riccardo.lencioni@med.unipi.it

1) Discuss the role of image-guided ablation in the multidisciplinary management of patients with early-stage HCC. 2) Understand advantages and disadvantages of the various ablation technologies used for local treatment of HCC. 3) Describe the status of clinical research investigating potential synergies between image-guided ablation and novel drugs.

To evaluate whether antitumor immunity is enhanced bycombining radiofrequency ablation (RFA) and anti-CTLA-4 therapy, and itssynergism anti-tumor effect on untreated tumors.

Our experiments were approved by the institutional animalcare committee. 40 mice with tumor established on both side flanks wererandomly divided into 4 groups: Control group (no treatment), RFA group (RFA ofthe right flank tumor ), Anti-CTLA-4 group (anti-CTLA-4 monotherapy),Combination therapy group (RFA+Anti-CTLA-4). In each group, 8 mice were usedfor untreated tumor evaluation and survival observation, another 2 mice were sacrificed for histopathological study.Then, rechallenge test was performed to confirm whether the systematic antitumorimmunity was established by RFA+Anti-CTLA-4 therapy.

Although untreated tumor volume continued to increase untilthe end of the observation in all groups, SGRs of RFA+Anti-CTLA-4 group weresignificantly smaller than that in other groups (vs. control: p = 0.003; vs. RFA: p = 0.04; vs. Anti-CTLA-4: p= 0.10). Animals in RFA + Anti-CTLA-4 group survived significantly longer than thatin control group (p = 0.001),RFA group (p = 0.000) andAnti-CTLA-4 group (p = 0.008). The tumor metastasis free survival of RFA +Anti-CTLA-4 group was significantly longer than that in control group (p = 0.006), RFA group (p = 0.001) and Anti-CTLA-4 group (p =0.014). Histopathological studyshowed marked CD4 and CD8 positive lymphocyte around the tumor in mice of RFA +anti-CTLA-4 group. In rechallenge test, tumor free survival time was longer in miceof RFA+anti-CTLA-4 group than that in control group (p = 0.000), RFA group (p =0.017) and anti-CTLA-4 group (p = 0.001) and 75% of animals presented tumorrejection.

The present study demonstrates that RFA-induced systemicantitumor immunity was enhanced by combine use of anti-CTLA-4 therapy in a multisubcutaneous murine hepatoma model.

This treatment regimen is apotential clinical approach to enhance systemic antitumor immunity in patientswith unresectable multicentric HCC or multiple liver metastases.

gregory.nadolski@uphs.upenn.edu

1) Discuss differences between BCLC and Hong Kong Classification system regarding treatment recommendations. 2) Evaluate data regarding embolization for locally advanced HCC. 3) Compare differences in technique, complications, and outcomes for different embolization procedures for BCLC B/C HCC.

Julius.chapiro@yale.edu

To compare the pharmacokinetic (PK) profiles of doxorubicin (DOX) and its metabolite doxorubicinol (DOXOL) after conventional transarterial chemoembolization (cTACE) using lobar or segmental injection.

This interim report of an ongoing single-site, prospective trial included 22 patients with hepatocellular (n=19), cholangiocellular carcinoma (n=1), and neuroendocrine tumor metastases (n=2), who were treated with lobar (n=7) or selective (n=15) cTACE defined by catheter placement (5/2016-10/2017). cTACE utilized 50mg DOX/10mg mitomycin-C emulsified with Lipiodol followed by embospheres. Peripheral blood was sampled after cTACE (5, 10, 20, 40 min, 1, 2, 4, 24 hrs, 3-4 weeks) to measure drug concentrations by standard non-compartmental analysis. Follow-up included cross-sectional imaging and adverse events (AE) recorded 3-4 weeks post-TACE. Statistics included Pearson coefficient, Mann-Whitney, and Chi-squared test.

Mean age was 62±9.21 years and 19 patients were males. HCC were BCLC stage A in 4, B in 11, and C in 4 patients. According to 3DqEASL criteria available in 20/22, complete and partial response were achieved in 1 and 6, stable and progressive disease in 8 and 5 patients, respectively. Full DOX dose was given in 17/22. DOX concentration peaks occurred earlier (median Tmax 0.25 [0.13-0.98] vs. 0.59 [0.12-1.72hrs]) and were higher after lobar than selective cTACE (mean dose normalized Cmax 4.74±3.6 vs. 3.08±3.11ng/mL/mg) and in nonresponders compared to responders (p=0.022). The DOX area under the curve was significantly larger in patients with higher enhancing tumor volume (p=0.009) or enhancing tumor burden (p=0.033) on baseline imaging. DOXOL was similar whereas DOX concentrations were higher after lobar than selective cTACE at each timepoint but without statistical significance. Both DOX and DOXOL were undetectable 3-4 weeks post-cTACE. AE were rare but occurred more often after lobar cTACE (fever, p=0.040; abdominal pain, p=0.030).

