Wen, Sijin

Abstract Introduction: The development of hepatocellular carcinoma (HCC) is associated with underlying chronic liver disease from viral hepatitis or nonviral etiologies, such as nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease. An area of current research interest is the relationship between etiology of chronic liver disease in HCC patients and the response to specific treatment modalities. The purpose of this study is to identify prognostic indicators and compare survival outcomes among HCC patients within an Appalachian patient population. Methods: A single-institution, retrospective chart review was conducted for all patients diagnosed with HCC between August 2009 and March 2017 at West Virginia University Hospital. Patient demographics, tumor characteristics, laboratory data and treatment information were obtained from the electronic medical record (EMR). Survival analyses were performed using Kaplan-Meier method and multivariable Cox regression analysis. Results: The study sample (n=100) had a mean age of 62 years and was comprised of 82% males and 18% females. Nonviral etiologies of chronic liver disease were predominant (55%) over chronic viral hepatitis (45%). Significant adverse prognostic indicators of overall survival (OS) were Child-Pugh class C and tumor size >5 cm at diagnosis (p<0.0001, log-rank test). Patients who received liver-directed therapy (LDT) or liver resection had greater OS compared to those not treated with either modality (15.5 vs. 2.0 months, p<0.0001). Liver ablation or resection as initial modes of treatment had greater OS compared to those who initially received transarterial chemoembolization (TACE) or transarterial radioembolization (TARE) (17.2 vs 14.9 months, p<0.05). Patients who received TACE or TARE (n=60) as initial treatment had characteristics of advanced disease, with 45% having a tumor greater than 5 cm in size and 77% having multifocal unilobar or bilobar tumors. Among all patients who received LDT or resection, post-treatment albumin-bilirubin grade (ALBI) of 1 or 2 correlated with greater OS than grade 3 (22.5 vs 6.2 months, p<0.0001). In the multivariate Cox analysis, tumor size, Child-Pugh class and mode of initial treatment (resection/ablation vs. TACE/TARE) were independent predictors of OS (p<0.05). Conclusions: Treatment with LDT or liver resection correlated with greater overall survival in this predominantly nonviral cohort of HCC patients. Post-treatment ALBI grade correlated with overall survival and may have prognostic value in guiding clinical management. Mode of initial treatment was a predictor of overall survival, but further studies are needed to compare tumor characteristics between groups. Research is ongoing to evaluate the relationship between chronic liver disease etiology and survival among HCC patients treated with LDT, immunotherapy or a combination of both. Citation Format: Michelle Hartzell, Gary Monroe, Jon Shakesprere, Sijin Wen, J. Wallis Marsh, Jacob Fuqua, Robert Grammer, Beau Toskich, Midhun Malla. Prognostic indicators and outcomes of hepatocellular carcinoma (HCC) in an Appalachian population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6745.

Abstract Purpose: p27 localization and expression has prognostic and predictive value in cancer. Little is known regarding expression patterns of p27 in renal cell carcinoma (RCC) or how p27 participates in disease progression or response to therapy. Experimental Design: RCC-derived cell lines, primary tumors, and normal renal epithelial cells were analyzed for p27 expression, phosphorylation (T157 of the NLS), and subcellular localization. RCC-derived cell lines were treated with phosphatidylinositol 3-kinase (PI3K) and mammalian target of rapamycin (mTOR) inhibitors and effects on p27 localization were assessed. The potential contribution of cytoplasmic p27 to resistance to apoptosis was also evaluated. Results: p27 was elevated in tumors compared with matched controls, and cytoplasmic mislocalization of p27 was associated with increasing tumor grade. Cytoplasmic localization of p27 correlated with phosphorylation at T157, an AKT phosphorylation site in the p27 NLS. In RCC cell lines, activated PI3K/AKT signaling was accompanied by mislocalization of p27. AKT activation and phosphorylation of p27 was associated with resistance to apoptosis, and small interfering RNA knockdown of p27 or relocalization to the nucleus increased apoptosis in RCC cells. Treatment with the PI3K inhibitors LY294002 or wortmannin resulted in nuclear relocalization of p27, whereas mTOR inhibition by rapamycin did not. Conclusions: In RCC, p27 is phosphorylated at T157 of the NLS, with increasing tumor grade associated with cytoplasmic p27. PI3K inhibition (which reduces AKT activity) reduces T157 phosphorylation and induces nuclear relocalization of p27, whereas mTOR inhibition does not. Clinical testing of these findings may provide a rational approach for use of mTOR and PI3K/AKT pathway inhibitors in patients with RCC.