Evaluation of the impact of transient interruption of antiangiogenic treatment using ultrasound-based techniques in a murine model of hepatocellular carcinoma.

BACKGROUND: Development of escape pathways from antiangiogenic treatments was reported to be associated with enhanced tumor aggressiveness and rebound effect was suggested after treatment stop. Aim of the study was to evaluate tumor response simulating different conditions of administration of antiangiogenic treatment (transient or definitive treatment stop) in a mouse model of hepatocellular carcinoma. METHODS: Subcutaneous tumors were created by inoculating 5 × 10(6) Huh7 cells into the right flank of 14 nude mice. When tumor size reached 5-10 mm, mice were divided in 3 groups: group 1 was treated with placebo, group 2 was treated with sorafenib (62 mg/kg via gavage) but temporarily suspended from day +5 to +9, whereas in group 3 sorafenib was definitively stopped at day +5. At day +13 all mice were sacrificed, collecting masses for Western-Blot analyses. Volume was calculated with B-mode ultrasonography at day 0, +5, +9, +11 and +13. VEGFR2-targeted contrast-enhanced ultrasound using BR55 (Bracco Imaging) was performed at day +5 and +13 and elastonosography (Esaote) at day +9 and +11 to assess tumor stiffness. RESULTS: Median growth percentage delta at day +13 versus day 0 was 197% (115-329) in group 1, 81% (48-144) in group 2 and 111% (27-167) in group 3. Median growth delta at day +13 with respect to day +5 was 79% (48-127), 37% (-14128) and 81% (15-87) in groups 1, 2 and 3, respectively. Quantification of targeted-CEUS at day +13 showed higher values in group 3 (509 Arbitrary Units AI, range 293-652) than group 1 (275 AI, range 191-494) and group 2 (181 AI, range 63-318) (p=0.033). Western-Blot analysis demonstrated higher VEGFR2 expression in group 3 with respect to group 1 and 2. CONCLUSIONS: A transient interruption of antiangiogenic treatment does not impede restoration of tumor response, while a definitive interruption tends to stimulate a rebound of angiogenesis to higher level than without treatment.

The ART score is not effective to select patients for transarterial chemoembolization retreatment in an Italian series.

BACKGROUND: The ART score (a point score for the assessment of retreatment with transarterial chemoembolization, TACE) has been recently developed in Austria to differentiate patients who may benefit from multiple sessions of TACE for hepatocellular carcinoma (HCC) treatment. The primary aim of the study was to test the validity of the ART score in an Italian study cohort. The secondary aims were to evaluate overall survival (OS) and clinical determinants of improved survival in patients treated with multiple TACE sessions. METHODS: The ART score and the clinical outcome of 51 consecutive patients with HCC submitted to multiple TACE sessions from April 2002 to December 2009 were retrospectively analyzed. RESULTS: Median OS was 26.0 months (95% confidence interval 18.4-33.6) with 1-, 3- and 5-year survival rates of 75, 33 and 11%, respectively). Thirty-three patients had an ART score of 0-1.5 and in 18 it was ≥2.5, but in our patient series, the ART score was not found to be a predictor of survival (p = 0.173). At univariate analysis, tumor extent (uni- vs. bilobar: 34.0 vs. 9.0 months; p < 0.001), Child-Pugh score before the second TACE (A vs. B7 vs. B8-9: 26.0 vs. 16.0 vs. 5.0 months; p = 0.005) and Child-Pugh score increase between the first and second TACE (absent vs. + 1 point vs. + ≥2 points: 27.0 vs. 4.0 vs. 5.0 months; p < 0.001) were statistically related with survival. At multivariate analysis, only Child-Pugh score increase remained a significant predictor of worse survival (p = 0.001, hazard rate = 11.6). CONCLUSIONS: The ART score was not found to work as an objective tool to guide TACE retreatment in our Italian patient series, only the Child-Pugh score increase was an independent predictor of a shorter survival.

Use of VEGFR-2 targeted ultrasound contrast agent for the early evaluation of response to sorafenib in a mouse model of hepatocellular carcinoma.

PURPOSE: The aim of this study was to assess the early response to sorafenib using ultrasound molecular imaging in a murine model of hepatocellular carcinoma (HCC). PROCEDURES: A xenograft model of HCC was established. Then, mice were divided in two groups and received treatment (sorafenib) or placebo for 14 days. The treatment group was further divided into non-responders and responders according to the degree of growth. Contrast enhanced ultrasound (CEUS) was performed using VEGFR-2 targeted microbubbles (BR55, Bracco Suisse SA, Geneva, Switzerland). Dedicated software was used to quantify the amount of bound microbubbles in the tumor as a numerical value (differential targeted enhancement (dTE)). Tumors were then excised and western blot analysis performed. RESULTS: The dTE values decreased from day 0 to day +14 both in the treatment and control groups, but were lower in the former. The non-responder group had higher dTE levels at day 2 compared to responders (p = 0.019). CONCLUSION: BR55 appears to be useful in the prediction of response to sorafenib in a xenograft model of HCC.

Adherence to AASLD guidelines for the treatment of hepatocellular carcinoma in clinical practice: experience of the Bologna Liver Oncology Group.

BACKGROUND: Few data exist on real-life adherence to international guidelines for the treatment of hepatocellular carcinoma. We analysed the rate of adherence to American Association for the Study of Liver Diseases guidelines, to identify reasons for discrepancy with treatments performed in our centre. METHODS: 227 consecutive cirrhotics with a first hepatocellular carcinoma diagnosis (2005-2010) were retrospectively evaluated and stratified based on Barcelona Clinic Liver Cancer system: 126 early, 50 intermediate, 40 advanced, and 11 end stage. RESULTS: Early hepatocellular carcinomas were theoretically eligible for resection (n=27), liver transplantation (n=36), and percutaneous treatment (n=63). In practice, 15/27 (55.5%), 31/36 (86.1%), and 22/63 (34.9%) respectively were treated as recommended. Reasons for discrepancy were age/comorbidity, tumour location, ultrasound visibility, surgical contraindications. Transarterial chemoembolisation was performed in 25/126 early hepatocellular carcinomas (19.8%), resection in 11/63 early hepatocellular carcinomas eligible for percutaneous treatment (17.5%). Transarterial chemoembolisation was excluded in 16/50 intermediate hepatocellular carcinomas (32%). Resection or transarterial chemoembolisation was performed in 6/40 advanced hepatocellular carcinomas (15%). CONCLUSION: Overall, 60% of patients were treated according to American Association for the Study of Liver Diseases guidelines. Approximately 28% of hepatocellular carcinomas were "under-treated" and 7% treated more aggressively than recommended. Peculiarities of individual patients can lead the multidisciplinary team to personalise real-life treatments.