The preliminary results of this prospective trial show a consistent trend suggesting higher systemic chemotherapy exposure and toxicity after lobar compared to selective cTACE.

If confirmed in the complete cohort, these findings may lead to a paradigm shift in intra-arterial therapy in favor of selective cTACE as a safe and efficient treatment for liver cancer.

1) Identify the commonality and particularities of BCLC advanced and metastatic HCC Recognize the multiple biologic and immunotherapy available for the treatment of BCLC C HCC. 2) Learn about strategies to combine local plus systemic therapy for BCLC B and C HCC.

EYLin@mdanderson.org

To evaluate the real-time hemodynamic change of tumor arterial feeder (TAF) of HCC during drug-eluting beads transarterial chemoembolization (DEB-TACE) by using an intravascular Doppler wire (IVDW) at subsegmental TAF.

This single-center prospective study included three patients with HCC submitted to DEB-TACE between June 2016 and November 2016. One vial of 100 - 300 µm DEB (Biocompatibles UK) was loaded with 75 mg doxorubicin and mixed in 40 mL 50% diluted contrast medium. A 2-French microcatheter (Asahi Intecc, Aichi, Japan) and a 0.014 inch IVDW (FloWire, Philips, Netherlands) were advanced to the level of subsegmental TAF. The arterial flow velocity was continuously monitored by IVDW during embolization procedure. The embolization procedure protocols were as follows: slow pulsatile infusion of 1mL per minute LC beads solution without contrast reflux ; embolization endpoint as contrast medium washout in 2-5 heartbeats. Average peak velocity (APV) and highest instant peak velocity (IPV-H) were analyzed.

Although the individual arterial flow varied among different patients and tumors, the IVDW measured arterial flow decreased at an early stage of the embolization procedure in all three patients. The APV decreased more than 50% of peak-trough flow difference when beads were infused in 35.7%, 10%, and 7.5% of the total infused beads amount in patient #1, #2, and #3, respectively. The IPV-H decreased more than 50% of peak-trough flow difference when beads were infused in 42.8%, 12.5%, and 17.5% of the total infused beads amount in patient #1, #2, and #3, respectively. The contrast medium washout rate remained less than 0.5 heartbeat when objective arterial flow significantly decreased more than 50%.

TAF flow decreases significantly at an early stage during DEB-TACE delivery. The objective TAF flow measurement was not proportional to the contrast medium washout rate.

TAF flow decreased significantly at early stages of DEB-TACE delivery, potentially reducing beads penetration. A thorough investigation of TAF change could shed light on optimal DEB-TACE delivery protocol.

1) Discuss options for downstaging tumors to resection or transplantation. 2) Discuss mechaism of action of trans atrterial therapies.

johannes.uhlig@med.uni-goettingen.de

To evaluate current treatment approaches and survival trends among surgically ineligible patients with surgically intrahepatic cholangiocarcinoma (ICC).

The 2004-2015 National Cancer Database was retrospectively analyzed for histopathologically proven ICC. Interventional oncology (IO) included local tissue destruction and radioembolization. Baseline variables were evaluated as predictors for treatment allocation. Overall survival was analyzed via multivariable Cox models.

9,655 patients with ICC were included, of which 401 patients received IO (4.1%), 776 patients radiation oncology (RO; 8%), 4,749 patients chemotherapy (49.2%), and 3,729 patients remained untreated. Increased likelihood of treatment via interventional oncology was observed for younger male patients, those with Medicare or private insurance, higher income and education, lower comorbidities and cancer stage, and patients treated at academic centers compared to other treatment approaches (p<0.05).Interventional oncology yielded highest overall survival compared to all other treatment approaches (2-year overall survival rate: IO 41.5%; RO 28.2%; chemotherapy 17.6%; no treatment 7.2%). After multivariable adjustment for potential confounders, a statistically significant survival benefit was observed for interventional oncology versus radiation oncology (HR=0.86, p=0.02), chemotherapy (HR=0.7, p<0.001) and no treatment (HR=0.31, p<0.001). A significant interaction term between treatment year and approach was evident (p<0.01), indicating that treatment effectiveness of IO, RO and chemotherapy increased from 2004-2015.

