLUSIONS: MELD score is superior to Child-Pugh score as predictor of short-term outcome after TIPS. Its accuracy, however, decreases for long-term predictions.