Direct-Acting Antivirals Improve Overall Survival in Interventional Oncology Patients with Hepatitis C and Hepatocellular Carcinoma.

PURPOSE: To investigate the impact of direct-acting antivirals (DAAs) and 12-week sustained virologic response (SVR12) in patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) treated by interventional oncology (IO) therapies. MATERIALS AND METHODS: Retrospective analysis of patients diagnosed from 2005 to 2016 with HCC and receiving IO therapies. A total of 478 patients met inclusion criteria. Patients were age 29-90 years (mean 63.6 ± 9.4 years) and 78.9% (n =3 77) male. Two hundred and eighty-five (57%) patients had chronic HCV, 93 (33%) received DAAs, and 63 (68%) achieved SVR12. Liver function, tumor characteristics, and IO therapy including ablation, image-guided transcatheter tumor therapies (ITTT) (eg, chemoembolization and radioembolization), and combination locoregional therapy were assessed in analysis. RESULTS: Median overall survival (OS) of the cohort was 26.7 months (95% confidence interval [CI] 21.9-29.9). OS for ablation, combination locoregional therapy and ITTT, was 37.3 (CI 30.7-49.9), 29.3 (CI 24.2-38.0), and 19.7 months (CI 16.5-22.8), respectively (P < .0001). OS in patients with HCV was 30.7 months (CI 24.2-35.2) versus 22.2 months in non-HCV patients (CI 17.8-27.8, P = .03). Patients with HCV who received DAA had higher survival, 49.2 months (CI 36.5-not reached) versus those not receiving DAA, 18.5 months (CI 14.1-25.3, P < .0001). OS was 71.8 months (CI 42.3-not reached) for patients who achieved SVR12 after DAA versus 26.7 months in the non-SVR12 group (CI 15.9-31.1, P < .0001). Multivariable analysis revealed independent factors for OS including IO treatment type, DAA use and achieving SVR12 (P < .05). CONCLUSIONS: DAA use and SVR12 is associated with higher OS in patients with HCV-related HCC treated by IO therapies.

Decreasing maternal myostatin programs adult offspring bone strength in a mouse model of osteogenesis imperfecta.

During fetal development, the uterine environment can have effects on offspring bone architecture and integrity that persist into adulthood; however, the biochemical and molecular mechanisms remain unknown. Myostatin is a negative regulator of muscle mass. Parental myostatin deficiency (Mstntm1Sjl/+) increases muscle mass in wild-type offspring, suggesting an intrauterine programming effect. Here, we hypothesized that Mstntm1Sjl/+ dams would also confer increased bone strength. In wild-type offspring, maternal myostatin deficiency altered fetal growth and calvarial collagen content of newborn mice and conferred a lasting impact on bone geometry and biomechanical integrity of offspring at 4 mo of age, the age of peak bone mass. Second, we sought to apply maternal myostatin deficiency to a mouse model with osteogenesis imperfecta (Col1a2oim), a heritable connective tissue disorder caused by abnormalities in the structure and/or synthesis of type I collagen. Femora of male Col1a2oim/+ offspring from natural mating of Mstntm1Sjl/+ dams to Col1a2oim/+sires had a 15% increase in torsional ultimate strength, a 29% increase in tensile strength, and a 24% increase in energy to failure compared with age, sex, and genotype-matched offspring from natural mating of Col1a2oim/+ dams to Col1a2oim/+ sires. Finally, increased bone biomechanical strength of Col1a2oim/+ offspring that had been transferred into Mstntm1Sjl/+ dams as blastocysts demonstrated that the effects of maternal myostatin deficiency were conferred by the postimplantation environment. Thus, targeting the gestational environment, and specifically prenatal myostatin pathways, provides a potential therapeutic window and an approach for treating osteogenesis imperfecta.

Forkhead Box O3A (FOXO3) and the Mitochondrial Disulfide Relay Carrier (CHCHD4) Regulate p53 Protein Nuclear Activity in Response to Exercise.

Although exercise is linked with improved health, the specific molecular mechanisms underlying its various benefits require further clarification. Here we report that exercise increases the nuclear localization and activity of p53 by acutely down-regulating coiled-coil-helix-coiled-coil-helix domain 4 (CHCHD4), a carrier protein that mediates p53 import into the mitochondria. This response to exercise is lost in transgenic mice with constitutive expression of CHCHD4. Mechanistically, exercise-induced nuclear transcription factor FOXO3 binds to the CHCHD4 promoter and represses its expression, preventing the translocation of p53 to the mitochondria and thereby increasing p53 nuclear localization. The synergistic increase in nuclear p53 and FOXO3 by exercise can facilitate their known interaction in transactivating Sirtuin 1 (SIRT1), a NAD+-dependent histone deacetylase that mediates adaptation to various stresses. Thus, our results reveal one mechanism by which exercise could be involved in preventing cancer and potentially other diseases associated with aging.

