These data suggest that the mHVI and rHVI at SACST may be useful in differentiating insulinoma from nesidioblastosis with high specificity in patients with hyperinsulinemic hypoglycemia and negative or inconclusive noninvasive imaging.

Purpose To determine if tumor stiffness by MR Elastography (MRE) is associated with hepatocellular carcinoma (HCC) pathologic features. Material and Methods A retrospective review was undertaken of all patients with pathologically confirmed HCC who underwent MRE prior to locroregional therapy, surgical resection or transplant between 1/1/2007 to 12/31/2015. An independent observer measured tumor stiffness (kilopascals, kPa) by drawing regions of interest (ROI) covering the HCC and in the case of HCCs with non-enhancing/necrotic components, only the solid portion was included in the ROI. HCC tumor grade (WHO criteria), vascular invasion and tumor encapsulation were assessed from retrievable pathology specimens by an expert hepatobiliary pathologist. Tumor stiffness was compared by tumor grade, size, presence of capsule and vascular invasion using student’s t-test (or Exact Mann-Whitney test). Results 21 patients were identified who had pathologically confirmed HCC and tumor MRE data. 17 patients (81.0%) had underlying chronic liver disease. The mean±SD tumor size (cm) was 5.3±3.9 cm. The mean±SD tumor stiffness was 5.9±1.4 kPa. Tumors were graded as well differentiated (N=2), moderately differentiated (N=11) and poorly differentiated (N=8). There was a trend toward increased tumor stiffness in well/moderately differentiated HCC (6.5k±1.2 kPa; N=13) compared to poorly differentiated HCC (4.9±1.2 kPa; N=8) (p<0.01). There was no significant correlation between tumor stiffness and liver stiffness or tumor size. There was no significant difference in tumor stiffness by presence or etiology of chronic liver disease, vascular invasion or tumor encapsulation. Conclusion Preliminary data suggest that tumor stiffness by MRE may be able to differentiate HCC tumor grade.

Thermal ablative therapies are important treatment options in the multidisciplinary care of patients with hepatocellular carcinoma (HCC), but lesions larger than 2–3 cm are plagued with high local recurrence rates and overall survival of these patients remains poor. Currently no adjuvant therapies exist to prevent local HCC recurrence in patients undergoing thermal ablation. The molecular mechanisms mediating HCC resistance to thermal ablation induced heat stress and local recurrence remain unclear. Here we demonstrate that the HCC cells with a poor prognostic hepatic stem cell subtype (Subtype HS) are more resistant to heat stress than HCC cells with a better prognostic hepatocyte subtype (Subtype HC). Moreover, sublethal heat stress rapidly induces phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dependent-protein kinase B (AKT) survival signaling in HCC cells in vitro and at the tumor ablation margin in vivo. Conversely, inhibition of PI3K/mTOR complex 2 (mTORC2)-dependent AKT phosphorylation or direct inhibition of AKT function both enhance HCC cell killing and decrease HCC cell survival to sublethal heat stress in both poor and better prognostic HCC subtypes while mTOR complex 1 (mTORC1)-inhibition has no impact. Finally, we showed that AKT isoforms 1, 2 and 3 are differentially upregulated in primary human HCCs and that overexpression of AKT correlates with worse tumor biology and pathologic features (AKT3) and prognosis (AKT1). Together these findings define a novel molecular mechanism whereby heat stress induces PI3K/mTORC2-dependent AKT survival signaling in HCC cells and provide a mechanistic rationale for adjuvant AKT inhibition in combination with thermal ablation as a strategy to enhance HCC cell killing and prevent local recurrence, particularly at the ablation margin.

Tunneled peritoneal drainage catheters are effective and relatively safe in the management of malignant and non-malignant ascites. Longer catheter dwell time may be a risk factor for catheter-associated infection, particularly in patients with a longer anticipated survival in the palliative setting.

Purpose To develop a translational rat hepatocellular carcinoma (HCC) disease model for magnetic resonance imaging and image-guided interventional oncologic investigations. Methods and Materials Male rats underwent sham control surgery (N=6), selective bile duct ligation (SBDL; N=4) or common bile duct ligation (CBDL; N=6) with procedure optimization in 4 rats and N1S1 cell injection into 2–3 sites in the liver of 12 rats. All rats subsequently underwent MRI to assess tumor establishment and volume. Mesenteric angiography and percutaneous MR-guided laser ablation of the liver were performed in a subgroup of animals (N=4). Animal weight and liver tests were monitored. After harvesting, the livers were subjected to gross and microscopic analysis. Tumor volume and laboratory parameters were assessed between ligation groups. Results MRI demonstrated hyperintense T2 and hypointense T1 lesions with tumor induction in 5/10 (50.0%), 7/8 (87.5%) and 12/12 (100%) sites in the control, SBDL and CBDL groups, respectively. Tumor volumes differed significantly by group (p<0.02). Mesenteric angiography demonstrated an enhancing tumor stain. Clinical and laboratory assessment revealed a significant decrease in weight (p = 0.01) and albumin (p<0.01) and increase in total bilirubin (p = 0.02) in CBDL rats but not SBDL rats (p=1.0). Histologic examination showed high-grade HCCs with local and vascular invasion within the context of early fibrosis in CBDL and SBDL rats. MR-guided laser ablation generated a 1–2 cm ablation zone with histology consistent with reversible and irreversible injury. Conclusion A biologically relevant rat hepatocellular carcinoma disease model was developed for MR imaging and preliminary interventional oncologic applications.