Treatment allocation for surgically ineligible ICC patients shows marked variation depending on socioeconomic and cancer factors. Interventional oncology demonstrated superior overall survival compared to other non-surgical treatment options. Healthcare access and utilization must be targeted to address outcome discrepancies, potentially providing interventional oncology to a broader patient population.

For surgically ineligible ICC, interventional oncology via local tissue destruction or radioembolization offers superior overall survival compared to radiation oncology, chemotherapy and no treatment.

dcm9006@med.cornell.edu

1) To examine the importance of future liver remnant size determination prior to major hepatic resection for hepatocelluar carcinoma and intrahepatic cholangiocarcinoma. 2) To review the role of portal vein embolization and Y90 radiation lobectomy to hypertrophy the liver for faciltation of curative resection. 3) To assess the currently available literature to determine which procedure should be used and when.

m201675489@hust.edu.cn

To investigate the therapeutic effect of the Transcatheter arterial chemoembolization (TACE) with adopted iodized oil containing Apatinib in rabbit VX2 hepatocellular carcinoma (HCC) model. The effect and mechanism of Apatinib inhibits tube formation of human umbilical vein endothelial cells (HUVECs) will be explored as well in anoxic environment.

In this Animal Experiment Committee approved study, 40 New Zealand rabbit VX2 liver tumors were randomly divided into four groups and respectively treated transarterially with saline (Group NS); iodized oil containing Apatinib (Group AI); iodized oil alone (Group I); Apatinib solution (Group A). The tumor growth rates of each group were measured by enhanced CT, Microvessel density (MVD) in the adjacent tissues of implanted VX2 tumor were estimated by detecting the expression of CD34, HIF-1a and VEGF level in tumor adjacent tissues were also examined by Immunohistochemistry. And in vitro experiment, HUVECs were cultured with different concentration gradients Apatinib(0, 1, 10, 50μmol/L, 24h) in the culture medium of HepG2 with normal oxygen or hypoxia, which is manufacturing by 200μM CoCl2. CCK8 method was used to detect the effects of apatinib on HUVECs. And the PI3K-akt, RAF-mek-erk and P38MAPK pathways were detected by western blot method. The Kruskal-Wallis test, Mann-Whitney U test, and Fisher exact test were used to look for statistically significant differences between groups.

The TACE procedure were successfully performed in all experimental rabbits. The observation period of 7 days after embolization, the tumor growth rate of Group AI was significantly lower than other three groups of rabbits (P=0.000<0.01). Immunohistochemistry results showed that the microvessel density(MVD) of apatinib loaded lipiodol embolization group (Group AI) was significantly lower than that of the other three groups of rabbits (P<0.01). Apatinib have a stronger inhibitory effect of tube formation of HUVECs in anoxic environment rather than in normal circumstances. Apatinib inhibits HUVECs proliferation by down-regulating the PI3K-akt, RAF-mek-erk and P38MAPK pathways.

Apatinib inhibits the growth of liver cancer by down-regulating the PI3K-akt, RAF-mek-erk and P38MAPK pathways, and has a stronger inhibitory effect in hypoxic environments

Our findings may provide new treatment options and stragies for the treatment of liver cancer.

j.chapiro@googlemail.com

1) To recapitulate and refresh knowledge of conventional tumor response criteria. 2) To learn about the most commonly used imaging-based clinical endpoints of tumor therapies (eg time-to-progression, progression-free-survival). 3) To understand the value of 3D quantitative and computer-assisted tumor analysis techniques. 4) To learn about novel machine-learning based approaches and molecular imaging techniques and decision support systems.

This lecture will provide an overview of image analysis techniques and imaging-based endpoints for the assessment of tumor response to loco-regional therapies of liver cancer. The talk will provide an overview of the currently available response criteria (including RECIST, mRECIST, EASL, qEASL) as well as outline the challenges of assessing tumor response in light of novel pharmacotherapeutic agents available in liver cancer, including immuno-modulatory agents as well as novel molecular-targeted agents that are increasingly used in combination or sequentially with loco-regional therapies. Additionally, the talk will touch on novel molecular-imaging based techniques as well as the role of aritifical intelligence and machine learning for the assessment of the tumor microenvironment and tumor response.