Co-inhibitor expression on tumor infiltrating and splenic lymphocytes after dual checkpoint inhibition in a microsatellite stable model of colorectal cancer.

Checkpoint inhibitors have demonstrated clinical impact in colorectal cancer with deficient mismatch repair and high microsatellite instability. However, the majority of patients have disease with stable microsatellites that responds poorly to immunotherapies. Combinations of checkpoint inhibitors are under investigation as a way of increasing immunogenicity and promoting a robust anti-tumor immune response. The purpose of this study is to quantify the immune responses induced by mono and dual checkpoint inhibition in a mismatch repair proficient model of colorectal cancer (CRC). Tumor growth rates were monitored over time and compared between groups. We utilized fluorescence-activated cell sorting to analyze CD8+ and CD4+ T cells after treatment with either single PD-1 inhibition or dual PD-1 and CTLA-4 inhibition. Additionally, we sought to quantify the expression of co-inhibitory surface molecules PD-1, LAG3, and TIM3. Dual checkpoint inhibition was associated with a significantly slower growth rate as compared to either mono PD-1 inhibition or control (p < 0.05). Neither monotherapy nor dual checkpoint inhibition significantly affected the tumoral infiltration of lymphocytes. After treatment with dual inhibitors, infiltrating CD8+ T cells demonstrated significantly less expression of PD-1 (1700 vs. 2545 and 2462; p < 0.05) and LAG3 (446.2 vs. 694.4 and 707; p < 0.05) along with significantly more expression of TIM3 (12,611 vs. 2961 and 4259; p < 0.05) versus the control and anti-PD-1 groups. These results suggest that dual therapy with anti-CTLA-4 and anti-PD-1 antibodies significantly inhibits growth of microsatellite stable CRC by suppressing immunosuppressive checkpoints. Upregulation of TIM3 represents a potential escape mechanism and a target for future combination immunotherapies in CRC.

Impact of Direct Acting Antivirals on Survival in Patients with Chronic Hepatitis C and Hepatocellular Carcinoma.

With the increasing use of direct-acting antivirals (DAA) for treatment of chronic hepatitis C virus (HCV) infection, we looked at the impact of DAA use and 12-week sustained viral response (SVR12) in patients with hepatocellular carcinoma (HCC) and HCV. This is a retrospective analysis of 969 HCC patients diagnosed from 2005 to 2016 at an urban tertiary-care hospital. Kaplan-Meier curves and multivariable Cox proportional hazards models were used to assess survival. Median overall survival of the cohort was 24.2 months. 470 patients had HCV (56%). 123 patients received DAA therapies for HCV (26.2%), 83 of whom achieved SVR12 (67.4%). HCV-positive and HCV-negative patients had similar survival, 20.7 months vs 17.4 months (p = 0.22). Patients receiving DAA therapy had an overall survival of 71.8 months vs 11.6 months for patients without (p < 0.0001). DAA patients who achieved SVR12 had an overall survival of 75.6 months vs. 26.7 months in the non SVR12 group (p < 0.0001). Multivariable analysis revealed AJCC, Child-Pugh Score, MELD, tumor size, tumor location, cancer treatment type, receiving DAA treatment and achieving SVR12 had independent influence on survival (p < 0.05). This suggests DAA therapy and achieving SVR12 is associated with increased overall survival in HCV patients with HCC.

TP53 mutation, mitochondria and cancer.

Under normal conditions, basal levels of wild-type p53 promote mitochondrial function through multiple mechanisms. Remarkably, some missense mutations of p53, in contrast to the null state, can result in the retention of its metabolic activities. These effects are particularly prominent in the mitochondria and demonstrate a functional role for mutant p53 in cancer metabolism. This review summarizes accumulating data on the mechanisms by which p53 missense mutations can regulate mitochondrial metabolism and promote the viability and survival of both normal and cancer cells, thus acting as a double edged sword for the host. Greater understanding of these mechanisms may provide insights for developing new treatment or preventive strategies against cancer.