Background and Objective The aims of the present study were to investigate the thermal-dose dependent effect of heat stress on hepatocyte and HCC cell death mechanisms using clinically relevant experimental heat stress conditions in vitro and to investigate apoptotic cell death induced by laser thermal ablation in vivo. Study Design/Materials and Methods Institutional Animal Care and Use Committee approved all studies. Hepatocyte and HCC cell lines were heat stressed from 37°C to 60°C for 2 or 10 minutes and assessed for viability, cytotoxicity and caspase-3/7 activity at 6 and/or 24 hours post-treatment (N=3). Viability experiments were repeated with the RIPK1 inhibitor Necrostatin-1 to block necroptosis (N=3). Rats with orthotopic HCC tumors stably expressing luciferase (N1S1luc2) were randomized to US-guided laser ablation (3W-45s for an intentional partial ablation; N=6) or sham (N=6) and followed by post-ablation caspase-3/7 bioluminescence imaging at 6 and 24 hours and cleaved caspase-3 immunostaining. p<0.05 was considered statistically significant. Results Heat-stress induced apoptosis and necrosis in hepatocytes and HCC cells in a thermal dose and cell-type dependent manner. Inhibition of RIPIK1-mediated necroptosis induced a significant, differential increase in HCC cell viability under physiologic and hyperthermic heat stress (p<0.001). Intentional partial laser thermal ablation induced a significant increase in caspase-3/7 activity in the laser versus sham ablation groups at both 6 hours (10.1-fold, p<0.01) and 24 hours (16.7 fold, p<0.02). Immunohistochemistry confirmed increased cleaved caspase-3 staining at the tumor ablation margin 24 hours post-ablation. Conclusions Both regulated and non-regulated cell death mechanisms mediate heat stress-induced HCC cell killing and vary between hepatocytes and HCC subtypes. Apoptosis is a significant mechanism of cell death at the HCC tumor ablation margin.

In patients with non-cirrhotic, non-alcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC), absent HCC washout and capsule appearance are associated with increasing hepatic steatosis, thereby potentially impacting the noninvasive imaging diagnosis of HCC in these patients. Lack of washout or capsule appearance in steatotic livers at MRI may require alternative criteria for the diagnosis of HCC in patients with non-cirrhotic NAFLD.

Prostate‐specific membrane antigen (PSMA) is a validated target for molecular diagnostics and targeted radionuclide therapy. Our purpose was to evaluate PSMA expression in hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and hepatic adenoma (HCA); investigate the genetic pathways in HCC associated with PSMA expression; and evaluate HCC detection rate with 68 Ga‐PSMA‐11 positron emission tomography (PET). In phase 1, PSMA immunohistochemistry (IHC) on HCC (n = 148), CCA (n = 111), and HCA (n = 78) was scored. In a subset (n = 30), messenger RNA (mRNA) data from the Cancer Genome Atlas HCC RNA sequencing were correlated with PSMA expression. In phase 2, 68 Ga‐PSMA‐11 PET was prospectively performed in patients with treatment‐naïve HCC on a digital PET scanner using cyclotron‐produced 68 Ga. Uptake was graded qualitatively and semi‐quantitatively using standard metrics. On IHC, PSMA expression was significantly higher in HCC compared with CCA and HCA ( P < 0.0001); 91% of HCCs (n = 134) expressed PSMA, which principally localized to tumor‐associated neovasculature. Higher tumor grade was associated with PSMA expression ( P = 0.012) but there was no association with tumor size ( P = 0.14), fibrosis ( P = 0.35), cirrhosis ( P = 0.74), hepatitis B virus ( P = 0.31), or hepatitis C virus ( P = 0.15). Overall survival tended to be longer in patients without versus with PSMA expression (median overall survival: 4.2 vs. 1.9 years; P = 0.273). FGF14 (fibroblast growth factor 14) mRNA expression correlated positively (rho = 0.70; P = 1.70 × 10 ‐5 ) and MAD1L1 (Mitotic spindle assembly checkpoint protein MAD1) correlated negatively with PSMA expression (rho = −0.753; P = 1.58 × 10 ‐6 ). Of the 190 patients who met the eligibility criteria, 31 patients with 39 HCC lesions completed PET; 64% (n = 25) lesions had pronounced 68 Ga‐PSMA‐11 standardized uptake value: SUV max (median [range] 9.2 [4.9‐28.4]), SUV mean 4.7 (2.4‐12.7), and tumor‐to‐liver background ratio 2 (1.1‐11). Conclusion: Ex vivo expression of PSMA in neovasculature of HCC translates to marked tumor avidity on 68 Ga‐PSMA‐11 PET, which suggests that PSMA has the potential as a theranostic target in patients with HCC.